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Diabetes - Clinician's Desk Reference - Leslie, David R. (SRG)
Diabetes - Clinician's Desk Reference - Leslie, David R. (SRG)
M Cecilia Lansang
MD, MPH
Simon Coppack
MD, FRCP
Consultant and Reader in Diabetes and Metabolism,
St. Bartholomews and Royal London Hospitals,
and the Blizard Institute, University of London
Laurence Kennedy
MD, FRCP
Chairman, Department of Endocrinology, Diabetes,
and Metabolism,
Cleveland Clinic,
Cleveland, Ohio
MANSON
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ISBN: 978-1-84076-158-0
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Preface 7 CHAPTER 3
Acknowledgments 7 Type 1 diabetes 37
Abbreviations 8 Epidemiology 37
Causes of type 1 diabetes 38
Prediction of type 1 diabetes 40
CHAPTER 1
Genetic factors 40
The nature of diabetes 11 Nongenetic factors 42
What is diabetes? 11 Development of type 1 diabetes 42
Overview 11 Pancreatic -cell dysfunction 42
Epidemiology 12 Insulin resistance 43
Definitions and classification 13 Mortality 43
Forms of diabetes 17 Screening for potential type 1 diabetes 44
Type 1 diabetes 17
Type 2 diabetes 17 CHAPTER 4
Maturity onset diabetes of the young Type 2 diabetes 45
(MODY) 17
Gestational diabetes mellitus (GDM) 18 Epidemiology 45
Neonatal diabetes 19 Causes of type 2 diabetes 46
Secondary diabetes 19 Environmental risk factors 46
Clinical presentations of diabetes 19 Genetic factors 47
Complications of diabetes 20 Associated conditions 48
Macrovascular complications 20 Hyperinsulinemia and hyperglycemia 49
Microsvascular complications 20 Hypertension 49
Acute metabolic complications 20 Abnormalities of lipid metabolism 50
Infections 21 The metabolic syndrome and obesity 50
Disorders of the joints, ligaments, Development of type 2 diabetes 52
and skin 22 Glucoregulatory defects in type 2 diabetes 52
The cost of diabetes 23 Pancreatic -cell deficiency 52
Insulin resistance 53
CHAPTER 2 The role of amylin 54
Glucose, insulin, and diabetes 25 Glucotoxicity and lipotoxicity 54
Glucotoxicity 54
The role of glucose 25 Lipotoxicity 55
Glucose levels and diabetes 26 Screening and prevention 56
Normal glucose metabolism 27 Type 2 diabetes prevention studies 57
Glucose transporters 28
The role of insulin 30
The structure of insulin 31
Normal insulin secretion and kinetics 32
The insulin receptor 33
The actions of insulin 34
Second messenger systems 36
Insulin-like growth factors (IGFs) 36
Abnormalities of insulin synthesis
and secretion 36
4
Macrovascular disease 73
CHAPTER 8
Pathogenesis of macrovascular complications 74
The diabetic foot 97
Treatment and management principles for
macrovascular disease 75 Overview 97
General principles 75 Pathophysiology and risk factors 97
Glucose control 75 Neuropathy 97
Lipid-lowering drugs 76 Peripheral arterial disease 98
Revascularization procedures 76 Infection 98
Pathogenesis of microvascular complications 77 Pressure 98
Hyperglycemia 78 Clinical presentation and evaluation 98
High intracellular glucose 79 Evaluation 98
Advanced glycation endproducts 79 Examination 99
Reactive oxygen species 80 Treatment and management 100
Sorbitol accumulation 80 Infection 101
Activation of protein kinase C-beta 80 Peripheral arterial disease 101
Hemodynamic changes 80 High plantar pressure 102
Treatment and management principles for Deformities 102
microvascular disease 81
The wound environment 102
Surgery 102
Charcots arthropathy 103
5
CHAPTER 14 CHAPTER 15
Insulin treatment 155 Special management considerations 173
Overview 155 The diabetic inpatient 173
Therapeutic insulin 155 Diabetes and surgery 174
Regular (or soluble) insulin 155 Major surgery 175
Rapid-acting insulin analogs 155 Minor surgery 176
Insulins with prolonged action 156 Surgery and blood pressure 176
Alternative insulin delivery systems 157 Conception, contraception, and pregnancy 176
Indications for insulin treatment 158 Contraception and diabetes 178
Insulin regimen: type 1 diabetes 159 Glucose monitoring and glycemic goals
Continuous subcutaneous insulin in pregnancy 178
infusion: insulin pump treatment 160 Type 1 diabetes patients 180
Implantable glucose monitors 163 Type 2 diabetes patients 181
Insulin regimen: type 2 diabetes 163 Risks to the diabetic mother 182
General considerations 163 Gestational diabetes mellitus (GDM) 183
Basal insulin 165 Labor and delivery 184
Mealtime insulin 166 Neonatal problems 184
Premixed insulin 167
Metabolic instability on insulin 167 Further reading 187
Complications: hypoglycemia 168
Hypoglycemic unawareness 170
Resources 191
Nocturnal hypoglycemia 170 Glossary 193
Recurrent severe hypoglycemia 170 Index 201
Treating hypoglycemia 171
Mild hypoglycemia 171
Severe hypoglycemia 171
Preventing hypoglycemia 172
Other complications or adverse effects
from insulin treatment 172
7
Preface
THE AIM OF THIS BOOK is to provide clinicians and other health professionals with an
easily readable and clinically applicable text on diabetes. The joint European and American
authorship indicates the widespread international agreement on the best way to manage
diabetes, both in terms of limiting the disease risk and of treating complications once they
develop. The book integrates the physiology and anatomy of the disease with clinical and
laboratory analysis. Summaries of key clinical trials emphasize the knowledge base underlying
the practical recommendations. A range of treatment options is provided, reflecting the need for
customized treatment strategies. The authors have sought to provide a clear and concise guide
to the optimal treatment approach. The text is intended for clinicians with an interest in diabetes
at all levels, including primary-care physicians, medical students, nurse specialists, physician
assistants, diabetes educators, and those in postgraduate training.
R DAVID LESLIE
M CECILIA LANSANG
SIMON COPPACK
LAURENCE KENNEDY
Acknowledgments
Drs. Leslie, Coppack, and Kennedy would especially We also thank Dr. Ernesto Lopez, Dr. Frida
like to acknowledge the major role of their co-author, Djukiadmodjo, Dr. Lily Ho-Le, Dr. Serena Chiu,
Dr. Lansang, in reviewing and updating the text and Dr. Lina Paschou for their help in preparing
during the gestation of this book. and editing the text and figures.
We would all like to thank Professor David In addition, the authors would like to thank
Hadden, Belfast, Northern Ireland, and Professor Dr Michael Tolentino and Dr. Rishi Singh for
David Bell, Birmingham, Alabama, for providing supplying the retinal photos.
constructive criticism and comments while we were
preparing the text, and specifically acknowledge the
valuable input of Professor Hadden concerning the
most up-to-date views on diabetes and pregnancy.
8
Abbreviations
CHAPTER 1
Comparative
prevalence (%)
>12
912
79
57
45
<4
Epidemiology
Diabetes is the most common metabolic disorder, 2 Comparative prevalence of diabetes in adults 2079 years
with 510% of adult populations living affluent, of age in 2010. The global prevalence of diabetes in 2010 was
westernized lifestyles developing the condition at 6.6% of the adult population and, with the population set to
some time in their life. rise, is projected to reach 9.9% by 2030. Source: International
According to the World Health Organization Diabetes Federation.
(WHO) estimate for 2000, there were 171 million
adults with diabetes in the world (2.8%). In 2011
the International Diabetes Federation (IDF) set
the figure at 366 million (8.3%); this is predicted Latin America & Caribbean
to rise to 552 million (9.9%) by 2030. 80
India
The rates of both type 1 and type 2 diabetes are 2000 Middle East
70
Numbers of cases (millions)
increasing: 2030
Former socialist economies
Established market economies
Sub-Saharan Africa
50
ages is increasing exponentially.
40
The incidence of type 1 diabetes has also
been increasing for many years for reasons 30
that are much less apparent. 20
There is a wide variation in the prevalence of
10
diabetes worldwide, though people in developed
countries, Europe and North America, have
Region
shown the highest prevalence. However, in the
next 25 years, developing countries around these
industrialized zones, such as Mexico, the Gulf 3 Regional changes. The greatest absolute increase in the
States, India, and Russia, are likely to show a number of people with diabetes by 2030 will likely be in India,
higher prevalence (2, 3). The greatest increase is with high relative increases also seen in the Middle East and
expected to be seen in India. sub-Saharan Africa.
13
14
It is estimated that the number of people Males
12
with diabetes will more than triple between Females
10
2000 and 2030.
Percent
8
6
4
2
4 Diabetes prevalence by age and sex. Although diabetes
0
prevalence is slightly higher in men than in women, the greater 19 24 29 34 39 44 49 54 59 64 69 74 79
number of elderly women leads to a higher overall number of 0 20 25 30 35 40 45 50 55 60 65 70 75
Age (years)
women with the disease.
The predicted increase in incidence is, to a large It is difficult to obtain accurate figures for deaths
extent, related to the increasing numbers of related to diabetes, because people with diabetes
people living to more than 65 years of age. most often die from cardiovascular and renal
Diabetes is more prevalent in men, but there are disease, and it is these that are recorded on death
more women than men with diabetes, as more certificates. The excess adult mortality due to
women than men survive to old age in most diabetes in 2011 was estimated by the IDF to be
societies (4). 4.6 million worldwide, 8.2% of global (all cause)
Figures for 2011 show the greatest number of mortality. This mortality rate ranged from 6% in
people with diabetes to be in the 4059 age group Africa to 15.7% in North America.
179 million; more than three-quarters of these It is considered that, worldwide, diabetes is
people live in low- and middle-income countries. the fifth most common cause of death.
By 2030, it is estimated that this number will
increase to 250 million, with more than 86% Definitions and classification
living in low- and middle-income countries. Diabetes mellitus is characterized by increased
Population screening programs typically reveal blood glucose concentrations.
that up to half of the subjects found to have type 2 Such glucose concentrations vary as a
diabetes had previously been undiagnosed. continuum in different people and so the def-
It is currently estimated that 490,000 children inition of diabetes is somewhat arbitrary, but
under the age of 14 have type 1 diabetes. the cut-off points were chosen in relation to
The incidence of type 2 diabetes in children is levels of glycemia associated with specific
approaching that of type 1 diabetes, having been diabetic complications such as retinopathy.
only around 24% prior to 1994, and is predicted Historically we define diabetes by either a raised
to outstrip type 1 diabetes in about 2020 on fasting glucose or a raised glucose following oral
current trends. glucose challenge. Random glucose levels can
A particularly high proportion of children with also be used if the patient has symptoms typical
type 2 diabetes, typically presenting around the of hyperglycemia, such as thirst and polyuria.
time of puberty, require insulin on presentation. The WHO defined diabetes mellitus in 1979 but
Whether this is due to the accelerator hypo- the definition was updated in 2000 to reflect
thesis (double diabetes effect), whereby an better understanding of milder glucose intoler-
individuals risk (and age at onset) of con- ance and its impact on vascular disease.
tracting type 1 diabetes is increased by the
prior existence of a predisposition to type 2
diabetes or insulin resistance, is not clear.
Globally, diabetes is considered to be the fifth
leading cause of death.
14
1 Symptoms of diabetes plus casual plasma glucose ocal hyperglycemia, these criteria should be confirmed by
concentration of 11.1 mmol/l (200 mg/dl) repeat testing on a different day. In 2011 the WHO accepted
(Casual is defined as any time of day without regard to the use of the HbA1c test in diagnosing diabetes, with 48
time since last meal. Symptoms of diabetes include
mmol/mol (6.5%) recommended as the cut-off point.
polyuria, polydipsia, and unexplained weight loss)
OR
2 Fasting plasma glucose 7.0 mmol/l (126 mg/dl)
(Fasting is defined as no caloric intake for at least 8 h)
The WHO criteria for diagnosis are shown in 5
OR and 6.
3 2 h postload glucose 11.1 mmol/l (200 mg/dl) during WHO criteria only consider fasting and 120-
an OGTT*
(The test should be performed as described by WHO, min values in the oral glucose tolerance test
using a glucose load containing the equivalent of 75 g (OGTT). Intermediate time points are used in
anhydrous glucose dissolved in water. Not recommended the National Diabetes Data Group (NDDG)
for routine clinical use)
criteria.
The reproducibility of the OGTT leaves much
to be desired (the coefficient of variation of
120-min plasma glucose concentrations is
reported to be up to 50%).
6 Diagnostic glucose values. For epidemiological or popula- Even if a subject fulfils the WHO criteria for
tion screening purposes, the fasting or 2 h value after 75 g oral diabetes, subsequent improvement in glucose
glucose may be used alone. For clinical purposes, the diagnosis tolerance can possibly occur (for example, as a
of diabetes should always be confirmed by repeating the test result of weight loss or spontaneously), but such
on another day, unless there is unequivocal hyperglycemia with individuals are considered to have a lifelong
acute metabolic decompensation or obvious symptoms. tendency to diabetes.
Glucose concentrations should not be determined on serum Impaired glucose tolerance (IGT) and impaired
unless red cells are immediately removed, otherwise glycolysis fasting glycemia (IFG) are metabolic states inter-
will result in an unpredictable underestimation of the true con- mediate between normal glucose tolerance and
centrations. Note that glucose preservatives do not totally diabetes mellitus (6). People with IFG or IGT are
prevent glycolysis. If whole blood is used, the sample should be at high risk of progression to diabetes and/or
kept at 04C or centrifuged/assayed immediately. cardiovascular disease.
Impaired glucose Fasting (if measured) <6.1 (<110) <6.1 (<110) <7.0 (<126)
tolerance (IGT) and
2 h post-glucose load >6.7 (>120) and >7.8 (>140) and >7.8 (>140) and
<10.0 (<180) <11.1 (<200) <11.1 (<200)
Impaired fasting Fasting >5.6 (>100) and >5.6 (>100) and >6.1 (>110) and
glycemia (IFG) <6.1 (<110) <6.1 (<110) <7.0 (<126)
and (if measured)
2 h post-glucose load <6.7 (<120) <7.8 (<140) <7.8 (<140)
15
HbA1c
(%)
8 9
6 11
High risk 12
5 ate risk
Moder Ver y
high
isk ris k
r
Low
10.2 11.8
13.4
8.6 Blood glucose 14.9
7.0 (mmol/l) 16.
5
5.4
7 HbA1c and diabetes risk. The higher the HbA1c the higher
Diabetes is characterized by hyperglycemia. the risk of diabetic complications.
I TYPE 1 DIABETES
(-cell destruction, usually leading to absolute insulin deficiency)
Immune-mediated
Idiopathic
II TYPE 2 DIABETES
(may range from predominantly insulin resistance with relative insulin deficiency
to a predominantly secretory defect with insulin resistance)
8 Classification categories. There are four major categories of diabetes: type 1 diabetes and type 2 diabetes are the
most common.
17
Age of onset Peak at 1014 years old, Predominantly in middle to Typically childhood to
but increasingly recognized old age, but increasingly young adulthood
in adults recognized in children
Gender ratio Males and females Females affected more Males and females
equally affected than males equally affected
Treatment required Insulin required in >95% Insulin required in 1737% Insulin may be required
of children, but less frequent but infrequently
initially in adults
fashion; there are several forms (10). (see also chapter 15)
MODY2 and MODY3 are due to defined insulin GDM occurs when abnormal glucose tolerance
secretory defects. develops during pregnancy in a woman not
MODY should be considered in young people known to have diabetes before pregnancy, unless
presenting with a typical family history (diabetes she has had GDM in a previous pregnancy.
affecting a parent and 50% expression of the The abnormal glucose tolerance usually resolves
disease in the family). after delivery, but women with GDM are quite
likely to develop it again in a subsequent
10 MODY subgroups. The clinical and genetic characteristics pregnancy, and are at considerably increased risk
of the different subgroups are outlined. Frequency and pene- of developing type 2 diabetes some time in
trance are most pronounced with MODY3. the future.
Severity of Progressive IGT Mild, stable Progressive IGT Progressive IGT Progressive IGT Variable
hyperglycemia (may become hyperglycemia; (may be severe) (may become (may be severe)
severe) little deterior- severe)
ation with age
Microvascular Can occur Rare Can occur Can occur Especially renal Variable
complications
Treatment Usually Diet and Usually diet Usually Usually insulin Usually insulin
sulfonylureas; exercise alone or sulfonylureas;
occasionally sulfonylureas occasionally
insulin insulin
FPG, fasting plasma glucose; HNF, hepatic nuclear factor; IGT, impaired glucose tolerance; IPF, insulin promoter factor;
NeuroD1, neurogenic differentiation 1.
19
Risk factors for GDM include obesity, older age, Clinical presentations of diabetes
11 Symptoms of diabetes. Those symptoms in orange are The classic symptoms directly due to hyperglycemia
typically confined to patients with type 1 diabetes. are polyuria, thirst, and weight loss.
20
disease and some already have arterial disease on These include retinopathy, neuropathy, and
presentation, including myocardial infarction and nephropathy (see also Chapters 6, 7, 8, 9, 10).
gangrene. Very small blood vessels can become blocked or
A fraction of cases present without symptoms, leaky as a result of hyperglycemia. The blood
either on routine blood screening or with glyco- vessels most frequently affected are in the eye,
suria. the kidney, and nerve sheaths. This microvascular
Glycosuria is not diagnostic of diabetes but disease is specific to diabetes, and may occur in
indicates the need for further investigation. any type of diabetes.
About 1% of the population have renal glyco- Damage to the blood vessels of the retina can
suria, inherited as an autosomal dominant or result in loss of vision.
recessive trait associated with a low renal Damage to blood vessels in the kidneys can
threshold for glucose. result in kidney failure.
As a common disease that can have multiple con- Damage to blood vessels in nerve sheaths
sequences, diabetes may be discovered fortu- can result in numbness or tingling. If nerves
itously in patients being investigated for a wide to the digestive system are affected, the indi-
range of symptoms. vidual may suffer associated symptoms, e.g.
nausea or constipation. Loss of sensation in
Complications of diabetes the feet can lead to the development of
ulcers.
If diabetes is not well managed or controlled, the
high blood glucose levels can lead to damage to Acute metabolic complications
blood vessels, nerves, and organs. Even non- These include hypoglycemia, ketoacidosis,
symptomatic, mild hyperglycemia can have hyperosmolar nonketotic hyperglycemia (see
damaging effects in the long term. High blood also Chapter 11).
sugar levels can also reduce the efficiency of Hypoglycemia most commonly results from
white blood cells in fighting infections. treating diabetes with exogenous insulin or
insulin secretagogues.
Macrovascular complications In a person without diabetes, endogenous
(see also Chapter 6) production of insulin decreases and counter-
Macrovascular problems associated with diabetes regulatory hormones (mostly epinephrine
mellitus include heart disease, stroke, and periph- and glucagon) increase, in response to hypo-
eral vascular disease (which can lead to ulcers, glycemia. This fine-tuned system is dysregu-
gangrene, and amputation). Prolonged, poorly lated in patients with diabetes, and patients
controlled hyperglycemia increases the likeli- have to resort to intake of carbohydrates to
hood of atherosclerosis. An individual with raise the blood glucose back up to normal.
diabetes is approximately five times more likely Symptoms range from mild to moderate
to suffer heart disease and stroke than someone (palpitations, diaphoresis) to severe
without diabetes. (convulsions, coma).
Diabetic ketoacidosis and hyperosmolar hyper-
glycemic nonketotic state occur as a result of
insulin deficiency during episodes of stress, when
counter-regulatory hormones are in excess.
Patients are dehydrated, and frequently
present with altered sensorium. Treatment
Diabetes dramatically increases an individuals risk includes hydration to correct the fluid deficit,
of heart disease and stroke. insulin administration, and correction of the
underlying disease.
21
Common infections
Hyperglycemia can affect the immune
Outpatient Institutional
medication and care
supplies
Type 2 diabetes accounts for 5% of the total 17 The cost of diabetes. Healthcare expenditures attributed
healthcare costs in Europe. to diabetes in the USA, by age group and type of service,
2007. Direct medical costs were $116 billion.
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25
CHAPTER 2
Glucose, insulin,
ate risk
High risk
Moder
Low
risk and diabetes Ver y
high
ris k
om
Glucose is a vital metabolic fuel, being the main
se
co
ot
es
glu
source of energy in many tissues. It is metabo-
ins
od
u
lized during the process of cellular respiration,
blo
lin
rele
s
which breaks it down to release adenosine
Raise
GLUCAGON
a
se
triphosphate (ATP).
It is a monosaccharide, or simple sugar, with cog
Gly en ulates glycogen breakdow
Stim n
the formula C6H12O6. Its six carbon atoms can Liver Pancreas
be arranged in open-chain or ring forms. Stim tion
ulates gly
G lu cogen forma
Red blood cells and brain cells use glucose c os e
almost exclusively for energy production,
Lowe
se
INSULIN
a
whereas other cells in the body can meta-
rele
rs b
n
loo
ago
Tissue cells
Most glucose in the body comes from
dg
luc
luc
sg
digested carbohydrates, but it can also be
os
te
o
e
Insulin (mol/l)
40
tration rises in response to a meal, NEFA response is sup-
Glucose, insulin,
and diabetes
7
Glucose levels and diabetes 6
Glucose (mmol/l)
Diabetes is defined by an increase in blood 5
glucose levels above normal values. To under- 4
stand how hyperglycemia may occur, we should
3
consider factors that maintain blood glucose
2
within a strict range.
In healthy people, blood glucose concentrations 1
are maintained within very close limits (19), with 8.00 13.00 18.00 8.00
a strictly maintained postabsorptive (e.g. fasted
overnight) blood glucose concentration of 500
4.55.2 mmol/l (8194 mg/dl).
Inter-individual coefficients of variation 400
NEFA (mol/l)
Glucose, insulin,
and diabetes
of prolonged hyperglycemia: long-term molecules which combine to form the
diabetic complications or tissue damage. 6-carbon glucose molecule.
Increased susceptibility to infection may be In the resting postabsorptive state, hepatic
seen acutely with moderate hyperglycemia. glucose output is ~2.0 mg/kg bodyweight/
min or 200300 g during the average day
Normal glucose metabolism (depending on the availability of glucose
Glucose enters the circulation from three main from food and the bodys requirements).
sources: Glycemia is determined by the balance of
The gut, as the result of hydrolysis, or hepatic glucose influx into the circulation (principally
conversion of a variety of ingested carbo- from hepatic glucose production) and
hydrates. peripheral clearance.
Hepatic and other glycogen stores (glyco- Glycogenesis converts excess glucose into
genolysis). glycogen, via glucose-6-phosphate, for storage in
New synthesis from precursors (gluco- the liver and muscles, while glycogenolysis is the
neogenesis) (20). process by which it is converted back again.
Glycogen is synthesized from both glucose
and the gluconeogenic precursors.
A 70 kg man typically has a total of 700
20 Gluconeogenesis and glycogenolysis. Gluconeogenesis 1000 g of (hydrated) glycogen, mostly stored
is the synthesis of glucose in the liver from noncarbohydrate in the liver (60125 g) and skeletal muscle
sources, including lactic acid from the muscles. In glyco- (400600 g).
genolysis, glycogen reserves in the liver and muscles are Glycogen in skeletal muscle can provide
converted back into glucose-6-phosphate to begin the glyco- local fuel but does not provide a source of
lytic process, the end results of which are pyruvic acid and, glucose for release into the circulation.
via the citric acid cycle, ATP.
Blood Glucose
Gluconeogenesis Glycogenolysis
Glycogenesis Glycogenesis
Glucose-6- Glucose-6-
Glycogen Glycogen phosphate
phosphate
Glucose
6 6
ADP ADP
Glycerol
LIVER Glycolysis
SKELETAL MUSCLE
Amino 6 6
acids ATP ATP
utilization by peripheral tissues must match independently of the action of insulin. However,
the rate of glucose production. these insulin-independent mechanisms cannot
The balancing of glucose production and maintain normoglycemia for very long.
utilization depends partly upon mass action, Insulin-independent (as well as insulin-
but also crucially upon endocrine regulation dependent) glucose clearance is impaired in
by insulin and its counter-regulatory subjects with type 2 diabetes and also in normo-
hormones (see 18). glycemic subjects with a family history of
Glucose provides approximately 4060% (on a diabetes. This suggests that abnormalities in
typical western diet) of the total fuel expenditure insulin-independent glucose disposal manifest at
of the body during a 24-hour period. a very early stage of disease evolution.
It provides almost all the energy of the central This phenomenon of glucose resistance
nervous system. appears to be quantitatively important: as
During high-intensity exercise and during the much as half an intravenous glucose load is
46 hours postprandially, glucose is the pre- cleared by virtue of the effect of hyper-
dominant fuel of the whole body. glycemia on insulin-independent glucose
Glucose is the most efficient fuel for disposal in normal subjects.
oxidation in terms of the liberation of energy
(112.2 kcal or 6 mole ATP per mole of oxygen Glucose transporters
consumed). Glucose is a hydrophilic molecule unable to
Many tissues can use ketone bodies, fatty penetrate the lipid bilayer of cell membranes.
acids, or glucose for their energy supply, Its uptake into cells is achieved by an energy-
depending upon their relative availability in independent process of facilitated diffusion
the circulation. mediated by a family of glucose transporter
Glucose is fully oxidized to carbon dioxide and proteins (GLUTs).
water in the brain, liver, skeletal muscle, and GLUT transporters allow the uptake of
some other tissues. glucose into cells from the interstitial fluid
The brain accounts for most of the glucose into which glucose diffuses from the blood-
oxidized in the fasting state (100125 g/24 h). stream. Differences in kinetics, tissue and
In the fasted state, resting skeletal muscle subcellular expression profiles, and substrate
takes up 1020% of hepatic glucose output: specificities enable specific functions such as
this is not all oxidized but can be converted to glucose sensing (GLUT2) and insulin-
lactate, pyruvate, glycerol, or amino acids, dependent glucose uptake (GLUT4) (21).
some of which subsequently returns to the The various sugar transporters recognized to date
liver as gluconeogenic precursors. are classified into those having high glucose
Fatty acids (or their partial oxidation affinity (class I, comprising GLUT14), high
products, ketone bodies) are the major fuel of fructose affinity (class II, e.g. GLUT5), and novel
resting muscle, heart, and liver. transporters whose physiology is not yet fully
Other tissues such as red blood cells, skin, understood (GLUT614).
adipose tissue, and the renal medulla derive
most energy from glycolysis to lactate and
pyruvate. Glycolysis to lactate is an anaerobic
process to which many cells may resort when
faced with hypoxia: for example, skeletal The entry of glucose into cells is mediated by a
muscle during high-intensity exercise. group of transporter proteins known as GLUTs.
29
Glucose, insulin,
and diabetes
GLUT2 Liver, small intestine, kidney High Km (~20 mmol/l, Facilitated diffusion,
cells 450 mg/dl), high Vmax bidirectional
Active GLUT4
Exocytosis Endocytosis
The different functions of the class I GLUTs are
related to their differing Km values (Km, the
Michaelis constant, is the substrate concentration Inactive GLUT4
Glucose, insulin,
and diabetes
patients with diabetes associated with mutant released.
insulins, others are different in other These ratios are characteristically disturbed in
mammalian species (cattle, pigs), while certain pathological states, including
others have been modified in therapeutic autonomous insulin secretion from an insuli-
insulin analogs (e.g. Lantus, Humalog). noma and in type 2 diabetes, and will be low
In the synthesis of insulin, translation of mRNA or undetectable in cases of surreptitious
yields preproinsulin, a prohormone containing administration of exogenous insulin.
110 amino acids, which undergoes post-transla- Assay of these substances may therefore, in
tional modification prior to the release of the some circumstances, prove helpful in the dif-
mature insulin molecule. ferential diagnosis of hypoglycemia.
Removal of 24 amino acids from prepro- Proinsulin may accumulate in renal failure
insulin yields proinsulin, with 86 amino acids, and is elevated in familial hyperproinsulin-
which is then stored in secretory granules emia.
within the cell. Substances stimulating the synthesis and storage
In healthy subjects, over 90% of proinsulin is of insulin include glucose, mannose, leucine,
converted to mature insulin by the removal of arginine, hormones such as GLP-1, and a variety
the metabolically inert C-peptide component of metabolizable sugars or sugar derivatives. Most
(23). of these also promote secretion and these factors
are collectively termed secretagogues.
Proinsulin Insulin
B-chain S B-chain
S S
S
S
Cleavage site S
S S
A-chain
S S
A-chain
S
C-peptide
Cleavage site Disulfide bond
32
Normal insulin secretion and kinetics Conversely, insulin secretion is inhibited by both
The mechanisms regulating insulin release are the neural sympathetic tone and circulating cate-
focus of much research. cholamines.
It is known that there is an ATP-dependent, A combination of cephalic and gastric effects
sulfonylurea-sensitive potassium (K+) channel makes oral glucose a more potent stimulus to
Glucose, insulin,
and diabetes
whose closure is a late event in the intracellular insulin secretion than an equivalent amount of
signaling mechanism within the cell. Potassium intravenous glucose. This is known as the
channel closure triggers calcium influx and exo- incretin effect and is, at least in part, attributable
cytosis (24). to gut-derived hormones such as GIP and GLP-1.
A wide range of secretagogues will stimulate In healthy adults, insulin is secreted in pulses with
closure of the K+ channel. The most important of a periodicity of 1115 min.
these stimulants is hyperglycemia. Stimuli of insulin secretion increase the
Other secretagogues include mannose, frequency and amplitude of these pulses.
lactate, some amino acids, glucagon, glucose- Approximately 3040 units (240 pmol) of
dependent insulinotrophic peptide (GIP), insulin are secreted every 24 hours in healthy
cholecystokinin, vasoactive intestinal peptide subjects of normal weight.
(VIP), ghrelin, glucagon-like peptide-1 Insulin secretion is basal (0.251.0 U/h) when
(GLP-1), sulfonylureas, and parasympathetic glycemia is below a threshold level of about 5
cholinergic (muscarinic) nerve activity; many mmol/l (90 mg/dl) and insulin output is
have synergistic effects. maximal at glycemia of 1520 mmol/l
(270360 mg/dl).
Insulin is secreted into the portal venous system
and must traverse the liver prior to reaching the
24 Insulin secretion. Extracellular glucose is transported into systemic circulation.
the cell via the GLUT2 receptor, where it is converted into The liver is thus exposed to insulin concen-
glucose-6-phosphate by the enzyme glucokinase (1). Glycolysis trations approximately three times higher
within the mitochondrion generates ATP, which leads to the than other tissues when insulin is secreted
closure of ATP-sensitive potassium channels (2) and depolar- endogenously.
ization of the cell membrane (3).This opens the voltage- About 50% of secreted insulin is extracted
dependent calcium channels (4) and allows the influx of and degraded in the first pass through the
calcium and the subsequent release of insulin (5). liver; much of the residue is broken down by
the kidneys.
The pulsatile pattern of insulin secretion and
Glucose clearance is controlled not only by prevailing
blood glucose concentration, but also by the
GLUT2 secretagogues mentioned above.
It is not hard to appreciate the difficulty in
Insulin granules
replicating such a physiological appearance
1 of insulin with the subcutaneous administra-
Mitochondrion tion of exogenous insulin.
5
ATP 4
2
K+ channel Ca2+ channel
Insulin
The insulin receptor
Insulins main glucoregulatory effects are
Glucose, insulin,
and diabetes
glycoprotein, comprising four peptide subchains,
two and two subunits, linked by disulfide
bridges.
There are two receptor isoforms, IR-A and IR-D,
formed by alternate splicing.
The DNA sequence and amino acid structure of
Insulin receptor the insulin receptor show homology with those of
Phosphate groups the insulin-like growth factor-1 (IGF-1) receptor.
Insulin receptor When insulin binds to the extracellular domain of
substrate
the subunit of the insulin receptor, an enzyme
Cellular (tyrosine kinase) on the the intracellular domain
CYTOPLASM responses
of the subunit is activated; the signal is thus
transferred across the membrane. Activation of
other intracellular enzymes follows (25).
25 Insulin receptor action. When insulin binds to the two After activation, the insulinreceptor complex is
extracellular subunits of the receptor, the transmembrane internalized by endocytosis. The receptor is later
subunits transmit a signal that activates their protein kinase recycled to the cell surface. Internalization of the
domain. Phosphorylation of the insulin receptor substrate insulin receptor is important (and possibly
triggers further reactions, leading to the uptake of glucose. essential) for insulin signals to reach the nucleus
and influence cell growth and protein synthesis.
Internalization is also a route by which insulin is
cleared from the circulation and degraded.
Autocrine and paracrine regulation of insulin Rare DNA mutations of the insulin receptor have
secretion by pancreatic and gut hormones (which been identified:
may reach very high concentrations within the Leprechaunism and RabsonMendenhall
islet) are incompletely understood. Increased syndrome result in severe glucose intolerance
secretion of insulin involves recruitment of more with resistance to exogenous insulin and pro-
cells to the secreting mode. foundly disordered growth, unlike the
Fasting peripheral insulin concentrations vary typical insulin resistance. These mutations
between 3 and 15 mU/l (~20100 pmol/l), as are usually lethal in infancy and adolescence,
measured by radio immunoassays in healthy respectively.
subjects, the higher values being associated with There are also commoner, milder polymor-
increasing age and obesity. phisms of the insulin receptor gene, but these
After a typical mixed meal (700800 kcal), the appear to explain only a small proportion of the
peak plasma insulin concentration will be marked variance in population insulin sensitivity
4080 mU/l (~280560 pmol/l) in young, lean and are considered a rare (<5%) cause of type 2
adults. diabetes.
The half-life of insulin injected into a peripheral Most recognized insulin receptor gene
vein is 26 minutes, with the liver clearing most of mutations are not sufficient alone to cause
this insulin and smaller amounts being cleared in diabetes, but render it more common in the
other tissues having insulin receptors, such as presence of other risk factors.
skeletal muscle, although there is also nonrecep-
tor-mediated clearance by a variety of tissue
proteases.
34
extensive research. These glucoregulatory of insulin that produces 50% of the maximal
and antilipolytic effects of insulin are rapid, effect) is <20 mU/l (~140 pmol/l) (and for
occurring within a few minutes. some adipose depots <70 pmol/l).
Insulin has effects on growth regulation and Inhibition of hepatic glucose output (HGO):
catabolism (synthesis of new proteins) which ED50 of 3050 mU/l (~210350 pmol/l).
occur over hours or days. Much less is known Stimulation of glucose uptake into skeletal
about the other possible actions, including muscle: ED50 of 5070 mU/l (~350490
effects on blood vessels (vascular smooth pmol/l).
muscle proliferation, vasodilatation), the A doubling of insulin concentration inhibits
central nervous system (CNS) (appetite, hepatic glucose output by around 80% and
learning, memory), and the immune increases peripheral glucose utilization by
response (apoptosis and anti-inflammation). around 20%.
These differential effects on lipolysis, HGO, and
glucose uptake are probably responsible for the
fact that most individuals with type 2 diabetes
retain sufficient insulin action to avoid the devel-
opment of ketoacidosis (for many years), despite
26 Actions of insulin. As well as promoting the uptake of the clear defect in glucoregulation.
glucose and inhibiting gluconeogenesis, insulin is significant in
the metabolism of lipids, promoting synthesis of free fatty acids
in the liver and inhibiting the breakdown of fats in adipose
tissues.The insulin receptor facilitates uptake of amino acids Insulin is significant in carbohydrate, protein,
and glucose across the cell membrane and activates protein, and lipid metabolism.
glycogen, and triglyceride synthesis.
Amino acids
Glucose
Glycogen
Glycolysis/
oxidation
Stimulatory action
Inhibitory action
35
Actions of insulin
Glucose, insulin,
Stimulation of hepatic glycogen storage Inhibition of glycogenolysis
and diabetes
Stimulation of hepatic glycolysis Inhibition of gluconeogenesis;
for intermediary metabolism stimulation of glycogen synthase
Adipose tissue Inhibition of lipolysis (stored lipid) Inhibition of hormone sensitive lipase
27 Actions of insulin. Insulin affects virtually every tissue Intravenous injection of insulin typically has
in the body. little effect on blood glucose for 25 minutes;
the maximal hypoglycemic action occurs
The different actions of insulin have different after 515 minutes.
time courses: Insulin stimulation of skeletal muscle glucose
Glucoregulatory and antilipolytic actions uptake declines with a half-life of 1020
occur within a few minutes, while growth minutes after the insulin stimulus is removed.
regulation and synthesis of new proteins
occur over periods of hours or days.
36
Proinsulin and partially split proinsulin have Insulin-like growth factors (IGFs)
metabolic activity generally similar to that of In addition to its acute effects on glucose uptake
insulin, although plasma half-life is three to five and release and on lipid metabolism, insulin has
times longer and biological potency is only growth-promoting activity in a variety of tissue-
815% that of insulin. Proinsulin may be relatively culture models.
Glucose, insulin,
and diabetes
more potent in terms of hepatic activity and less Two protein hormones, IGF-1 and IGF-2,
potent in terms of peripheral glucose uptake. have actions that partially resemble these
In sum, proinsulin has a limited role in actions of insulin. The amino acid sequences
general peripheral glucose metabolism but of these proteins and the base sequences of
may have a relatively more important role in their coding DNA are known and show
hepatic metabolism. homology with those of insulin.
IGFs are weak agonists for the insulin receptor
Second messenger systems and have weak glucoregulatory and antilipolytic
Insulin can have multiple actions even on a single effects. In addition, they have growth-promoting
responsive cell and hence there are several effects mediated by two IGF receptors.
different intracellular pathways mediating these Insulin is a weak agonist of IGF receptors.
actions (see 26).
Glucoregulatory and antilipolytic responses Abnormalities of insulin synthesis and
are rapid and probably mediated via serine secretion
and threonine kinases and cyclic adenosine The most common abnormality is the progressive
monophosphate (cAMP). loss of normal pulsatility, delayed insulin
Stimulation of lipid and protein synthesis, response to hyperglycemia, and gradual loss of
inhibition of proteolysis, the nuclear tran- insulin secretory capacity seen as obese individu-
scription of RNA, and the replication of DNA als move towards type 2 diabetes. The progres-
are slower and act via different second sive loss of insulin secretion in type 1 diabetes has
messenger systems. a different natural history.
As a result of these second messenger However, there are also some rarer, genetic
cascades, GLUT proteins are translocated to abnormalities of insulin structure involving
the surface membrane of the cell and mutations of the DNA code for insulin and hence
increase glucose flux into the cytoplasm. altered amino acid sequences. Consequences
The actions of insulin in stimulating DNA tran- include the inability to cleave insulin from pro-
scription and mRNA translation do not depend insulin, and impaired receptor binding.
upon the insulin receptor kinase activity and For these variants, there is reduced biological
second messenger systems discussed above, nor activity of the secretory product. This gives a
on the IGF receptors described below, but propensity to diabetes, although individuals
involve direct effects within the nucleus and who can sustain a compensatory hypersecre-
ribosome. tion may avoid it.
There are also recognized polymorphisms that
affect the insulin secretory mechanism (e.g.
calpain 10, a molecule that promotes the fusion of
the secretory granule with the cell membrane)
and are associated with diabetes.
37
CHAPTER 3
Type 1 diabetes
ate risk
High risk
Moder Ver y
high
ris
risk k
Low
40
highest rate of new cases (29). Type 1 diabetes
African-American
African-American
Rate (per 100,000/year)
30
Asian/Pacific islander
Hispanic
American Indian
20
White non-Hispanic
White non-Hispanic
10
29 Diabetes in the young. The average rate of new cases of
diabetes (20022003) among under-20s in the USA was 19
0
per 100,000 each year for type 1 diabetes and 5.3 per 100,000
<10 years 1019 years
for type 2 diabetes.
38
Slow progression to insulin deficiency occurs in 30 Type 1 diabetes subtypes seen in adulthood. The
about 10% of adult patients who present initially differential characteristics of these forms of diabetes overlap
with noninsulin-dependent diabetes. This is often in part, reflecting their complex and diverse pathogenesis.
called latent autoimmune diabetes of adults
(LADA).
LADA is characterized by the presence of The striking discordance between identical twins
diabetes-associated antibodies, including must be due to nongenetic, probably environ-
glutamic acid decarboxylase antibody mental factors. These environmental factors
(GADA). However, some patients appear to probably operate in early life, even in utero, at
have features of both type 1 and type 2 least in those cases which present in childhood.
diabetes (called double-diabetes) and some Patients presenting in adulthood have a more
ethnic groups, including those of Hispanic or potent environmental input but the origins of that
African origin, may present with ketoacidosis effect are unclear. The nature of the environmen-
which later passes through a period of not tal factor or factors is also unknown but candi-
requiring insulin treatment, so-called ketosis- dates include viruses and food, such as early
prone diabetes (KPD) (30). exposure to cows milk.
3
4 5
CD40
IFN
Type 1 diabetes
1 Toxins
CD154
3 IL-2
IL-12
4
5
2
ISLET OF LANGERHANS
Macrophage
CAPILLARY
more predictive than others (34). nonidentical twins is consistent with a genetic
The ability to predict the disease raises the influence in type 1 diabetes. About 40% of
hope that we may eventually be able to identical twins with type 1 diabetes have a co-
prevent it and clinical trials are now under twin with the disease (i.e. they are concordant for
way. type 1 diabetes), though that proportion falls as
Autoimmune diseases show three features: the age at diagnosis of the index twin rises.
Defined autoantigens and autoantibodies The remarkably low twin concordance rate
must be present. for adult-onset type 1 diabetes implies a
Passive transfer of T lymphocytes (specific or limited genetic impact, much less than in
nonspecific) must lead to disease develop- childhood-onset disease.
ment. HLA genes are associated with an increased risk
Immunomodulation of subjects with disease of a number of autoimmune diseases. Genes
must ameliorate symptoms. encoding these HLA molecules are found within
The first of these is true for type 1 diabetes and the major histocompatibility complex (MHC) on
the autoantibodies to autoantigens can predict the short arm of chromosome 6 (35). HLA genes
the disease with a degree of certainty. Some are highly polymorphic and this region has been
immunomodulation therapies can modify, albeit in balanced polymorphism for at least 10 million
transiently, the disease process. years. HLA associations with type 1 diabetes
Type 1 diabetes is associated with other auto- probably operate through susceptibility to
immune diseases, including Hashimotos thyroid- undefined infections.
itis, adrenalitis, celiac disease and pernicious This MHC complex is a polymorphic gene
anemia (with vitamin B12 deficiency). complex with multiple alleles at each genetic
locus. The MHC is divided into class I (HLA
-A, -B, and -C), class II (HLA-DR, -DQ, and
The presence of autoantibodies before clinical onset -DP), and class III (genes for complement
can predict diabetes. components).
The class I and class II proteins are trans-
membrane cell surface glycoproteins
involved in both self and foreign antigen
presentation to T lymphocytes.
80
Multiple antibodies
Diabetes frequency (%)
Single antibody
60
34 Islet autoimmunity. The German BABYDIAB study
monitored 1610 newborn children, who had at least 1 parent
40
with type 1 diabetes, for islet autoantibody and diabetes devel-
opment. Over a period of 11 years, 51 children developed
20 multiple islet autoantibodies, of whom 23 developed the
disease.The cumulative risk for developing diabetes within 5
years after first becoming autoantibody positive was 40% in
0
2 4 6 8 offspring who had multiple autoantibodies and 3% in those
Time from first Ab (years)
who had single autoantibodies.
41
Type 1 diabetes
DRA1 DRB9 DRB3 DRB1 DQA1 DQB1 DQA2 DQB2 DMA DOB DPA1 DPB1 DPA2 DPB2
3
Class II genes are more important than Class I
genes, and DQ genes are more important than 2
DR genes.
About 95% of European patients have either 1
HLA-DR3 or HLA-DR4, compared with about
II
PT S
22
LE 2
A
A4
2
IN
2B
BB
PN
PN
RA
R2
16
ss
PN
TL
cla
SH
ER
C
60% of the general population, and specific
IL
18
PT
PT
C
IL
LA
C
alleles of HLA-DR3 and HLA-DR4 have been
H
Immigrant children
6
Vaccinations and antibiotics.
4 Increasing wealth (possibly all relevant for
Yorkshire
Karachi
2
For type 1 diabetes, other factors are:
0 Overcrowding in childhood and virus infec-
tions.
Reduced rates or duration of breast feeding.
Early exposure to cows milk.
37 Nongenetic factors. The incidence of type 1 diabetes Reduced vitamin D consumption.
amongst Pakistani immigrants to Yorkshire between 1978 and Several or one of these factors could account for
1990 showed an increase to levels comparable with those of the disease in any given individual.
the local population. Adapted from Staines & Bodansky, 1997.
Development of type 1 diabetes
Type 1 diabetes
diabetes, can result from any cause of reduced cause of death in people over 30 years of age.
insulin sensitivity, as is seen with increased linear It has also been noted that South Asian patients
growth and increased childhood obesity, both of with insulin-treated diabetes suffer an exception-
which are related to age at presentation. ally high mortality, which may be related to a
higher risk of cardiovascular disease.
Mortality Cancer mortality among people with type 1
diabetes is thought to be generally similar to that
The Pittsburgh Epidemiology of Diabetes of the general population.
Complications study has demonstrated that the There may be greater incidence of ovarian
pattern of causes of death changes, depending on cancer and mortality, as implied by at least
the duration of type 1 diabetes (39). one study.
Cardiovascular disease was the principal Recent papers have questioned whether the
cause of death among people who had had use of an insulin analog, glargine insulin,
type 1 diabetes for more than 30 years. could be associated with an excess risk of
Renal disease formed the largest proportion breast cancer, but this observation requires
of causes of death among people whose confirmation in larger, prospective studies
disease duration was between 10 and 19 and the current recommendation is that clini-
years. cians should be cautious but continue use of
this therapy, much as before.
19501959
19601964
20
19651969
19701974
19751980
10
0
20 years 25 years 30 years 20 years 25 years 30 years
Duration of follow-up Duration of follow-up
44
disorders that develop over the course of years Have a positive predictive value that
and are characterized by autoantibodies, which increases for one, two, or three autoanti-
appear in the peripheral blood months, even bodies from approximately 10% to 50% and
years, before the onset of clinical symptoms. 80%, respectively, within 5 years and even
Since the genes associated with autoimmune higher thereafter.
diseases are susceptibility genes, and therefore The success of screening with autoantibodies for
carry a limited predictive value, attention has type 1 diabetes suggests that autoantibody
turned to the immune response, and specifically screening will be useful in predicting other
disease-associated autoantibodies, as potential chronic autoimmune diseases. Such screening
predictors. could be used to identify subjects at risk in the
Screening for autoantibodies as predictors of immediate family or general population, in order
disease has been convincingly demonstrated for a to identify those suitable for prevention therapy
number of autoimmune diseases, including type when it becomes available. They can also be used
1 diabetes. These studies, involving thousands of to classify the disease, notably when patients
subjects, showed that autoantibodies: present with noninsulin-dependent diabetes as
Can appear at an early age, even around the adults, of whom some 510% have autoimmune
time of birth. type 1 diabetes.
Can precede the clinical onset of diabetes by
some years.
45
CHAPTER 4
Type 2 diabetes
ate risk
High risk
Moder Ver y
high
ris
risk k
Low
30
BMI >30 (% population >15 years)
25
20
15
10
0
a
itz an
N nd
ay
Au ly
Fr ia
e ce
he k
Sw ds
Po n
Be d
Ice m
d
ain
Po nd
er l
ze Ir y
Re nd
N Ca ic
Ze da
H and
m y
g
Re ria
ic
M K
ico
SA
G uga
an
re
ur
xe ar
et ar
e
lan
lan
Ita
bl
bl
U
u
w
n
an
Sw Jap
ew na
ed
la
la
ch la
st
U
Sp
ex
lgi
Ko
Lu ung
N nm
bo
m
pu
va us
pu
rla
al
or
rt
er
Fin
A
D
k
Slo
C
46
With time (typically 515 years from diagnosis), which is independent of, and additional to, that of
glycemic control in type 2 patients usually elevated BMI (41).
becomes more difficult, insulin deficiency more Other independent risk factors for type 2 diabetes
apparent and a subgroup of patients will become include lack of exercise, being born to a mother
ketosis-prone. Data from the UKPDS trial with gestational diabetes , being of exceptionally
suggested that the average time to insulin use was high or low birth weight.
approximately 8 years after diagnosis of type 2 Low birth weight is postulated by the Barker
diabetes and confirmed the clinical impression of Hypothesis to predispose to diabetes and
a progressive rather than static disease process. obesity by various mechanisms, including
switching on thrifty genes to counter the
effects of intrauterine malnutrition.
Leaner patients with type 2 diabetes tend to show
Determinants and risk factors
for type 2 diabetes more severe insulin deficiency (and within this
subgroup one typically finds LADA patients).
Greater degrees of obesity are associated with
Lifestyle and behavior Westernization, urbanization,
related modernization more insulin resistance.
Obesity (including distribution There is longstanding controversy as to whether,
of obesity and duration) for the type 2 diabetes typical of patients of
Physical inactivity
Diet European origin, the prime defect in glucose
Stress homoeostasis is insulin deficiency or insulin
resistance, or both. Given that many individuals
Genetic Genetic markers
Thrifty gene(s) with severe insulin resistance do not have
Family history diabetes and that some patients with type 2
diabetes have little insulin resistance, it is
Demographic Sex, age, ethnicity
probable that insulin resistance alone is not the
Other demographic
characteristics cause; rather, some degree of -cell dysfunction
(either as an inherited tendency or a result of
Metabolic determinants Impaired glucose tolerance reduced -cell function as part of a degenerative
and intermediate risk Insulin resistance
categories Pregnancy-related determi- process) is the sine qua non of type 2 diabetes.
nants (parity, gestational Such -cell dysfunction may take the form of
diabetes, diabetes in offspring a relative lack of insulin secretion and/or of
of women with diabetes
during pregnancy, intrauterine abnormal patterns of insulin secretion.
mal- or overnutrition) Such abnormalities have been described in
patients who later developed type 2 diabetes
and include changes in the amplitude and
41 Risk factors. The main determinants for type 2 diabetes frequency of insulin secretory pulses, and in
are linked to social factors, such as socio-economic status. the loss of first-phase insulin secretion with
Age, family history, poor diet and physical inactivity are the prolongation and augmentation of second-
main risk factors. phase secretion.
47
Type 2 diabetes
Secondary diabetes implies that another 10
Ba USA
M os
ico
Jam SA
C a
B ba
ol ia
a
U gen il
an a
Pa eru
ay
m ile
la
aic
bi
rb tin
Ar Braz
C oliv
ue
gu
Ve Ch
u
ad
om
ex
P
history and treatment approach for type 2
ez
ra
rb
a,
m
Pi
diabetes, this is less so for secondary
Selected countries of the Americas
diabetes. Occasionally, the secondary
diabetes may be significantly improved by
treating the primary condition. 42 Genetic versus environmental factors. The Pima Indians
of Arizona have the highest prevalence of type 2 diabetes in
Genetic factors the world, far higher than other American populations.
Family studies suggest that type 2 diabetes is A homogeneous group, they have been extensively studied.
strongly inheritable: There is an increased prevalence among Native Americans in
Concordance rates for identical twins exceed general, possibly due to the interaction of genetic predisposi-
70%. tion and a change from traditional diets. Genetically similar
Some racial groups have a very high Pimas in Mexico, among whom the prevalence of obesity is
incidence of type 2 diabetes; notable less, are also much less susceptible to diabetes.
examples of this include the Pima Indians of
Arizona (42) and South Sea Islanders, with
prevalence rates of up to 50%.
In the UK, the prevalence of type 2 diabetes Men
5
among people of South Asian extraction is Women
Standardized risk ratio
an
ni
hi
sh
n
es
ca
be
ta
es
Iri
di
kis
rib
lad
In
Ch
kA
Pa
Ca
ng
Ba
k
Bl
ac
Bl
risk by 1020% (OR 1.11.2), compared to obesity Other associated conditions include hyper-
510% (OR 5.1). tension, hyperuricemia, high plasma
Molecular biological techniques have not yet androgen:estrogen ratios, hypercoagulability of
shown type 2 diabetes to be consistently associat- blood, endothelial dysfunction, and accelerated
ed with any abnormalities of the DNA coding for atherosclerosis.
insulin, the insulin receptor or glucose transporter
peptides (except in a small percentage [<5%] of
cases). Abnormalities of the glucokinase gene 44 The etiology of type 2 diabetes. Interaction between
and of certain hepatic nuclear factor genes cause genes and the environment can lead to obesity/insulin resist-
some cases of MODY (see 10), but not typical ance. Genetically susceptible cells are unable to compensate
type 2 diabetes. for the increased secretory demand, resulting in dysfunction
and cell death. Adapted from Kahn, Hull, et al, 2006.
Obesity/
insulin resistance genes -cell dysfunction/
growth genes
Leptin; leptin receptor; PC1;
POMC; PC4 receptor; HNF1; HNF4; Kir6.2;
Insulin receptor; PPAR- TCF7L2; mitochondrial
Obesity/
insulin resistance
Increased hepatic
TYPE 2 DIABETES gluconeogenesis
49
-cell insufficiency
Insulin concentration
obesity- and alcohol-related cancers, such as Insulin action
Glucose level ia
pancreatic and liver cancers, have been em
lg yc
observed in type 2 diabetes. However, this r
pe
Hy
observation may be due to confounding
factors and not diabetes per se.
Type 2 diabetes
changes over a period of years (45). diabetes
Patients become insulin resistant, almost
always because of obesity and physical 45 Natural history of type 2 diabetes. This model (the De
inactivity. Fronzo hypothesis) shows that patients progress from normal
Insulin resistance causes the patient to glucose tolerance to IGT to diabetes.Though decreased insulin
progress over the years through a phase of action is a contributor, it is the decline in -cell production of
hyperinsulinemia (metabolic syndrome, insulin that heralds the onset of diabetes.
insulin resistance syndrome).
The hyperinsulinemia puts a strain on the
cells and progressive pancreatic failure is In type 1 diabetes, hypertension is strongly linked
added to the pathophysiology. with diabetic nephropathy. Although it is often
Thereafter, the patient proceeds through uncertain whether this is initially cause or effect, it
phases of increasingly severe hyperglycemia. becomes a vicious cycle.
At first, the glycemic defect will be subtle, There appear to be familial effects, with non-
such as IGT or IFG, but will then become diabetic relatives of diabetic nephropathic
Type 2 diabetes. hypertensive patients showing defects in ion
Initially, therapy for type 2 diabetes may involve transport function (erythrocyte Na+/Li+
just lifestyle interventions, but, typically, oral counter transport and leukocyte Na+/H+
hypoglycemic agents and, later, exogenous antiport) and an increased propensity to
insulin will be needed as worsening -cell failure develop essential hypertension.
supervenes. Sodium retention and impaired natriuresis are
characteristically found in both type 1 and type 2
Hypertension hypertensive patients; exchangeable body
The association between diabetes and hyper- sodium is increased by an average of 10%; this
tension is strong and long recognized. The may be seen even before the development of any
incidence of hypertension in obese patients with clinically detectable complications of diabetes.
type 2 diabetes is about 50% in some series. Possible mechanisms include increased
Hypertension is associated with obesity and short glomerular filtration of glucose leading to
stature in nondiabetic as well as diabetic groups. enhanced proximal tubule sodiumglucose
Diabetic patients are liable to develop the same co-transport, hyperinsulinemia-induced over-
secondary forms of hypertension as the non- activity of tubular sodium transporters, an
diabetic population (and renal artery stenosis is extravascular shift of fluid with sodium and,
commoner in diabetes), but most diabetic hyper- in later stages, renal impairment.
tensive patients have a low renin hypertension
unlike that of nondiabetic patients with essential
hypertension.
Hypertension is common in type 2 diabetes patients
and is often refractory to treatment.
50
Qualifying criteria Central obesity (defined Presence of either: Insulin resistance Any three of the
as waist circumference diabetes ; impaired (defined as the top factors below
with ethnicity-specific glucose tolerance; 25% of the fasting
values) AND any two of impaired fasting insulin values among
the other factors below glucose; OR insulin nondiabetic individu-
resistance AND any als) AND any two of
two of the other the other factors
factors below. below
Type 2 diabetes
NB: If BMI is >30 kg/m2, males: >0.90; females: of males: >94 cm; of males: >102 cm;
central obesity can be >0.85 AND/OR BMI females: >80 cm females: >88 cm
assumed and waist cir- >30 kg/m2
cumference does not
need to be measured
Triglycerides Levels of >1.7 mmol/l Dyslipidemia counts Dyslipidemia counts Levels of >1.7
(150.5 mg/dl) OR as one criterion: as one criterion: mmol/l (150.5 mg/dl)
specific treatment for triglyceride levels triglyceride levels
this lipid abnormality of >1.695 mmol/l of >2.0 mmol/l
(150 mg/dl) (177 mg/dl)
High-density lipo- Levels of <1.03 mmol/l AND HDL levels of AND/OR HDL levels Levels of males:
protein cholesterol (39.8 mg/dl) (males); 0.9 mmol/l of <1.0 mmol/l (38.6 <1.03 mmol/l;
(HDL) <1.29 mmol/l (49.8 (34.7 mg/dl) (males); mg/dl) OR treated for females: <1.29
mg/dl) (females) OR 1.0 mmol/l dyslipidemia mmol/l
specific treatment for (38.6 mg/dl) (females)
this lipid abnormality
Blood pressure (BP) Systolic BP of >130 Levels of >140/90 Levels of >140/90 Levels of >130/85
mmHg OR diastolic BP mmHg mmHg OR treatment mmHg OR
of >85 mmHg OR of previously treatment of previ-
treatment of previously diagnosed hyper- ously diagnosed
diagnosed hypertension tension hypertension
Fasting plasma Levels of >5.6 mmol/l As above Levels of >6.1 mmol/l Levels of >5.6
glucose (FPG) (100 mg/dl) OR (110 mg/dl) mmol/l (100 mg/dl)
previously diagnosed OR use of medica-
type 2 diabetes tion for hyper-
glycemia
Not all components are measured in routine 46 Metabolic syndrome. People with metabolic syndrome
clinical practice and the labels have no have a five-fold greater risk of developing type 2 diabetes.
especial management implications. Some The International Diabetes Federation (IDF) and the National
workers specifically exclude obese subjects Cholesterol Education Program (NCEP) have both recently
from syndrome X but there are many features issued updated diagnosis guidelines.
in common between slim subjects with
syndrome X and those who are obese with
metabolic syndrome.
52
Type 2 diabetes
The time course of insulin secretion in type 2 subjects had different anti-hyperglycemic effects.
diabetes is abnormal, with patients typically Those with lesser anti- hyperglycemic responses
exhibiting relative insulin deficiency during both were termed insulin-insensitive (or insulin-
the early phase of insulin secretion after an oral resistant). When the development of radio-
glucose load or meal and the first-phase insulin immunoassay showed that many patients with
response to an intravenous glucose load. This type 2 diabetes had high levels of circulating
loss of early insulin response to glucose is paral- insulin, the concept of insulin resistance was
leled by defects in the pulsatility of insulin reinforced. Such patients are hyperglycemic,
secretion. and hence by definition relatively insulin-
Insulin clearance is thought to be normal in type deficient, yet they actually have more immuno-
2 diabetes, so hyperinsulinemia is a reflection of reactive insulin than other people, such that their
true hypersecretion. This hypersecretion repre- true insulin requirement was believed to be
sents a load on the pancreas and explains why larger still.
increased concentrations of insulin precursors Hyperinsulinemia with eu- or hyperglycemia is
(such as pro-insulins) are seen in type 2 patients. taken to indicate insulin resistance, since hyper-
However, over time, even patients who were insulinemia produces hypoglycemia in subjects
hyperinsulinemic at diagnosis become progres- with normal insulin sensitivity.
sively more insulin deficient. Such patients, As insulin has several actions, resistance to insulin
together with those who are insulin deficient action may take several forms:
from diagnosis, often need exogenous insulin Some subjects show resistance to hepatic
treatment to maintain near-normal glycemia. effects.
These patients may then be termed insulin- Some show resistance to skeletal muscle
treated or insulin-requiring, but it should be rec- effects. (Activation of muscle glycogen
ognized that such insulin-treated patients form a synthase by insulin is often defective.)
heterogeneous group, very different in character Some show resistance to liporegulatory
from type 1, insulin-dependent patients. effects.
The degree of resistance may be different for
different actions of insulin so that some
subjects may have marked liver insulin resist-
ance but relatively normal lipids (or other
combinations).
All patients with type 2 diabetes have some Insulin resistance means that
beta-cell deficiency, which often gets more severe more insulin than normal is needed to exert
with time. the glucoregulatory effects.
54
There is incomplete consensus as to the cellular Pathophysiological roles of amylin include the
mechanisms underlying insulin resistance in most suggestion that it may induce insulin resistance in
patients with type 2 diabetes, though multiple skeletal muscle, but this only occurs at pharmaco-
mechanisms have been suggested: logical concentrations.
Competition between carbohydrate and lipid Amylin fibrils (with typical amyloid features of
fuels (Randle cycle hypothesis). High circu- secondary protein structure and insolubility) are
lating concentrations of alternative fuels, such deposited in islet cells in conditions of excess
as triglycerides, NEFA, lactate and ketone insulin secretion (such as insulinoma) and in situ-
bodies, compete with glucose for metabolism ations where insulin secretion may have initially
and, in their presence, glucose clearance will been increased but has subsequently declined
be reduced. (such as old age and type 2 diabetes). The
Type 2 diabetes
Some insulin resistance can be interpreted as possible role of amylin in the islet damage of type
a result of cellular satiety, seen whenever 2 diabetes is under intensive investigation.
intracellular sensors, such as UDP glucos-
amine, detect overabundant energy supply. Glucotoxicity and lipotoxicity
Some insulin resistance is attributable to
specific cellular abnormalities, such as Glucotoxicity
reduced numbers of insulin receptors, It has long been known that acute elevation of
reduced receptor function, dysfunction of plasma glucose concentrations is able to induce a
second messenger systems, and intracellular state of insulin resistance, coupled with impair-
antagonists of insulin effects. ment of insulin secretion in response to glucose
These different hypotheses are not necessarily (49).
mutually exclusive. Lipid fuel competition may In the presence of normal -cell mass, transient
contribute to cellular satiety and provoke specific elevation of plasma glucose to levels just above
second messenger changes. the physiological range potentiates insulin
Most glucose clearance occurs independently of secretion in both humans and animals, but
insulin. This insulin-independent glucose chronic hyperglycemia reduces insulin secretion.
clearance is defective in type 2 diabetes and con- Conversely, strict metabolic control is able to
tributes to hyperglycemia. Reduced tissue blood induce improvements in both insulin secretion
flow, particularly within skeletal muscle, may also and sensitivity, although not usually to normality.
reduce clearance of plasma glucose in diabetes. It is likely that multiple mechanisms contribute to
this effect, including:
The role of amylin Changes in the Km of glucose sensing
Amylin (also known as islet amyloid polypeptide, systems, such as glucokinase/hexokinase,
IAPP) is a 37-amino-acid peptide co-secreted with which may lead to alteration of the dose
insulin by cells in all subjects with intact insulin response curve of the islet cell to blood
secretion (and so not those with type 1 diabetes glucose concentrations.
or those type 2 patients with severe insulin defi- Changes in the ratio of proinsulin to insulin
ciency). The amino acid structure has some secretion.
homology with calcitonin gene-related peptide. Alteration in the functional activity of the
Plasma concentrations of amylin are very low membrane sulfonylurea-sensitive K+ channel.
(<10-10 molar) in both diabetic and non-diabetic It is likely that the honeymoon period often
subjects. observed in new-onset type 1 diabetes is at least
There is no established physiological role for partly attributable to a reduction in glucotoxicity.
amylin in the systemic circulation, but it has been
suggested that it may have a physiological role in
the regulation of insulin secretion within the islet,
or have some effects on bone metabolism.
55
Type 2 diabetes
Increased activity of protein kinase C via
Gluc
mia
INSULIN intermediates of fatty acid metabolism, such
ose/
ysli
uced i
nsulin produc ing phosphorylation of the insulin receptor.
lyce
ia/d
em
s
e
yc
Several additional factors determine the risk of acarbose, orlistat, troglitazone, simvastatin,
progression from IGT to type 2 diabetes: family and angiotensin-converting enzyme
history of diabetes, age, central and total obesity, inhibitors. For example, lifestyle changes
physical inactivity, fetal maturation, and ethnic (diet and exercise) reduced the 4-year
origin. The risk of progression to diabetes is incidence of diabetes by 58% in middle-aged,
greater for those with IGT than for those with IFG obese, IGT subjects in one study; by 58% in
(50). similar subjects by 3 years in another study;
and by 31% by 3 years with metformin.
The prospect of population screening for IGT
is daunting, but the potential for successful
therapeutic intervention is there.
Type 2 diabetes
Theoretically, it would be possible to delay XENDOS: orlistat 37
over 70% of cases of type 2 diabetes in DPP: metformin 75
persons at increased risk, if they were able to DREAM: rosiglitazone and ramipril 60
NAVIGATOR: nateglinide/valsartan 0/14
maintain normal body weight and engage in
physical activity throughout their lives.
More than preventing diabetes, a healthy diet
and lifestyle could prevent or retard heart
disease. 51 Type 2 diabetes prevention studies. Several long-term
trials have studied the effectiveness of a range of medications
Type 2 diabetes prevention studies as well as lifestyle changes: lifestyle change and glitazones have
Type 2 diabetes may be prevented or at least proved the most successful, although both troglitazone and
delayed by relatively modest degrees of weight rosiglitazone have since been withdrawn due to concerns over
loss and exercise. The interventions have side-effects.
involved individual counseling regarding weight
loss, total fat intake, saturated fat intake, fiber
intake, and physical exercise.
In recent studies, lifestyle interventions
resulting in average weight loss of <7 kg over
6 months with some later regain resulted in a Lean
Incidence (per 100 person years)
16
58% reduction in cumulative diabetes Obese
14
incidence in the intervention groups during
the period of the studies. 12
There is evidence that tablet therapy can be bene- 10
ficial in reducing progression to diabetes, espe- 8
cially in younger subjects; tablets that have been 6
used successfully include metformin, rosiglita-
4
zone, acarbose, orlistat, and simvastatin.
For patients unable to lose weight after appropri- 2
CHAPTER 5
Diabetes screening
ate risk
High risk
Moder
Low
and patient care
risk
Ver y
high
ris k
Legs
Peripheral neuropathy
Since prevention of complications is better and easier (sensation using
than cure, early referral is preferable. microfilament;
reflexes) Hands
Peripheral pulses Liver-related changes
Injection sites (palmar erythema)
Lipid-related
changes (nodules)
Feet Peripheral neuropathy
Shape/deformities (e.g. median nerve
Sensory nerves: palsy)
vibration, warmth Nicotine stains
Motor nerves: reflexes,
53 Examination of a diabetic patient. It is specifically weakness
Autonomic nerves:
important to look out for potential causes of secondary distended veins
Vascular status:
diabetes and diabetes-associated microvascular and macro- pulses, edema,
vascular changes. cold feet
61
Kidneys
Urine is tested for protein using a dipstick.
Remember that trace positive is not positive if
fresh urine is being used for the test.
Some centers check for microalbuminuria, which
can also be done using a dipstick.
This is valid as a marker of early kidney
disease in children and young adults only
when present on at least two separate
occasions in an early morning urine sample.
If microalbuminuria is confirmed, treatment
with an angiotensin-receptor blocker (ARB)
or angiotensin-converting enzyme (ACE)
inhibitor should be started.
Diabetes screening
and patient care
Serum creatinine should be analyzed annually.
Referral to a renal specialist is advised once the
creatinine level has reached 150 mol/l (1.7
mg/dl). An investigation and management plan
should have been devised with the local clinic.
Feet
Inspection of the feet is performed to identify
anatomical distortions, pressure points, ulcers,
54, 55 Screening for complications. Indirect ophthalmo- injuries, or problems with footwear.
scopy and ankle-reflex testing. Examination is carried out for blood supply (by
checking peripheral pulses) and nerve supply (by
checking peripheral sensation and reflexes [55]).
Refer to a chiropodist if any problems are identi-
The ophthalmoscope is advanced until the fied. Since prevention is better and easier than
retina is in focus. Examination of the retina cure, early referral is preferable.
begins at the optic disc, moves through each
quadrant in turn, and ends with the macula Erectile dysfunction
(since this is least comfortable for the patient) History should assess whether the patient can get
by requesting the patient to look into the an erection, penetration or emission. Questions
light. should be direct and unequivocal, as otherwise
The ophthalmoscope is then adjusted to the the response may not be informative.
+10 diopter lens for examination of the Examination should exclude hypogonadal
cornea, anterior chamber, and lens. features, small testes and penile changes, such as
Fundal photography, graded by a trained Peyronies disease.
individual, is increasingly being used to
screen fundi for retinopathy. Vascular disease
Patients with retinopathy should be examined History should be assessed, e.g. pain in chest or
regularly by a diabetologist or an ophthalmolo- legs, erectile dysfunction.
gist. The following circumstances dictate Examination includes checking for bruit in
immediate referral to an ophthalmologist: carotids, palpating peripheral foot pulses.
Deteriorating visual acuity. Special investigations may be necessary, e.g. an
Hard exudates encroaching on the macula. electrocardiogram (ECG).
Pre-proliferative changes (cotton-wool spots Refer to a cardiologist if there is either angina or
or venous beading). cardiac dysfunction.
New vessel formation.
63
Management of young patients Even when there is reason to question the level of
Management of children is not unlike manage- competence for self-management among
ment of the adult. However, it often requires par- children with diabetes and their families, instruc-
ticular sensitivity to the balance between the tion on intensive insulin treatment can be very
childs social independence and dependence on beneficial (58).
others. Younger children will be much more Sometimes the fear of hypoglycemia limits
dependent on family and friends for supervision attempts to obtain optimum diabetes control, and
of their care. Developing independence as this is understandable.
children get older is important for their ability to Optimal use of newer insulin analogs in basal
manage diabetes throughout their lifetime. and bolus regimens, or of subcutaneous insulin
Understanding and dealing in a sympathetic way infusion pumps (see p. 160), should enable most
with parents understandable reluctance to cede young diabetic people to achieve reasonably
too much independence is crucial to the manage- good control with less risk of hypoglycemia.
ment of teenage diabetes. Adolescents and many young children embrace
Diabetes screening
and patient care
Hypoglycemia is a particular problem in children, the technologies of newer delivery devices and
in whom the warning symptoms can differ from monitoring systems much more readily than older
hypoglycemia in adults. patients.
Symptoms of note due to hypoglycemia in young
children include:
Bedwetting.
Naughtiness.
Tearfulness. High level of competence
Bad temper.
9 Usual care
Poor performance in school.
HbA1c (%)
Intensive insulin
Glycemic targets should be essentially the same treatment
patients.
8
58 Diabetes self-management. In a study of 142 young
people, intensive therapy gave improved glycemic control
irrespective of self-management competence, but competence 7
level was more significant with usual care. Adapted from 3 6 9 12 15 18
Months
Wysocki T et al, Diabetes Care, 2003.
64
Height (cm)
140
reduction in HbA1c is associated with a
marked decrease in complication risk. Thus, 130
never abandon trying to get better control.
120
Common issues regarding children with diabetes:
Onset of puberty
Onset of diabetes
Immunization programs in diabetic children
Menarche
110
are unaltered.
Illness is no more prevalent in diabetic 100
Diabetes screening
and patient care
Weight (kg)
60
hyperglycemia or hypoglycemia. 50
0
Reluctance to take injections should be 255
10 50
sympathetically handled and expert advice 5
Diabetes screening
and patient care
decreased insulin sensitivity (60). efficiently as in the young, and dosages may
Hyperglycemia in an elderly person is usually due need to be lower.
to type 2 diabetes, but type 1diabetes may also It may be considered necessary or prudent to
present late in life. identify the most important areas for intervention
Diabetes as a feature of underlying pancreatic rather than identify all therapies required. There
cancer is more likely in the elderly, but accounts may be circumstances where intensifying
for only a small proportion of all cases of treatment would not be expected to have a signif-
diabetes. icant impact or, worse, may have an adverse
Clinical presentation in older people may be one on a patients overall sense of well-being or
atypical and not as clear cut as in children or eventual outcome.
younger adults for example, unexplained
weight loss without other classic symptoms of
hyperglycemia.
Hyperosmolar, nonketotic coma with extreme
hyperglycemia, but no antecedent history of thirst
Beta cells
or polyuria, may be a presenting feature of Reduced insulin
diabetes in the elderly, particularly in patients secretion
1.0
61 Glycemic control and survival rates. Survival rates in
groups of diabetic patients on chronic hemodialysis over a
Cumulative survival rate
0.4
Living alone, poverty, poor diet poor compliance Determine current quality of life and prognosis
Intellectual impairment, depression, and dementia Assess priorities in treating diabetes and other diseases
poor compliance
Avoid hypoglycemia
Poor vision and dexterity difficulty with blood test
and injections Treat diabetes according to individual targets
Coexisting diseases and drugs potential for confusion Screen for complications and treat to maintain
and drug interaction quality of life
Multiple drug therapy poor compliance Be cautious with drug dosages and insulin use
Diabetes screening
and patient care
62 Management problems. Social, economic, and other 63 Therapy key points. Therapy should be chosen based on
health problems may lead to poor compliance with diabetes the individual needs, wishes, and abilities of each patient.
management among the elderly.
no peak action, should help to reduce the risks of Patient education and
hypoglycemia and dehydration. Hypoglycemia, community care
if it does occur, is a justifiable reason to break
the fast. The care of diabetes is based on self-management
During Ramadan, the diet changes as one by the patient, who is advised by those with
only eats twice per day: at Sehri (before specialized knowledge.
sunrise) and at Iftar (after sunset), but not Education should begin when the patient is
between those times. Patients with diabetes diagnosed.
should take Sehri just before sunrise and not The diabetes team members include the patient,
earlier, and be very strict about avoiding doctors, nurses, diabetes educators, dietitians,
sweet food. and chiropodists (64). Lack of motivation,
Patients of differing ethnicities have diverse expertise or education of any one of these
dietary preferences, and one of the features of the individuals can disrupt the quality of care.
ethnic heterogeneity of modern western society is A particular challenge is the diverse socio-
Diabetes screening
and patient care
the much greater variety of cuisine available to, economic and ethnic background of diabetic
and enjoyed by, all. It is important, therefore, that patients presenting to the educators. Culture-
the nutritional advice offered takes into account appropriate educational materials and illustra-
the fact that many patients will not be following a tions, such as examples of carbohydrate servings
traditional western-type diet. and food groups, can be made more understand-
able and effective when adapted to the patients
local setting.
Diabetes self-management education (DSME) is
helpful, at least in the short term, in improving
glycemic control and psychosocial outcomes in
diabetic patients. The amount of time spent with
the educator correlates with outcome.
In the US, it is recommended that DSME
The amount of time spent with an educator programs fulfil the following:
correlates with outcomes. Describe the diabetes disease process and
treatment options.
Incorporate appropriate nutritional manage-
ment into lifestyle.
Incorporate physical activity into lifestyle.
Use medications safely for maximum thera-
peutic effectiveness.
Monitor blood glucose and other parameters
and use the results for self-management
decision-making.
Prevent, detect, and treat acute
complications.
Prevent, detect, and treat chronic
complications.
Develop personal strategies to address
psychosocial issues and concerns.
Develop personal strategies to promote
health and behavior change.
64 Patient care. Management involves a team: physician,
dietitian, nurse specialist, and patient discuss a problem.
69
Lifestyle problems
Living with diabetes
AREA EXAMPLES
There may be aspects of the lives of diabetes
patients that have an influence on the choice of Employment Shift-workers
Long working day (resulting in early
treatment (65).
breakfast, late evening meal, or
erratic meal times)
Employment Skipping midday meal or frequent
All jobs are open to people with diabetes except a business lunches
International travel
few in which the risk of hypoglycemia, due to
insulin therapy, might put others at risk (66). Eating National and cultural variations
(e.g. time of main meal, varying
dietary compositions)
Finance Individual variations (e.g. availability,
It is important that life and car insurance preferences, affordability, dining out)
companies are informed of the diagnosis of
Diabetes screening
and patient care
Exercise Sportsmen and women
diabetes or the start of insulin therapy.
Sedentary office workers
Some brokers and companies are more Manual laborers
accommodating than others towards insuring
patients with diabetes, and will offer better Travel Long-haul air travel
Means of traveling to work
deals, though the premium will be (e.g. cycling, long walks)
dependent on the type of insurance, the
nature of the therapy, the risk of hypo- Leisure Strenuous hobbies (e.g. sports,
gardening)
glycemia, and the presence of complications.
Visual acuity and fields must be assessed to
determine suitability for driving.
In the UK, patients with diabetes are exempt from 65 Living with diabetes. The choice of treatment may need
prescription charges; their general practitioner to take into account a patients lifestyle.
should sign an SP92 form to claim exemption.
Sport
Employment exclusions, UK and USA
Having diabetes should rarely be a bar to partici-
pation in sport. People with diabetes can play, EMPLOYMENT EXAMPLES
and many excel at, most sports.
Some sports are wary of allowing patients on Vocational driving Large goods vehicle (LGV),
passenger-carrying vehicles (PCV),
insulin to participate in competition such as scuba locomotives or underground trains,
diving, motor rally driving, and boxing. professional drivers (chauffeurs),
Patients exercising intensively are at risk of hypo- taxi drivers (variable, depending
on local authority)
glycemia and should:
Measure blood glucose before exercise Civil aviation Commercial pilots, flight engineers,
(perhaps with a general rule of not starting aircrew, air-traffic controllers
exercise if blood sugar is less than 5.6 mmol/l
National and Armed forces (army, navy, air force),
[100 mg/dl] or greater than 14 mmol/l emergency police force, fire brigade or rescue
[250 mg/dl]). services services, merchant navy, prison and
security services
Take 20 g carbohydrate every 45 minutes When traveling westwards, the day is longer
during exercise. and an additional insulin injection may be
Keep fast-acting glucose preparations (such required; use soluble (regular insulin in the
as Dextrosol in Europe) in their pocket in US) or rapid-acting insulin for the extra
case they feel hypoglycemic. injection, take an additional meal, and
Avoid dangerous situations, such as monitor the blood glucose carefully. Again,
swimming alone. resume the usual schedule in the new time
zone.
Holidays and travel If the trip is very long, perhaps with
Patients with insulin-treated diabetes who are stopovers, a change in regime may be
traveling will need: necessary so that it is possible to use soluble
Insulin and insulin syringes, or pen devices or (regular) or rapid-acting insulin before each
insulin pump supplies, and glucose-monitor- meal.
ing equipment. Bring spare insulin and
Diabetes screening
and patient care
Diabetes screening
and patient care
have just started insulin, have erratic control, have
difficulty with hypoglycemia, or have impaired
vision not corrected with glasses.
The American Diabetes Association has a useful
set of tips aimed mainly at younger and recently
qualified drivers, accessible at www.diabetes.org/
living-with-diabetes/parents-and-kids/everyday-
life/driving.html:
Pass the test. Check your blood glucose
before getting into the car. Every time.
No exceptions.
Stop for a diabetes red light. Treat low blood
glucose and then recheck in 15 minutes.
Do not get behind the wheel until blood
glucose is in the target range.
Slow down. Treat blood glucose even if it
means being late. Its never OK to drive with
a low blood glucose. Call whoever is waiting
for you and explain why youll be a little late.
Theyll understand.
Always have enough fuel. Stock the car with
healthy, nonperishable snacks and fast-acting
sugars. And keep your diabetic supplies
within easy reach.
Pull over. Pull over immediately if you are
feeling sick or low while driving. Check your
blood glucose, treat yourself, wait 15
minutes, and then recheck.
ID, please. Dont leave home without a
drivers license and medical ID bracelet or
necklace. Always wear medical ID.
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73
CHAPTER 6
Diabetes and
ate risk
High risk
Moder
Low
risk vascular disease Ver y
high
ris k
50
associated with hyperinsulinemia metabolic No diabetes (men)
or insulin-resistance syndrome (see p. 50). 40
No diabetes (women)
Such an insulin-resistant state may be present
in 25% of the nondiabetic population, and 30
function occurs early in the pathology of athero- and its expression precedes the recruitment
Diabetes and
sclerosis and is common in patients with of leukocytes at the surface of the vessel
traditional risk factors even in the absence of wall. Since levels of CRP and other pro-
inflammatory mediators, such as fibrinogen,
are increased in the plasma of patients with
diabetes they may serve as clinical bio-
69 Atherosclerosis. Damage to arterial endothelium allows markers of vascular risk.
entry of monocytes and lipids (1) and activation of macro- The pathogenesis of atherosclerosis in diabetes is
phages (2).The macrophages engulf the lipids, subsequently as in nondiabetic subjects, but with the added
breaking down into foam cells and causing lipid accumulation burden of hyperglycemia and its impact on cell
on the vessel wall (3, 4).The release of cytokines stimulates function, allied to the clustering of other risk
migration of smooth muscle cells to form a fibrous cap (5, 6). factors found in the metabolic syndrome.
Lipid
Monocyte
ARTERIAL LUMEN
Endothelial cell
Smooth muscle cell
Foam cell
6
Macrophage
Cytokines
4
1
IM A
I NT
DIA
2 ME
3
5
75
vascular disease
with macrovascular disease, plus fibrates to
Diabetes and
correct hypertriglyceridemia and increase
HDL as necessary. Glucose control
Fibrates must be used cautiously in patients Patients with hyperglycemia on admission for a
taking statins because of the risk of rhabdo- myocardial infarction have a poorer prognosis
myolysis. than patients with normoglycemia.
If statins and fibrates have to be used concur- The rise in creatine kinase (CK)-MB enzymes,
rently, fenofibrate is recommended over which reflects the extent of cardiac muscle infarc-
gemfibrozil, as gemfibrozil interferes with tion, is greater in patients with elevated blood
statin glucuronidation, thereby conferring a glucose concentrations.
higher risk of myopathy and rhabdomyolysis In patients presenting with an acute myocardial
than does fenofibrate. infarction, the Diabetes Mellitus Insulin Glucose
To reduce mortality risk there is also the need to Infusion in Acute Myocardial Infarction (DIGAMI)
achieve tight glycemic control. study showed that strict glycemic control in the
To correct the anatomical lesions, consider diabetic patient significantly improved cardio-
surgical intervention to improve revasculariza- vascular outcomes (70).
tion, in order to control symptoms and improve This study used an insulinglucose infusion
prognosis. There are two techniques for success- for about 24 hours followed by multiple sub-
ful cardiac revascularization: cutaneous insulin dosing for 3 months.
Percutaneous intervention. DIGAMI-2 tried to discover whether it was
Coronary bypass surgery. the insulinglucose infusion, the sub-
The role of cerebrovascular revascularization cutaneous insulin, or both that led to the
remains unclear in diabetes and it should be used improvement; however, difficulties in
as for nondiabetic patients. carrying out the study resulted in all three
groups achieving similar glucose control.
The question of acute versus subsequent tight
control was not answered by this study, but
the overall excellent HbA1c achieved at the
end of the study (~6.8% [51 mmol/mol] for all
Strict glycemic control significantly improves groups) was associated with improved
the prognosis in the diabetic patient with a cardiovascular outcomes in all groups. A 2%
myocardial infarction. increase in HbA1c was associated with a 20%
increase in mortality.
76
In the Cholesterol and Recurrent Events (CARE) The Bypass Angioplasty Revascularization
trial, pravastatin was given to adults with myo- Investigation (BARI) Trial showed that coronary
cardial infarction, total cholesterol levels less than artery bypass grafting (CABG) resulted in a lower
6.2 mmol/l (240 mg/dl) and LDL-cholesterol cardiac mortality than percutaneous transluminal
levels of 3.04.5 mmol/l (115174 mg/dl). The coronary angioplasty (PTCA) in diabetic patients.
primary endpoint of fatal coronary event or a However, the introduction of stenting plus the
nonfatal myocardial infarction was significantly more potent antithrombotic agents, particularly
reduced with pravastatin compared to placebo. glycoprotein IIb/IIIa receptor blockers, has
This reduction was seen in both diabetic and non- improved prognosis.
diabetic patients. In the Evaluation of PTCA to Improve Long-
With regard to fibrates, the Veterans Affairs HDL term Outcome by c7E3 GP IIb/IIIa Receptor
Intervention Trial (VA-HIT) showed that gemfi- Blockade (EPILOG) Trial, abciximab (a
brozil reduced the incidence of myocardial infarc- platelet aggregation inhibitor) given during
tion and stroke in patients, including diabetes PTCA was associated with a significant
patients, with coronary artery disease plus low reduction in death or myocardial infarction in
HDL- and high LDL-cholesterol levels. both diabetic and nondiabetic patients.
In a predefined subgroup analysis from the
Evaluation of Platelet IIb/IIIa Inhibitor for
Stenting (EPISTENT) trial showed that
DM symptoms Usual symptoms stenting combined with infusion of
abciximab improved the long-term outcome
Faintness,
sweating in diabetic patients substantially. In a
Spreading pain
combined analysis the 1-year incidence of
Breathlessness
to shoulder, neck, ischemic endpoints was comparable to that
and arm
achieved in nondiabetic patients.
Nausea
Pressure in the
chest
71 Symptoms of angina. Diabetic patients may exhibit
atypical symptoms, such as weakness, faintness, sweating,
nausea, and breathing difficulty, as well as a reduced pain
sensitivity.
77
vascular disease
known, but several factors are understood to play
Diabetes and
showed that abciximab (ABX) substantially decreased the
mortality of diabetic patients. Adapted from Bhatt DL et al. a role (73).
In some ways the factors causing this form of
vascular disease are similar to those involved in
The results of the EPILOG, EPISTENT, and macrovascular disease, for example:
one other study on abciximab, the Evaluation Hypertension is a risk factor in microvascular
of Platelet IIb/IIIa Inhibition for Prevention of renal and eye disease.
Ischemic Complications (EPIC) trial, were Smoking is a risk factor in renal disease.
pooled. The combined analysis showed that Hyperglycemia is not a major factor in macro-
abciximab reduced the mortality of diabetic vascular disease, but is critical in the development
patients to the level of nondiabetic patients of microvascular disease. Hypertension is just as
receiving placebo (72). important in predisposing to microvascular
disease as hyperglycemia and all the five modifi-
able factors targeted by therapy are relevant:
Hyperglycemia.
Hypertension.
Hyperlipidemia.
Lack of exercise.
Factors associated with the pathogenesis Smoking.
of microvascular complications
Hyperglycemia
Hyperglycemia is critical in the development
Protein glycation of microvascular disease.
Advanced glycation endproducts (AGE)
Basement membrane
vascular disease
Diabetes and
thickening
Increased permeability
Occlusive angiopathy
Organ failure
While hyperglycemia is the primary metabolic In the UKPDS study of newly diagnosed type
dysfunction in microvascular complications, the 2 diabetic patients, intensive glycemic control
main target is the endothelial cell (74). was associated with a reduced risk of micro-
vascular endpoints, including microalbumin-
Hyperglycemia uria retinopathy.
Hyperglycemia predisposes to diabetic micro- In the Kumamoto study on thin type 2
vascular disease; reducing hyperglycemia can diabetic Japanese patients, those in the
limit that progression and prevent disease devel- intensive glycemic treatment group had a
opment, as illustrated by DCCT for type 1 76% risk reduction for retinopathy and 57%
diabetes and UKPDS for type 2 diabetes: for microalbuminuria in the primary preven-
In terms of reducing risk for microvascular tion cohort.
complications, the DCCT showed that There are several possible mechanisms linking
intensive glycemic control in type 1 diabetes hyperglycemia and diabetic microvascular
reduced the risk of developing retinopathy in disease (75).
the primary prevention cohort (no retino-
pathy at baseline) by 76%, microalbuminuria
by 34%, and neuropathy by 71% compared to
conventional treatment.
79
vascular disease
reactive oxygen species (ROS). ROS can cause glycation and oxidation leads to the formation of
Diabetes and
strand breaks in nuclear DNA, which can reduce advanced glycation endproducts (AGE) (76).
the activity of key enzymes and activate less AGE precursors damage cells via:
beneficial pathways. Modification of intracellular proteins,
Broadly, the consequence of high intracellular including proteins involved in regulation of
glucose is that the cell is stressed and mounts an gene transcription.
anti-stress response to try to restore homeostasis. Modification of extracellular matrix
molecules on diffusion out of cells, which
alters matrixcell signaling and causes
76 AGE reactions. The interaction of advanced glycation cellular dysfunction.
endproducts (AGE) with arterial wall components increases Modification of circulating blood proteins
vascular permeability and wall thickness, the expression of pro- which bind to AGE receptors and activate
coagulant activity, the generation of reactive oxygen species them, causing inflammation and vascular
(ROS), and the endothelial expression of adhesion molecules. pathology.
NFB, a transcription factor; IGF-1, insulin-like growth factor 1; Tissue levels of AGE increase with age, and can
VEGF, vascular endothelial growth factor;VCAM-1, vascular cell be derived from exogenous sources such as food
adhesion molecule-1. and tobacco smoke.
ROS
Inactive
alcohols Sorbitol NAD+
high, aldose reductase also reduces that glucose
to sorbitol, which is later oxidized to fructose
(77).
In the process of reducing high intracellular NAD
Fructose
glucose to sorbitol, the aldose reductase
consumes the cofactor NADPH. NADPH is also
the essential cofactor for regenerating a critical
intracellular antioxidant, reduced glutathione. 77 Sorbitol conversion. Aldose reductase reduces toxic
By decreasing reduced glutathione, the polyol aldehydes generated by ROS to inactive alcohols, and excess
pathway increases susceptibility to intracellular glucose to sorbitol, subsequently oxidizing the sorbitol to
oxidative stress. fructose, and using NADPH and NAD+ as co-factors.
As a result, there is a cellular pseudohypoxia as However, this consumption of NADPH can lead to decreased
well as accumulation of the osmotically active glutathione reductase and further oxidative stress.
sorbitol. Sorbitol can damage these cells.
Aldose reductase inhibitors limit sorbitol
formation.
Microvascular disease is influenced by several In the diabetic patient without vascular disease,
modifiable factors, including hyperglycemia, management is directed at reducing risk for these
hypertension, dyslipidemia, and smoking. complications, primarily by addressing a set of
Microvascular disease is also influenced by modifiable risk factors (78).
several unmodifiable factors, including: Prevention of microvascular complications
Duration of diabetes. Complications tend to reduces morbidity in diabetic patients, while
manifest themselves 1020 years after reduction of cardiovascular risk is of prime
diagnosis in young patients. A patient who importance, since this is the major contributor to
does not develop renal disease by 30 years both mortality and morbidity.
postdiagnosis is unlikely to develop that The Multiple Risk Factor Intervention Trial
complication. Retinopathy can be present at (MRFIT) showed increasing likelihood of
diagnosis of type 2 diabetes, probably death from cardiovascular disease, according
because the patient had unrecognized to the number of risk factors present (79).
diabetes for several years prior to diagnosis.
vascular disease
Genetic factors. Diabetic siblings of diabetic
Diabetes and
patients with renal and eye disease have a 78 Risk factors in vascular disease. Risk factors can be either
35-fold increased risk of the same complica- modifiable by therapy or life-style changes, or as with age or
tion compared to siblings of patients without gender not modifiable.
renal or eye disease. Patients with diabetes
due to a glucokinase polymorphism associat- D IFIABLE FACTO
MO RS
ed with raised fasting glucose but minimal UN
RACE AGE
postprandial hyperglycemia rarely develop
Obesity
microvascular complications.
Racial factors. Some races are at higher risk
of microvascular complications than others. Hypertension Hyperglycemia
For example, in the US, the rank order of risk MODIFIABLE
FACTORS
is Pima American Indians > Hispanic/ Sedentary
Mexican origin > US African origin > US lifestyle Dyslipidemia
20
0
None One Two Three
Risk factors
82
Exercise Diet
Obesity and sedentary lifestyle
Moderate-intensity Saturated fat limited to
Central to the prevention of cardiovascular aerobic activity <7% of total calories.
disease is behavior modification (80). 150 minutes per week. >2 servings of fish
Resistance training 3 per week.
Diet and exercise are always advocated, though times per week Increase consumption of
their importance has been cast aside by many fruits, vegetables, legumes,
low-fat dairy produce,
patients because of the difficulty in achieving the and whole grains
goals as compared with the relative ease of Smoking
taking pills, or doing nothing to address hyper- Encourage the patient to
tension and dyslipidemia. stop smoking
Dietary recommendations include limiting
MANAGEMENT GOALS
saturated fat to <7% of total caloric intake, having
two or more servings of fish per week to provide Blood pressure Glycemic control
polyunsaturated fatty acids, and incorporating With micro/macro- HbA1c <6.57.0%
vascular disease: (4853 mmol/mol)
fruits, vegetables, legumes, low-fat dairy systolic <130 mmHg; (nonpregnant adults).
diastolic <80 mmHg Increasing disease
products, and whole grains into meals. duration/more drugs
Aim for 150 minutes per week of moderate <7.5% (58 mmol/mol)
intensity aerobic physical activity (5070%
vascular disease
Hypertension
The UKPDS trial concluded that tight blood
pressure (BP) control in patients with hyper- UK NICE guidelines recommend ACEIs in
tension and type 2 diabetes achieves a clinically general, but for Afro-Caribbean patients ACEIs
important reduction in the risk of diabetes-related plus either a diuretic or calcium-channel blocker.
deaths and complications. These three agents are first- and second-line
The initial therapy for borderline hypertension in therapy and can then be used in any combination
diabetes patients (within 10 mmHg of the target to achieve the target.
pressure) is exercise (30 minutes brisk walking Multiple studies, such as the Hypertension
per day) and sodium restriction (<100 mmol or Optimal Treatment (HOT) trial, UKPDS, and the
<2.3 g per day). Weight loss also improves BP, Anti-Hypertensive and Lipid-Lowering Treatment
partly by reducing insulin resistance. to Prevent Heart Attacks Trials (ALLHAT), have
If the BP target which varies with a number of shown that two or more antihypertensive agents
factors including age and recommending agency are usually needed.
has not been reached with these nonpharmaco- For most patients, ACEIs are the initial treatment
logical measures, thiazide diuretics, angiotensin- of choice, assuming the patient can tolerate them.
converting-enzyme inhibitors (ACEIs), The second drug of choice is either a calcium-
angiotensin-receptor blockers (ARBs), beta- channel blocker (based on the ASCOT study) for
blockers, and/or calcium- channel blockers a patient without nephropathy, or a thiazide
should be employed. diuretic (based on the ALLHAT).
Particular care should be taken when initiating Women who are pregnant or might become
therapy in patients aged above 70 years, or if pregnant should avoid ACEI and ARB drugs
there is postural hypotension, hypovolemia, or and start with calcium-channel blockers.
renal impairment. In the ALLHAT, there was no significant differ-
ence in the risk of fatal coronary heart disease and
nonfatal myocardial infarction between a
thiazide, ACEI, and calcium-channel blocker.
83
An ACEI reduced the risk of microalbuminuria in If ACEIs are indicated but not tolerated, then
type 2 diabetes patients with hypertension and ARBs should be considered.
normoalbuminuria in the Bergamo Nephrologic The commonest reason for withdrawing an
Diabetes Complications Trial (BENEDICT), so it ACEI is a chronic dry cough, which reflects
can be argued that the renoprotective effect angioedema of the bronchus.
makes ACEIs the first choice. With either ACEIs or ARBs, it is recommended
ACEIs are also debatably the initial drug of that serum potassium and creatinine be checked
choice, based on a cardioprotective effect, in 1 week after starting since hyperkalemia and
patients aged over 55 years with type 2 diabetes further renal dysfunction can ensue if con-
and a cardiovascular risk of at least 20% in the comitant renal artery stenosis is present.
next 10 years. Beta-adrenergic blockers and alpha-adrenergic
The Micro-HOPE study demonstrated decreasing blockers are useful as add-on medications to
risk of major vascular events with ramipril in control BP, though the adverse metabolic risk
diabetes patients with a previous cardiovascular with hyperglycemia and dyslipidemia favors the
event. latter and adrenergic blockers are now relegated
577 people with diabetes aged 55 years or in the list of options below calcium-channel
older, with a previous cardiovascular event or blocking agents and thiazides (81). Potassium-
vascular disease
at least one other cardiovascular risk factor, sparing diuretics can also be used at this stage.
Diabetes and
were randomly assigned ramipril (10 mg/ Short-acting calcium-channel blockers should
day) or placebo. The study was stopped after be avoided.
4.5 years.
Ramipril lowered the risk of the combined
primary outcome by 25%, myocardial infarc-
tion by 22%, stroke by 33%, total mortality by 81 Drug therapy for hypertension. Of the six main classes of
24%, and overt nephropathy by 24%. The antihypertension drugs used in diabetes ACEIs are the drug of
cardiovascular benefit of ramipril was greater choice, partly because they tend to give the greatest BP
than that attributable to the decrease in blood reduction and improved cardiovascular outcomes. However,
pressure. there is substantial variation among individuals.
Pharmacological management of
Dyslipidemia adverse lipid profile
Different therapies are available depending on
the nature of the dyslipidemia (82). LIPID ABNORMALITY DRUG
The Collaborative Atorvastatin Diabetes Study
Elevated LDL-cholesterol Statins
(CARDS) showed that statins can reduce the risk Ezetimibe
of a first cardiovascular event (83). Niacin
In type 2 diabetic patients who had no Bile acid sequestrants
previous history of cardiovascular disease Elevated triglycerides Fibrates
but with either hypertension, albuminuria, Fish oils
retinopathy, or were currently smoking, Ezetimibe
atorvastatin 10 mg daily resulted in primary Niacin
prevention of acute coronary events and Low HDL-cholesterol Niacin
stroke. Mean LDL-cholesterol at entry was Fibrates
3.04 mmol/l (117.4 mg/dl) for the atorvastatin
group and 3.02 mmol/l (116.6 mg/dl) for the
placebo group; and at the end of the study 82 Dyslipidemia therapies. Different drugs are used for
these were 2.11 mmol/l (81.5 mg/dl) and different lipid abnormalities.
vascular disease
Atorvastatin Fenofibrate
10 1.2
Placebo Placebo
Cumulative risk (%)
1.0
8
0.8
6
0.6
4
0.4
2 0.2
0 1 2 3 4 0 1 2 3 4 5 6
Years Years
83 Effect of statins. Diabetes patients taking atorvastatin 84 Effect of fibrates. Fenofibrate lowered the long-term risk
demonstrated reduced cardiovascular and mortality risk. of minor amputations for diabetes patients. Adapted from the
Adapted from the CARDS study: Colhoun H et al. FIELD study: Rajamani K et al.
85
If statins and fibrates have to be used concurrent- 85 Lipid-lowering drugs. Very-low-density lipoproteins
ly, fenofibrate is recommended over gemfibrozil (VLDL) are precursors of cholesterol-rich, atherogenic LDL.
because of a lower risk of myopathy and rhabdo- Some drugs target the metabolism of VLDL by affecting
myolysis. This greater risk is because gemfibrozil apolipoprotein expression, some improve the clearance of
interferes with statin glucuronidation. LDL from the circulation, and others increase HDL production.
Other medications such as ezetimibe, niacin, and
bile acid sequestrants play a role when desired Statins
lipid levels are not achieved with statins and
fibrates.
VLDL
The mode of action of statins, fibrates, and other
VLDLR
lipid-lowering drugs is shown in 85. Reduced Increased
cholesterol LDL receptor Increased
synthesis synthesis receptor-mediated
LDL
Smoking uptake of LDL and
VLDL remnants
Stopping smoking reduces the risk of cardio-
vascular disease by up to 70% in nondiabetic
subjects and the same is probably true in patients
with diabetes. Hepatocyte Systemic circulation
vascular disease
All patients of any age should be advised against
Diabetes and
Niacin
smoking. This is especially true in children who
are at greatest risk of starting to smoke. ApoB100 VLDL
HDL
At the annual review smoking habits should be
documented and patients encouraged to stop or Reduced Reduced Reduced
triglyceride VLDL lipolysis to Increased
reduce the numbers of cigarettes. synthesis secretion LDL HDL
Counseling in combination with nicotine supple-
ments is more effective at reducing smoking than VLDL LDL
nicotine supplements alone.
Buproprion or varenicline are alternative
therapies to stop smoking but should be pre-
scribed for short periods, in combination with Fibrates
counseling, and with strict adherence to guide-
HDL
lines, such as avoiding their use in depression.
Apo AI,AII VLDL
Increased
Hyperglycemia HDL e
Increased Decreased nc
Glycemic control can be assessed by measuring ara Decreased
protein protein Cle VLDL and
expression expression
the average blood glucose levels with glycated LDL
(or glycosylated) hemoglobin (HbA1/HbA1c). Apo CIII
Glycation of hemoglobin occurs as a non- LDL
HbA1c provides an index of the average By contrast, tight glycemic control has a marked
blood glucose concentration over the life of effect on the onset of microvascular complica-
the hemoglobin molecule (over a 612-week tions (see p. 78) in both type 1 and type 2
period). The level of HbA1c provides an diabetes patients. However, only 11% of the
index of hyperglycemia, and thus diabetes variation in microvascular complication risk is
control, over that period. attributable to HbA1c change.
The figure will be misleading if the lifespan of In the UK, NICE recommends the initiation of
the red cell changes, either due to altered red therapy with lifestyle intervention and then with
cell survival, as in renal failure, or an metformin. Should the HbA1c rise above 6.5%
abnormal hemoglobin, as in thalassemia. (48 mmol/mol) then a sulfonylurea or a glinide
Recently, HbA1c estimations have been standard- may be prescribed (for those with a nonroutine
ized and the improved accuracy, allied to the lifestyle). NICE recommend considering a thiazo-
poor reproducibility of oral glucose tolerance lidinedione (TZD) if the side-effects of sulfonyl-
tests, has led to suggestions that HbA1c could be ureas are unacceptable.
used as a screening test to alert physicians to the Should the HbA1c rise above 7.5% (58
possibility of diabetes. mmol/mol) then NICE recommend the
In broad terms, HbA1c levels >6.5% addition of TZDs or insulin or exenatide (if
vascular disease
diabetic microvascular disease (retinopathy), The stepwise increase in drug therapy is a topic
while lower levels, even into the normal of debate in academic circles, while the lack of
range, are associated with an increased risk of mention of DPP-4 inhibitors or the GLP-1 analog
macrovascular disease. liraglutide (as an alternative to exenatide) reflects
ADA guidelines aim for HbA1c <7.0% the inevitable delay in producing guidelines that
(53 mmol/mol) (nonpregnant adults). include current agents.
UK NICE guidelines aim for HbA1c <6.5% Exenatide has now been studied for use
(48 mmol/mol) initially; later with increasing in combination with insulin glargine, and
disease duration and more drugs aim less liraglutide with insulin glargine and insulin
low, i.e. <7.5% (58 mmol/mol). detemir.
Glycated plasma proteins (fructosamine) can also
be measured as an index of control and relate to a Antithrombotic agents
shorter period of diabetes control (23 weeks). Statins and aspirin are currently recommended
This can be of value in patients with a hemo- for all diabetes patients aged >40 years; some
globinopathy or in pregnancy (when hemo- physicians prefer to individualize cardiovascular
globin turnover is changeable) and other disease risk, starting statins when this is in excess
situations that require rapid changes of of 20% over 10 years.
treatment. Following recent studies, the case for aspirin
Strict glycemic control did not reduce macro- in those under 65 years of age without cardio-
vascular complications in the UKPDS by a statisti- vascular disease is much less clear. The UK NICE
cally significant degree in the first 15 years, but guidelines point out that aspirin is not licensed for
did so thereafter. primary prevention treatment.
A recent finding in type 1 diabetic patients The balance of benefit must be set against the risk
followed from the original DCCT showed that of hemorrhage when on aspirin, and both will
tight glycemic control resulted in less cardio- vary for different individuals with diabetes.
vascular disease (i.e. nonfatal myocardial
infarction, stroke, death from cardiovascular
disease, confirmed angina, or the need for
coronary artery revascularization), compared
to conventional treatment.
87
CHAPTER 7
ULCER
Absent Absent
Present (1) Present (1)
ANKLE REFLEXES
Present Present
Total /8 /8
89
88 Neuropathy screening. Foot examination for sensation in 89 Microfilament testing. The SemmesWeinstein mono-
a diabetic patient using a microfilament. A thorough annual filament test is performed at 10 sites on the foot.The filament
foot examination by a health care professional is recommend- exerts 10 grams of force when bowed against the skin for one
ed for all diabetes patients. second. Patients who cannot reliably detect this are considered
to have lost protective sensation.
Diabetic neuropathy
Chronic sensory polyneuropathy Unbalanced traction by the long flexor muscles
leads to a characteristic foot, with a high arch and
Diabetic neuropathies are usually sensory and clawed toes.
most commonly bilateral, symmetrical, peripher- This change in turn leads to abnormal
al, and chronic (see 90, next page). pressure distribution, resulting in callus
Chronic symmetrical sensory polyneuropathy formation under the first metatarsal head or
is the most common form. on the tips of the toes and perforating neuro-
Sensory deficits first appear in the distal lower pathic ulceration (see Chapter 8).
extremities. A slowing in nerve conduction is the Neuropathic arthropathy (Charcots joints)
first physiological change, and occurs even may sometimes develop in any joint, but most
before symptoms appear. often affects the ankle or mid-tarsal joints (see
Early clinical signs are impaired vibration sense Chapter 8).
(using a 128-Hz tuning fork), pain sensation
(deep before superficial), paresthesias, and tem-
perature sensation in the feet.
At later stages patients may complain of a
feeling of walking on cotton wool and can
lose their balance when washing the face or
walking in the dark, owing to impaired pro-
prioception.
Involvement of the hands is much less common
and results in a stocking and glove sensory loss.
Complications include unrecognized trauma at Early clinical signs of chronic sensory
pressure points, beginning as blistering due to an polyneuropathy are an impaired sense of vibration,
ill-fitting shoe or a hot water bottle, and leading to pain, and temperature in the feet.
ulceration.
90
Pattern of presentation
Sensory loss + ++ +
Tension reflexes
Prevalence; relationship to glycemia; Common; usually unrelated Relatively rare; onset often
transience to glycemia during hyperglycemia; transient
III, IV,VI
VII
Phrenic
Thoracic
Median
ulnar
Lateral
peroneal
0 0+ ++ ++
+ +++ 0 ++ 0 ++
Diabetic neuropathy
+ +
Relatively rare; onset often Relatively rare; generally unrelated Relatively rare; Relatively rare;
during hyperglycemia to hyperglycemia generally unrelated sometimes related
to hyperglycemia to hyperglycemia;
transient
Isolated cranial nerve palsies are more commonly 90 Clinical patterns. Note that different forms of diabetic
seen in the elderly and are rare in children. neuropathy can coexist in the same patient.
Involvement of the third cranial nerve is the
most common, with characteristic pupillary
sparing, i.e. pupillary reflexes are often
retained owing to sparing of pupillomotor Isolated peripheral nerve palsies are more
fibers. It usually presents with unilateral commonly seen in diabetic than nondiabetic indi-
ophthalmoplegia that spares lateral eye viduals. Lesions are more likely to occur at sites
movement, and pain above or behind the for external pressure palsies or nerve entrapment
eye. However, pain may be absent or mild (e.g. the median nerve in the carpal tunnel).
in half of the cases. Carpal tunnel syndrome is a common cause for
The sixth cranial nerve is also commonly sensory symptoms in the hands in diabetes, and
involved. is twice as common in diabetics than in non-
The fourth and seventh cranial nerves are diabetics.
affected less often and not more frequently Radiculopathy (i.e. involvement of a spinal root)
than in nondiabetic patients. may occur. Thoracic radiculopathy presents as
Full spontaneous recovery is the rule for most dermatomal pain and loss of sensation.
episodes of focal cranial nerve involvement, Hypesthesia can occur. Spontaneous resolution
even in the elderly. usually occurs in 624 months.
92
Diabetic amyotrophy is a motor neuropathy Diabetic autonomic neuropathy (DAN) can affect
which is rare and more prevalent in older men. almost every organ system (91). It affects both the
It presents as weight loss, depression, and painful sympathetic and parasympathetic nervous
wasting of the quadriceps muscles. systems and can be disabling.
Depression may be severe and resolves as Asymptomatic autonomic changes can be
the weight increases. demonstrated on laboratory testing in many
The wasting may be marked, causing severe patients, but because of its variable manifestation,
proximal weakness, and knee reflexes may it can escape clinical recognition.
be diminished or absent. The affected area is Patients with severe autonomic neuropathy have
often extremely tender. an increased mortality possibly due to cardio-
Extensor plantar responses sometimes respiratory arrest, especially in those with marked
develop and cerebrospinal fluid (CSF) prolongation of the QTc interval on ECG.
protein content is elevated.
The presentation may be unilateral; the Cardiovascular system
contralateral thigh can be involved immedi- Autonomic neuropathy results in tachycardia at
ately following or months after the initial rest and loss of sinus arrhythmia. Cardiovascular
insult. reflexes including the Valsalva maneuver are
Diabetic amyotrophy is usually associated with impaired.
Diabetic neuropathy
periods of poor glycemic control and may be A fixed heart rate that does not respond to
present at diagnosis. It resolves like an acute exercise should alert one to cardiovascular
sensory neuropathy with the same management autonomic neuropathy.
regimen. Silent ischemia is more common in patients with
Nondiabetic causes for the amyotrophy must be DAN.
excluded, including spinal lesions. Myocardial infarction should be entertained in
diabetic patients with unexplained nausea,
vomiting, or diaphoresis even if there is no chest
pain.
Clinical manifestations of diabetic
autonomic neuropathy DAN is associated with impaired dilation of
coronary arteries and can predispose to
ORGAN SYSTEM MANIFESTATION arrhythmias.
Impaired blood pressure regulation is another
Cardiovascular Postural hypotension, tachycardia,
sudden cardiac death manifestation of DAN.
The normal diurnal blood pressure variation
Gastrointestinal Esophageal dysmotility, gastro- is lost, so that patients have supine hyper-
paresis, diarrhea, constipation,
incontinence tension at night.
Postural hypotension, where there is an
Genitourinary Erectile dysfunction, retrograde orthostatic fall in blood pressure by more
ejaculation, bladder dysfunction
than 30 mmHg, results from loss of sympa-
Neuroendocrine Hypoglycemia unawareness thetic tone to peripheral and splanchnic
arterioles. Patients complain of dizziness,
Sudomotor Dry skin, impaired skin blood flow, feeling faint, blurring of vision, or loss of
gustatory sweating
consciousness.
Pupillary Abnormal reflexes
Diabetic neuropathy
in intractable vomiting. Other milder Blood should be taken for luteinizing
symptoms are early satiety, nausea, bloated- hormone (LH), follicle-stimulating hormone
ness, and abdominal pain. (FSH), testosterone, prolactin, and thyroid
Scintigraphic gastric emptying studies are function.
used to diagnose gastroparesis. Sexual dysfunction is also a feature in women
Diarrhea often occurs at night with urgency and though the management has not yet been
incontinence. Bacterial overgrowth in the determined.
stagnant bowel, pancreatic exocrine insufficien-
cy, malabsorption, and incontinence can lead to Neuroendocrine disturbances
diarrhea and steatorrhea. In patients with longstanding diabetes, there is
loss of the adrenergic symptoms of hypoglycemia
Bladder involvement that usually precede neuroglycopenia. The
DAN can lead to decreased bladder sensation and counter-regulatory responses of glucagon and
reduced voiding frequency. catecholamines are impaired.
This can result in bladder enlargement, Patients have hypoglycemia unawareness, which
bladder stasis, loss of tone and incomplete increases the risk of going into a coma.
emptying (predisposing to infection) with
eventual urinary retention. Sudomotor dysfunction
Patients experience dribbling and urinary Upper body hyperhidrosis and lower body
incontinence. anhidrosis are seen in DAN.
A postvoiding residual of more than 150 ml Gustatory sweating (especially after cheese or
indicates bladder dysfunction and can be wine) is an often unrecognized manifestation.
ascertained by postvoiding catheterization or The dry and cracked skin commonly seen in
postvoiding ultrasonography. diabetes contributes to the development of skin
infection.
Pupillary effects
In DAN, there is decreased pupillary diameter in
dark adaptation that might result in difficulty
during night driving.
94
Diabetic neuropathy
muscle and increase penile blood flow. treatment should erection last for more than
About 60% of patients benefit (92). Side- 3 hours. To treat priapism, insert a large
effects, including headaches and altered butterfly needle into the cavernous tissue and
vision, are not uncommon. If a PDE5 aspirate blood with a large syringe until
inhibitor succeeds it is worth trying without it detumescence has occurred.
after a few months, since sometimes potency Vacuum devices. These provide a non-
will continue unaided after confidence is pharmacological aid. A perspex tube with a
restored. Psychological factors are important seal in the base is placed over the penis and a
and long-acting agents such as tadalafil can vacuum pump draws blood into the penis to
be helpful, as they reduce the need to plan achieve tumescence, which is then main-
precise treatment periods. tained by slipping a rubber band over the
base of the penis (then removing the tube)
until intercourse is complete.
60
40
20
0
Patient Partner
satisfaction satisfaction
96
CHAPTER 8
Infection
The damage resulting from neuropathy, ischemia,
trauma, or all three predisposes to infection.
Infection may be bacterial (in association with
ulcers) or fungal (especially of toe nails).
Pressure
Repetitive pressure, shear from walking and
weight bearing, or inappropriate footwear, leads
to increased plantar pressures, inducing callus
94 Neuropathic foot. Disrupted foot structure associated formation and skin breakdown.
with Charcots arthropathy. Note the distended veins associat-
ed with arteriovenous shunt. Clinical presentation and evaluation
Sensory defect Not necessarily a sensory 0 No open lesions; may have deformity
defect or cellulitis
Subluxed metatarsal heads Foot structure retained 2 Ulcer extension involving ligaments, tendon,
(cocked toes) joint capsule or fascia without abscess or
osteomyelitis
Ulceration of pressure Ulceration at points of
points ischemia, not pressure 3 Deep ulcer or osteomyelitis
95 Evaluating an ulcer in the diabetic foot. Ischemia and 96 Ulcer classification. Systematic evaluation and categoriza-
neuropathy can be difficult to differentiate; a thorough assess- tion of foot ulcers help guide appropriate treatment.The
ment is important. Wagner system is the most commonly used.
99
a b
97 Diabetic foot ulcers. (a) Ischemic
ulcer: digital ischemia is seen in the
second toe. (b) Extensive ischemia
affects all toes back to the level of the
midfoot. (c) A neuropathic lesion at the
base of the fourth toe has been the
point of entry of extensive cellulitis of
the whole foot. (d) Mixed neuro
ischemic lesion affecting the small toe.
Below: neuropathic lesions tend to occur
on plantar surfaces and ischemic ones
over bone prominences.
c d
100 Risk levels. The risk of diabetic foot Assess foot pulses,
The diabetic foot
ulceration are available but there is a paucity of allied to surgical bypass in the distal extremity
evidence relating to their effectiveness. They are may be valuable.
expensive (e.g. hyperbaric oxygen or growth Amputation inevitably changes the biomechanics
factors) and their role is yet to be established. of the limb(s) that remain and will necessitate a
Hydrogel dressings, hyberbaric oxygen review of footwear after recovery from the
therapy, and larval therapy have some procedure.
evidence for efficacy. The effort required to walk with a prosthesis
There is perhaps less evidence for alginate- is high and may be too much for the elderly,
based dressings, platelet-derived growth who are then confined to a wheelchair.
factors, negative pressure wound therapy, The shift in weight can promote ulceration in
dimethyl sulfoxide dressings, and cultured the contralateral limb.
dermis; the latter is like a skin graft but con-
structed from neonatal fibroblasts embedded
in a synthetic matrix.
The key components of ulcer management include Amputation has long-term implications and
avoiding pressure, treating infection, improving should be avoided if possible.
circulation, and promoting healing.
103
Charcots arthropathy
103 Charcots arthropathy. A patient with neuropathic feet 104 Charcots arthropathy. An end-stage Charcots foot
bilaterally; the right foot showing changes of Charcots with previous amputations and a severely distorted foot
arthropathy along its lateral border, with an overlying ulcer. structure with marked callus around a neuropathetic ulcer.
The left foot shows callus formation.
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105
CHAPTER 9
Patients with diabetes are at risk of eye disease Duration of diabetes is one of the best predictors
including: of retinopathy:
Retinopathy. About 5% of patients in the past Patients who have had type 1 diabetes for 5
became blind after 30 years of diabetes, and years or less rarely have evidence of retino-
diabetes is the commonest cause of blindness pathy.
in the population up to 65 years of age. After 510 years of diabetes, close to 30% of
Maculopathy. Increased permeability of the type 1 diabetes patients have retinopathy.
capillaries and microaneurysms in the retina After 2030 years, about 95% of patients have
can result in accumulation of fluid and thick- retinopathy, and 3060% of these progress to
ening in the macular area. sight-threatening proliferative retinopathy
Cataracts. The lens may be affected by (105).
reversible osmotic changes in patients with In type 2 diabetes, 20% of newly diagnosed
acute hyperglycemia, causing blurred vision. patients already have diabetic retinopathy, and
Senile cataracts develop 10 years earlier in most will subsequently develop the condition.
diabetic patients, compared to nondiabetic Without treatment, 50% of patients with prolifera-
subjects. tive retinopathy become blind within 5 years.
Glaucoma. Glaucoma is more prevalent in
diabetes due to new vessel formation in the
iris (rubeosis iridis). Open-angle glaucoma is
not more prevalent in diabetes. Retinopathy is more likely with increasing
Ocular nerve palsies. Ocular palsies of the duration of diabetes.
third and sixth cranial nerves can occur. Like
other causes of mononeuritis, these palsies
are acute and transient, always resolving
within 2 years and usually within 4 months.
100
80
Prevalence (%)
60
40
105 Prevalence of diabetic retinopathy in type 1 diabetes.
Data from the Wisconsin Epidemiologic Study of Diabetic 20 Any retinopathy
Proliferative retinopathy
Retinopathy (WESDR) reported by Klein et al. showed that by
25 years following the onset of the disease, almost all patients
0 5 10 15 20 25 30 35 40 45 50
had developed some sort of retinopathy, with over 50 percent Duration of diabetes (years)
having vision-threatening proliferative retinopathy.
106
Regular dilated eye examinations are recom-
Recommended ophthalmologic
examination mended (106).
Diabetic retinopathy can be classified into non-
TYPE 1 DIABETES proliferative (NPDR) and proliferative (PDR).
NPDR comprises: microaneurysms, dot and
First examination within 35 years after diagnosis of
diabetes once patient is age 10 years or older (since some blot hemorrhages, hard exudates, cotton-
evidence suggests that prepubertal duration of diabetes wool spots, intraretinal microvascular abnor-
may be important in the development of microvascular malities (IRMAs), while venous beading,
complications, use clinical judgment)
neovascularization, vitreous/preretinal
Yearly routine follow-up at the minimum (more frequent if hemorrhages, and traction-induced retinal
abnormal findings) detachment can be found in PDR (107).
TYPE 2 DIABETES
Nonproliferative diabetic
First examination at the time of diagnosis of diabetes retinopathy
Yearly routine follow-up at the minimum (more frequent if
abnormal findings) Diabetic retinopathy is caused by progressive
damage to the blood vessels that supply the
PREGNANCY IN PRE-EXISTING DIABETES retinal tissues (108, 109). Early changes are
First examination prior to conception, then during first detectable by fluorescein angiography (110).
trimester Hyperglycemia leads to tissue hypoxia and
reduced retinal function.
Follow-up is at physician discretion pending results of first- Leucocyte adhesion to the capillary wall
trimester examination
results in occlusion and reduced blood flow,
RETINOPATHY AND MACULAR EDEMA and ultimately greater hypoxia and ischemia.
Capillary nonperfusion can also cause com-
Ophthalmology referral in patients with macular edema,
severe NPDR, or any form of PDR pensatory dilation and microaneurysms in
other vessels.
Diabetic eye disease
Moderate Hemorrhages or microaneurysms (H/Ma) High-risk New vessels on the disc (NVD) of
Soft exudates, venous beading (VB) and >25% of the disc area OR
IRMAs definitely present Any NVD and vitreous or preretinal
hemorrhage
Severe H/Ma in all 4 quadrants
VB in 2 or more quadrants
IRMA in at least 1 quadrant
107
Basement
membrane
Endothelial
cell
Pericyte 1 2 3 4
Leukocyte
111 Vitreous hemorrhage. If vitreous hemorrhage is associ- 112 Maculopathy. Retinal fundus photograph showing
ated with visible neovascularization, this is considered high-risk exudates (black arrow), hemorrhage (yellow arrow), and
PDR and would require panretinal photocoagulation. edema in the area of the macula. Courtesy Rishi P. Singh, Cole
Courtesy Rishi P. Singh, Cole Eye Institute, Cleveland Clinic. Eye Institute, Cleveland Clinic.
In PDR, new blood vessels grow on the retinal Maculopathy is retinal damage concentrated at
surface in response to growth factors released the macula, which can threaten central vision.
Diabetic eye disease
from ischemic areas. These new vessels are It is a particular characteristic of type 2 diabetes.
fragile and bleed easily, so PDR is characterized There are three types of maculopathy:
by neovascularization, vitreous hemorrhage Exudative.
(111), or retinal detachment. Edematous.
The neovascularization often arises from Ischemic.
retinal veins, and may be seen on or near the Of these types, edematous may be difficult to
optic disc (NVD) or elsewhere (NVE). New visualize with direct ophthalmoscopy and
vessels either are superficial on the retina or ischemic is the least responsive to laser therapy.
grow forward into the vitreous. Macular edema (112) is the first feature of macu-
Hemorrhages can be preretinal or vitreous. lopathy and may in itself cause permanent
A vitreous hemorrhage can cause loss of macular damage, if not treated early. It can result
vision. Ophthalmoscopy shows a featureless, in deterioration of visual acuity especially if the
gray haze. Partial recovery of vision is the rule fovea centralis is involved even in the absence
as the blood is reabsorbed, but repeat of significant findings by ophthalmoscopy, since
bleeding may occur. retinal thickening is not easily detected by this
Fibrous proliferation associated with new method.
vessel formation can distort the retina and Diabetic macular edema can be seen in any
the vision. Such changes may give rise to level of diabetic retinopathy.
traction bands that contract, producing retinal It is essential to screen diabetes patients regularly
detachment. for changes in visual acuity.
109
Cataract is characterized by a gradual clouding of Medical treatment to limit diabetic eye disease
the lens; senile cataracts are the most common development or progression involves aggressive
form. Cataracts are 60% more common in diabetic treatment of blood glucose and blood pressure
than in nondiabetic patients. levels.
Cataracts result in reduced visual acuity that In the DCCT, type 1 diabetic patients who were in
cannot be improved by viewing through a pin- the intensive glycemic control group had a 76%
hole. In the early stages they are usually asympto- reduction in the rate of development of any
matic, but if left untreated can cause blindness. retinopathy in those who did not have retino-
Myotonic dystrophy and steroid therapy, which pathy at baseline (primary prevention cohort)
are associated with increased risk of diabetes, are and a 54% reduction in progression in those with
in turn associated with cataracts. established retinopathy (secondary intervention
Juvenile or snowflake cataracts are rare (about cohort) compared with the conventional
1%), diffuse, rapidly progressive cataracts associ- treatment group.
ated with very poorly controlled diabetes and The benefit of tight glycemic control has been
amenable to surgery. demonstrated for type 2 diabetes as well.
Posterior subcapsular cataracts are more common In the UKPDS, there was a 21% reduction in
in diabetic than nondiabetic patients. the 1-year rate of progression of retinopathy.
It is thought that with hyperglycemia, glucose in There is currently no specific medical treatment
the aqueous humor enters the lens cells, is for diabetic retinopathy.
converted to sorbitol, and leads to osmotic Based on the Early Treatment Diabetic
swelling. Retinopathy Study (ETDRS), aspirin treatment
does not alter the progression of retinopathy.
Glaucoma Smoking worsens the rate of retinopathy
progression.
Diabetic maculopathy
Patients should be referred to a specialist if there
is an unexplained change in visual acuity or hard
exudates within two disc diameters of visual
fixation.
Patients with clinically significant macular edema
may benefit from focal laser photocoagulation.
The use of the anti-VEGF agents pegaptanib
(Macugen) or bevacizumab (Avastin) is
promising, especially for people who present
late or in whom laser treatment has failed.
Cataracts
In the UKPDS, intensive glycemic control was
associated with a 34% reduction in cataract
113 Laser treatment. Retinal fundus photograph of laser extraction compared to conventional treatment.
photocoagulation for proliferative diabetic retinopathy. The patient should be referred to a specialist for
Courtesy Rishi P. Singh, Cole Eye Institute, Cleveland Clinic. cataract removal when loss of vision interferes
with their daily life.
Cataract surgery with intraocular lens implanta-
All patients with retinopathy should be examined tion is successful 9095% of the time in restoring
regularly by a diabetologist or ophthalmologist. vision.
The ophthalmologist may perform fluorescein Patients should be carefully selected since there
angiography to define the extent of the problem. are potential complications in diabetic patients.
Early referral is essential in the following circum- After cataract surgery in diabetic patients,
stances: there is an increased incidence of neovascu-
Diabetic eye disease
CHAPTER 10
Overview Glomerular
capillary
The kidney can be damaged by diabetes in three Urine
main ways: Protein
Glomerular damage. Red blood cell
Ischemia resulting from hypertrophy of
afferent and efferent arterioles.
Ascending infection.
Clinically significant nephropathy usually
appears between 15 and 25 years after diagnosis Epithelial cell
and rarely develops >30 years from diagnosis. Glomerular
basement membrane
Nephropathy affects 2535% of patients
Endothelial cell
diagnosed under the age of 30, but recent data
suggests this percentage is falling. It is the main
cause of renal failure in Europe, accounting for 114 Proteinuria. Thickening of the basement membrane is
more than 30% (40% in the US) of new renal the earliest detectable glomerular change. Damage to this
replacement therapy. membrane and adjacent capillary wall cells permits leakage of
Some ethnic groups, such as Native proteins into the urine.
Americans, African-Americans, and South
Asians are at particular risk.
Patients with type 2 diabetes develop nephro-
pathy less frequently than those with type 1
diabetes, however more than 80% of patients Natural history
who do need renal replacement in the US have
type 2 diabetes, since this is much more prevalent The progression of diabetic nephropathy towards
than type 1. end-stage renal failure proceeds through five
Both proteinuria and diabetic nephropathy are stages.
associated with an increased risk of developing Stage 1: Functional changes.
macrovascular disease. Stage 2: Structural changes.
There is a strong genetic effect predisposing to Stage 3: Microalbuminuria.
nephropathy. Stage 4: Overt clinical nephropathy.
Stage 5: End-stage renal disease.
After initial microalbuminuria, intraglomerular
pressure is raised and finally, frank proteinuria
develops with renal dysfunction (114).
Proteinuria is a marker of cardiovascular risk. Diabetic nephropathy does not become sympto-
matic until renal dysfunction is severe.
112
basement membrane (GBM) and increases pore sizes.This sample or more practically as an albumin/
consequently enables passage of plasma proteins, such as creatinine ratio from the first-voided urine
albumin and IgG, which is normally restricted. sample (117).
ve charge
GBM
Urinary space
uria is the hallmark of diabetic nephropathy; detection of Untreated infections in diabetic patients can lead
hematuria suggests a different cause, such as menstruation, to renal papillary necrosis, a rare condition in
urinary tract infection, or vasculitis. which renal papillae are shed in the urine. It
should be suspected in patients who have fever,
120 Differential diagnosis. There is a range of differentiating flank pain, poor response to antibiotics, and
tests to exclude nondiabetic kidney disease. rapidly deteriorating renal function.
Albumin/creatinine
ratio 30 mg/g
(23 specimens over
36 months)
General therapy
Look out for macrovascular risk factors Once renal dysfunction has been established
in patients with diabetic renal disease. therapy should include:
Phosphate binders such as calcium
carbonate.
Vitamin D analogs once serum parathyroid
hormone increases.
Erythropoietin once hemoglobin falls
significantly.
Multivitamins.
Antacids such as ranitidine.
116
Conventional therapy
20 Reduction of Endpoints in NIDDM with the
Intensive therapy
Angiotensin II Antagonist Losartan (RENAAL)
15 Trial.
Combining ACEIs with calcium-channel blockers
10 or thiazide diuretics may provide superior blood
pressure control.
5 Loop diuretics are used in preference to thiazides
once nephropathy is established, usually around
0 Microalbuminuria Overt proteinuria a serum creatinine of 160 mol/l (1.8 mg/dl).
Combination therapy is usually required to
achieve the blood pressure target.
123 Nephropathy event rates. The DCCT showed that
stringent glycemic control dramatically reduced the risk of
developing diabetic nephropathy.
117
g g
m m
10
15
20
25
30
124 Blood pressure measurement. Control of hypertension 125 Irbesartan in patients with diabetes and micro-
reduces the rate of progession to renal failure. albuminuria. The IRMA-2 study showed that patients receiving
daily irbesartan were significantly less likely to develop diabetic
nephropathy than those in the placebo group.
Beta-adrenoreceptor blockers should be consid- Mortality in patients with ESRD is usually cardio-
ered in all patients with coronary artery disease vascular in nature.
and in patients after a myocardial infarction, since Treatment with statins at high dose (or less
these agents improve survival. commonly and debatably statins with fibrates) is
The beta-blocker atenolol reduced micro- often needed to achieve targets: LDL-cholesterol
vascular complications in diabetic patients in <2.59 mmol/l (100 mg/dl), triglycerides <1.7
the UKPDS. mmol/l (150 mg/dl) and HDL-cholesterol to 1.17
However, beta-blockers are third-line mmol/l (45 mg/dl).
treatment in the management of hyper- The risk of myositis is increased in renal impair-
tension in diabetes certainly for type 2 ment when cyclosporins plus statins or fibrates
Hemodialysis
Hemodialysis is the renal replacement used in
80% of diabetic patients with ESRD in the US.
Hemodialysis requires vascular access, usually an
Diabetic kidney disease
60
Deceased ECD
6
Living donor
40
4
20
2
0
ar ar ar ar ar ar
ye ye ye ye ye ye
1 5 1 5 1 5 1991 1993 1995 1997 1999 2001 2003 2005
Follow-up time Calendar year
127 Transplant survival. Five-year survival (20022007) 128 Transplant failure rates. These have gradually improved.
of both patient and graft was clearly better for recipients of In the USA, by 2006 there were 6.9 graft failures (including
living-donor organs than for those of deceased-donor organs. death with function) per 100 patient-years with a functioning
ECD = expanded criteria donor (i.e. higher failure risk); transplant.
non-ECD = nonexpanded criteria donor.
CHAPTER 11
Amino acids
exceed the renal threshold. Hyperglycemia
Severe diabetic
Insulin deficiency
Cellular dehydration
DKA is fatal if untreated.
Volume depletion
metabolic disturbances
Hypotension Impaired renal function
Severe diabetic
Vomiting exacerbates loss of fluid and electro- As the pH falls below 7.0 ([H+] >100 nmol/l), pH-
lytes. dependent enzyme systems in many cells
The excess ketones are excreted in the urine but function less effectively.
also appear in the breath, producing a distinctive Untreated DKA is invariably fatal.
smell similar to that of acetone. In tertiary centers, the mortality rate is <5%.
Respiratory compensation for the acidosis leads The highest mortality occurs in patients aged
to hyperventilation, described as air hunger. 75 years or older.
Progressive dehydration impairs renal excretion In children, cerebral edema is a complication
of hydrogen ions and ketones, which are that increases the risk of mortality.
retained, aggravating the acidosis. Coma as a presenting sign also carries a high
risk of mortality.
124
It is important to differentiate DKA from other Other electrolyte disorders such as hyponatremia, hyper-
Severe diabetic
Other causes of high anion gap acidosis are If initial serum K+ is 5.0 mmol/l (mEq/l),
usually easy to distinguish from DKA, but should replacement is not given and K+ levels are
be kept in mind if the presentation is not straight- checked every 2 hr.
forward. When K+ is in the normal range (3.55.0
Salicylate poisoning can be tested by plasma mmol/l [mEq/l]), 2030 mmol/l [mEq] K+ is
salicylate levels in the toxic range. given in each liter of intravenous fluid.
Ethylene glycol or methanol poisoning is If K+ is less than 3.3 mmol/l (mEq/l), insulin is
suspected if there is an osmolal gap, i.e. the withheld until K+ is above 3.5 mmol/l (mEq/l)
measured plasma osmolality is greater than and K+ is given at 40 mmol/l/hr (mEq/l/hr).
the calculated plasma osmolality. Acidbase balance. Both fluid replacement and
Alcoholic acidosis and starvation acidosis insulin therapy will usually restore acidbase
also present with increased anion gap. imbalance.
Administration of bicarbonate is controversial
Acute management and seldom necessary and is only considered
The principles of management in adult patients if the pH is below 7.0 ([H+] >100 nmol/l); if
are given below. Children will require different given, bicarbonate is best administered as an
proportions and volumes. isotonic (1.35%) solution, if available.
Fluid. Fluid replacement must be started immedi- Prospective studies have not shown either a
ately. benefit or an increased morbidity or mortality
Normal saline is given at an initial rate of in patients where pH is 6.97.1. Below a pH
1 l/hr, or 1520 ml/kg/hr for the first 12 hr. of 7.0, even in the absence of solid data, it
Careful monitoring should be done when seems reasonable to administer bicarbonate
treating patients at risk of cardiovascular since severe acidosis can also lead to vascular
disease and cardiac or renal dysfunction. derangements.
Thereafter, fluids can be reduced to 414 Successful management of DKA depends upon
ml/kg/hr using normal saline or (contro- fluid resuscitation, insulin therapy, and correcting
versially) 0.45% saline depending on the metabolic acidosis and electrolyte imbalances.
patients sodium level and state of hydration. Frequent monitoring of these parameters is
Insulin deficiency. An initial dose of regular necessary (135). A treatment algorithm (136) is
insulin, 0.15 U/kg, can be given as an intravenous given overleaf.
bolus. Afterwards, regular insulin intravenous
infusion is given at 510 U/hr or at 0.1 U/kg/hr.
metabolic disturbances
This lowers blood glucose by suppressing
Severe diabetic
hepatic glucose output.
Regular insulin, 50 U, can be added to 500 ml
Initial monitoring interval for DKA
of normal saline to make a 1:10 concentra- parameters
tion. Some of the solution is then flushed to
prime the tubing. Vital signs and mental status Every hour
In some instances, the intramuscular route
can be used at an initial dose of 0.5 U/kg, Glucose Every hour
then hourly at a dose of 0.1 U/kg/hr. Potassium Every 2 hours
The subcutaneous route is usually avoided
because subcutaneous blood flow is reduced Other electrolytes, Every 4 hours
blood urea nitrogen (BUN),
in shocked patients and insulin action is creatinine
slower.
Electrolytes. Potassium levels must be monitored
both with blood tests and by ECG.
Although there is a total body potassium 135 Monitoring. Regular, frequent monitoring is required to
deficit, initially potassium in the blood may assess progress and avoid complications.
be high.
126
DIABETIC
KETOACIDOSIS
If serum K+
level is <3.3
Give IV insulin mmol/l, withhold Rarely used
Determine infusion insulin and give After 1 hr
hydration status (0.1 U/kg/hr) K+ (40 mmol/l of hydration,
IV) until >3.5 check pH
mmol/l
If serum K+ Repeat
High Na+ Normal Na+ Low Na+ level is 3.35.0 NaHCO3 every
metabolic disturbances
136 Treatment algorithm for DKA in adults. The corner- Subsequent management
stones of acute management are fluid resuscitation, insulin Once glucose reaches 13 mmol/l (235 mg/dl), the
therapy, correction of metabolic acidosis and electrolyte infusion is changed to 5% dextrose in 0.45% NaCl
abnormalities, as well as treatment of precipitating factors. at 150250 ml/hr until acidosis is corrected. The
addition of dextrose allows continued infusion of
insulin without hypoglycemia, since it takes
longer to clear the acidosis than to lower the
blood glucose.
When the acidosis has been corrected, insulin is
then given through the subcutaneous route.
Seek the underlying cause. Physical examination, The intravenous insulin infusion is turned off
chest radiography, and urine tests may reveal a 24 hours after the first subcutaneous dose of
source of infection. insulin is given, depending on the kind of
As fever may be absent even in the presence subcutaneous insulin used. The insulin
of infection, and polymorpholeukocytosis infusion is not discontinued right away since
can be present even in the absence of the half-life of intravenous insulin is just a few
infection, a search for other causes can be minutes.
directed by the patients clinical features. Once the patient is able to eat, the dextrose
For example, a 65-year-old male with hyper- infusion can be taken down.
tension and positive smoking history would One subcutaneous insulin regimen that closely
lead you to obtain an ECG to exclude a silent mimics the physiological secretion of insulin by
myocardial infarction, which can present the pancreas is the administration of long-acting
with ketoacidosis. insulin such as glargine once a day (occasionally
Other problems. These can include: even twice daily) or detemir, with rapid-acting
Altered sensorium. For patients in coma, insulin such as lispro or aspart or glulisine before
the insertion of a nasogastric tube can help meals.
reduce the risk of aspiration pneumonia. The total daily dose of subcutaneous insulin can
Hypotension. Intravenous fluid resuscitation be determined in three ways. Using a combina-
should be administered. If hypotension tion of these methods is helpful to make sure an
continues, plasma expanders or whole blood appropriate dose is arrived at:
may be considered, as well as insertion of a Estimation of the dose required via the intra-
central venous pressure line. venous insulin infusion (calculate require-
metabolic disturbances
Hypothermia. Mortality rate is high, about ments from the past 6 or 8 hours and multiply
Severe diabetic
3060%, in patients with DKA and hypo- by 4 or 3, respectively, to come up with a 24-
thermia. hour dose).
Cerebral edema. This is most often seen in Basing it on total body weight. 0.3 U/kg/day
children and adolescents. The cause is is usually a good dose for newly diagnosed
thought to be very rapid correction of hyper- diabetics; the dose increases if the duration of
glycemia and the use of excessive hypotonic diabetes is longer, or if the patient has
fluids. Though rare, it can be fatal. features of insulin resistance.
Deep venous thrombosis can be prevented Basing it on home insulin doses and adjusting
by prophylactic measures such as subcuta- for degree of control prior to the episode of
neous heparin. DKA.
Complications of therapy. With excess insulin
infusion, hypoglycemia and hypokalemia can
develop, hence the need for close monitoring
of these parameters. Excess fluid replacement
can cause cardiac dysfunction; in patients Monitoring of glucose, potassium, and fluid levels is
with cardiac compromise, monitoring of essential in order to avoid complications of therapy.
central venous pressure is recommended.
128
diabetes
diabetes
Type 1
Type 2
Insulin deficiency
DKA by an absence of ketoacidosis and a higher degree of
hyperglycemia. It is further characterized by high osmolality
and dehydration. HONK will often present in a patient with
previously undiagnosed type 2 diabetes.
Increased lipolysis Severe hyperglycemia
(plasma glucose >33 mmol/l)
metabolic disturbances
osmolality.
Severe diabetic
Abdominal complaints such as nausea and Complications
vomiting are not as common as in DKA. Vascular occlusions are important complications
On examination, patients have poor skin turgor, of HONK.
hypotension, and tachycardia. Kussmaul Arterial thrombosis is said to cause one third
breathing is uncommon. of the deaths in diabetic coma. Arterial throm-
bosis leads to cerebrovascular accidents,
Investigations myocardial infarction, or arterial insufficiency
Serum osmolality is usually greater than 320 in the lower limbs.
mmol/l (mOsm/kg), and glucose greater than Mesenteric artery occlusion and disseminated
33 mmol/l (600 mg/dl). Serum osmolality is intravascular coagulation may also occur.
measured as:
2 [Na + K (in mmol/l or mEq/l)] + blood glucose
(divided by 1 when using mmol/l, or by 18 when
using glucose in mg/dl).
Monitoring of serum osmolality and electrolytes is Patients with HONK are particularly prone to
key to management, and should be checked arterial thrombosis.
every 24 hours.
130
It has been said that there is no such thing as It is important to know that lactic acidosis was
brittle diabetes only brittle diabetics. associated with the biguanide phenformin in the
Once underlying causes and improvements in past, and can occur with the use of the biguanide
management have been implemented attention metformin. Though the risk of developing lactic
should focus on psychosocial issues. acidosis with the use of metformin is low, the
mortality rate is about 45%.
Symptoms of lactic acidosis include anorexia,
nausea, vomiting, and lethargy.
Predisposing factors in the setting of metformin
use include renal dysfunction and liver disease.
The use of bicarbonate for treatment is contro-
versial, and management is mainly through
hemodialysis.
A combination of chaotic food intake
and insulin omission is the primary cause of
recurrent ketoacidosis.
131
CHAPTER 12
Step 2 Step 3
Lifestyle + metformin Lifestyle + metformin
+ basal insulin + intensive insulin
Step 1
At diagnosis:
Lifestyle + metformin
Lifestyle + metformin
+ pioglitazone Lifestyle + metformin
No hypoglycemia; edema; + pioglitazone
CHF; bone loss + sulfonylurea
80
CSII Targets of treatment
MDI
OHA
Patients in remission (%)
40
levels and these targets will vary with age,
diabetes duration, and complication risk,
20
including risk of hypoglycemia.
The younger the patient, the lower the
0
HbA1c; the older the patient, the higher the
90 180 270 360
HbA1c (except for those under 12 years of
Days in remission
age when recommended levels are <8.0%
[64 mmol/mol] or when under 6 years of age
140 Intensive insulin therapy. A trial to compare the effects <8.5% [69 mmol/mol]).
of continuous subcutaneous insulin infusion (CSII) or multiple Self-monitored blood glucose (SMBG) can
daily insulin injections (MDI) with oral hypoglycemic agents improve glycemic control, particularly if it
(OHA) demonstrated that intensive insulin therapy in patients forms part of a program of patient education
with newly diagnosed type 2 diabetes improves -cell function and staff training that promotes management
and remission rates compared with treatment with oral hypo- adjustments according to the ensuing blood
glycemic agents. Adapted from Weng J et al, 2008. glucose values (143).
Dietary management
This suggests that, unless there is a specific
contraindication, oral antihyperglycemic The incidence of type 2 diabetes has risen in
therapy with metformin should be initiated, parallel with a massive increase in obesity, and it
in most cases, along with lifestyle modifica- is clear that the two are causally linked.
tion, as soon as diabetes has been diagnosed. Obesity greatly increases the likelihood that a
The rationale for this is that lifestyle modifica- susceptible individual will develop diabetes,
tion essentially diet and exercise on its and failure to address the problem once
own will inevitably be insufficient. diabetes has been diagnosed hampers
This issue is bound to remain under constant attempts to achieve glycemic control.
scrutiny as a less didactic, more personalized The main dietary issue in type 2 diabetes is that of
approach is widely employed. excessive calorie intake. This problem is also
For example, a recent randomized trial of becoming more prevalent in type 1 diabetes.
Long-term management
temporary intensive insulin therapy versus Despite the fact that diet has long been recog-
of hyperglycemia
the more traditional oral therapy at the onset nized as an important issue in both type 1 and
of type 2 diabetes showed that both type 2 diabetes, little of the dietary advice given to
approaches will induce relatively normal patients, other than the proven benefit of calorie
blood glucose levels in the majority of restriction, is truly evidence-based. It is important
patients, but the former appears to give a to observe that:
more sustained improvement in -cell Long-term adherence to any dietary plan is
function and normoglycemia (140). notoriously difficult, and this is a major
stumbling block both in performing the
appropriate studies and in applying the
results of short-term studies.
Dietary advice to patients with diabetes is
Long-term adherence to any diet plan is largely empirical and owes much to the
notoriously difficult. consensus views of nutritional experts and
to prevailing fashions.
133
Therapeutic targets
141 Therapeutic targets. These should be agreed between
Weight Body mass index <25 the patient and the healthcare team.
Waist:hip ratio men <0.95; women <0.8
Glucose HbA1c <7.0% (53 mmol/mol) It seems reasonable to suggest that the diet of a
(but depends on age, diabetes duration,
complication risk) diabetic patient should, in principle, be no
different from that considered healthy for the
Lipid profile Cholesterol <4.0 mmol/l (155 mg/dl) population as a whole, perhaps with special
LDL cholesterol <2.6 mmol/l
(100 mg/dl) (lower if overt vascular emphasis on the avoidance of refined sugar.
disease i.e. <2.0 mmol/l [70 mg/dl]) Diet and exercise should be regarded as the
Triglycerides <1.7 mmol/l (150 mg/dl) cornerstone of treatment for type 2 diabetes.
Blood pressure 130/80 mmHg (but depends on age,
diabetes duration, complication risk) Calorie intake
Smoking Nil Calorie intake should be tailored to individual
patients, taking into account their weight at the
time they come to medical attention.
At diagnosis, type 1 diabetic patients will
typically have lost weight and are likely to be
below ideal body weight.
Patients with type 2 diabetes will likely have
had weight gain for several years, but then
start losing weight in the weeks to months
leading up to the diagnosis of diabetes; most
remain overweight, sometimes substantially
so, when diabetes is diagnosed.
Those patients with latent autoimmune
diabetes of adults (LADA), who are initially
misdiagnosed as having type 2 diabetes
(about 812% of newly diagnosed adult
142 A large BP cuff, suitable for obese patients. Blood patients), will generally have had more
pressure levels are one of the clinical parameters which are weight loss and been more symptomatic than
used to monitor the effectiveness of diabetes management. true type 2 patients. However, the overlap
between the two groups in respect of these
features is considerable.
Long-term management
A reasonable goal is to try to achieve and
of hyperglycemia
Plasma glucose goals for SMBG
maintain a weight close to ideal body weight.
While there are usually advantages to a slow and
AACE and IDF
Fasting <110 mg/dl (6.1 mmol/l) steady approach to weight loss, others advocate
using a newly diagnosed patients high motiva-
2-hour postprandial <140 mg/dl (7.8 mmol/l)
tion to aim for more rapid loss.
ADA and EASD When considering a dietary strategy that will help
Preprandial 70130 mg/dl (3.97.2 mmol/l) achieve this it is useful to think in terms of overall
calorie intake, and composition of the diet in
12 hour peak <180 mg/dl (10 mmol/l)
postprandial terms of carbohydrate, protein, and fat content.
Fats
0 Prescribing a diet
Diet recommendations
Conventional wisdom has it that saturated fatty
acids should be restricted to less than 10% of the No refined sugar
total daily energy intake.
Foods that should be restricted but not elimi- Avoid diabetic foods
nated include dairy produce, chocolate, ice Small frequent meals
creams, shellfish including prawns, the fat
around meat especially pork and lamb, fried Reduce calorie intake
foods, coconut oil, avocado, and alcohol.
Encourage complex, high-fiber carbohydrates
The whole issue of fat content of the diet has
captured the public imagination over the last few Limit fat intake: saturated fats <10% of total energy intake
years through advocacy of diet plans such as the
Encourage monounsaturated fats (olive oil, rapeseed oil)
Atkins diet or the South Beach diet. These, and
other diets that have a relatively high fat content, Cholesterol <250 mg/day (less if dyslipidemia)
run counter to the prevailing conventional
Limit salt intake: <2.3 g per day
wisdom that a diet high in carbohydrates is most
appropriate for people with diabetes. Advocates Limit alcohol intake: men <28 units/week; women <21
of higher-fat diets would say that a greater fat units/week
content is associated with increased satiety and,
Long-term management
therefore, improved adherence to the diet with
of hyperglycemia
more successful weight reduction.
It is only quite recently that controlled studies
Fat 30%
have been performed to compare the relative
merits of these different approaches; in patients Carbohydrate 55%
CONTRAINDICATIONS
CAUTIONS
After 16 weeks
Insulin-stimulated
BLOOD EXERCISE
glucose disposal
8
GLUCOSE LEVEL CONDITIONS
6
Decreases Hyperinsulinemia exists during
4 exercise
Exercise is intensive or prolonged
2 (>3060 min in duration)
<3 h have elapsed since the
0 preceding meal
Diet Exercise Diet and
exercise No extra snacks are taken before
or during the exercise
Long-term management
150 Exercise and insulin sensitivity. A study of 25 non- Generally remains Plasma insulin concentration is
of hyperglycemia
unchanged normal during exercise
diabetic obese individuals demonstrated greater improvement
Exercise is brief
in insulin sensitivity through diet and exercise combined,
Appropriate snacks are taken
compared with either diet or exercise alone possibly as a before and during exercise
result of improved fatty acid metabolism. Adapted from
Goodpaster BH et al, 2003. Increases Hypoinsulinemia exists during
exercise
Exercise is marked, but not
prolonged
Excessive carbohydrates are taken
before and/or during exercise
Aerobic exercise improves insulin sensitivity and 151 Glycemic response. The glycemic response to exercise
reduces cardiovascular risk. in people with type 1 diabetes varies between individuals and
according to the intensity and duration of the exercise.
138
152 Types of bariatric surgery. Illustrated are the lapara- Bariatric surgery may be considered for adults who
scopic band (a), sleeve gastrectomy (b), jejunoileal bypass (c), have exhausted other methods of weight control.
and Roux-en-Y gastric bypass (d).
139
CHAPTER 13
Drugs
153 Effect of intensive blood-glucose control with 7
Conventional
metformin. The UKPDS group trial found that metformin Glibenclamide
appeared to decrease the risk of diabetes-related endpoints Chlorpropamide
6 Insulin
and was associated with less weight gain and fewer hypo- Metformin
glycemic attacks than insulin and sulfonylureas (glibenclamide
and chlorpropamide). Intial responses to all agents were similar, 3 6 9 12 15
Time from randomization (years)
but sulfonylureas demonstrated less later benefit.
140
In practice, there can be no strict rules regarding Since type 2 diabetes is characterized by both
the introduction of oral hypoglycemic agents. diminished insulin secretion and increased
Relief of hyperglycemia by any means will insulin resistance it makes sense to target each of
have a temporary beneficial effect on -cell these defects at an early stage, and the most
function and insulin secretion, at least early in common combination currently prescribed is
the course of type 2 diabetes. metformin plus a sulfonylurea. However, this tra-
There may be differences in the degree of ditional paradigm could well change.
HbA1c lowering with the different classes, Inhaled insulin did not prove an attractive option
but most studies show these to be minor. to many patients as an alternative to stimulating
The HbA1c level at the start of treatment is endogenous insulin secretion, and the market
one of the variables determining the likely leader, Exubera, was withdrawn in the US for
magnitude of HbA1c fall; so a drug may be commercial reasons.
able to cause a reduction in HbA1c from 10% These points serve to illustrate how the rapidly
(86 mmol/mol) to 8% (64 mmol/mol), but evolving therapeutic options are complicating
would be unlikely to cause a reduction from treatment paradigms that came into practice more
8% (64 mmol/mol) to 6% (42 mmol/mol). due to what was available than to what was nec-
The preventive effect of any class in relation to essarily best for the patient.
microvascular disease almost certainly depends The challenge facing patients and their medical
on the extent of improvement in glycemia. advisers is to keep pace with their changing
To date, the UKPDS is the only study to needs by whatever combinations of therapy
suggest an advantage of one agent over prove effective and to avoid the clinical inertia
another in terms of reducing the risk of mentioned above. An understanding of the merits
cardiovascular disease, in that metformin- and potential adverse effects of each of the
treated obese patients had fewer cardio- various classes of drugs is therefore essential
vascular events than those randomized to (155).
initial sulfonylurea or insulin treatment.
The UKPDS also confirmed that sulfonylurea
monotherapy, in comparison with diet and
exercise, does not increase cardiovascular
risk.
It is unlikely that any future trials will further
assess this question for monotherapy. 100
-cell function (% of normal)
Oral therapies
Metformin Weight gain not common; might result in Contraindicated in renal dysfunction, acute
weight loss; low risk of hypoglycemia when heart failure, or other conditions that predis-
used alone; inexpensive; may reduce HbA1c pose to lactic acidosis; gastrointestinal side
by1.52% effects are common
Insulin secretagogues: Inexpensive; may reduce HbA1c by 1.52% Hypoglycemia is common; may cause
sulfonylureas weight gain
Insulin secretagogues: Weight gain seems to be less than with Hypoglycemia may occur
nateglinide, repaglinide sulfonylureas
Thiazolidinedione Reduces insulin resistance; low risk of hypo- May cause weight gain and fluid retention;
glycemia when used alone mild anemia; increased risk of limb fracture and
microfracture; contraindicated in heart failure
and in patients with bladder cancer
Alpha-glucosidase inhibitors Weight gain not common Gastrointestinal side-effects are common
DPP-4 inhibitors Low risk of hypoglycemia when given alone Rare cases of angioedema and Stevens
or with metformin or thiazolidinediones; Johnson syndrome have been reported
weight gain not common
Colesevelam Lowers cholesterol and glucose levels Gastrointestinal side-effects are common
(though HbA1c reduction only 0.50.6%
on average)
Injectables
GLP-1 analogs: Weight loss is common Nausea is common at first; possible association
exenatide, liraglutide with pancreatitis; liraglutide contraindicated if
there is a history of medullary thyroid
carcinoma and in patients with multiple
endocrine neoplasia 2
0
20
HbA1c
1 10
0
2
9 13 17 21 25 29 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Weeks of treatment Years
156 Efficacy of metformin. Mean changes in HbA1c in 157 Metformin vs lifestyle intervention. In the DPP study,
treatment-naive noninsulin-dependent diabetes patients the cumulative incidence of diabetes was lower in the
treated with metformin or placebo. Adapted from metformin and lifestyle-intervention groups than in the
DeFronzo RA, et al. placebo group throughout the follow-up period.
Adapted from Knowler WC et al.
As monotherapy it typically reduces HbA1c by The drug did reduce the risk of diabetes
1.52% depending on baseline level, and in being diagnosed by 31% over a 4-year period
patients with type 2 diabetes on insulin treatment when compared with placebo, but was not as
it reduces HbA1c by about 1% (156). effective as a supervised program of lifestyle
Metformin can be used in combination with all change (diet and exercise), which reduced
other diabetic drugs. the likelihood of diabetes by 58% compared
Even obese patients with type 1 diabetes may with placebo.
benefit in terms of reduced HbA1c from using As yet, the prescription of metformin in this
metformin. situation is not generally approved or agreed.
Its doseresponse relationship is linear up to
a dose of 2000 mg per day, usually given as Side-effects
1000 mg morning and evening. The major side-effects are abdominal discomfort,
In Europe (but not in America) doses up to nausea, and diarrhea.
3000 mg per day are sometimes prescribed; These problems are idiosyncratic and often
at levels above 2000 mg per day there is little dose-related; they can be limited by initiating
further hypoglycemic effect, though there therapy at a low dose (500 mg daily), taking
may be an effect on lipids, particularly the drug with food, and then titrating
Noninsulin therapies
SU binding site
ATP ATP
Side-effects
Weight gain may be less than with sulfonylureas
O although full comparative studies are not yet
H available.
NH
As with any drug that stimulates the KATP
Nateglinide channels, hypoglycemia is possible. It was
initially hoped that their rapid onset and shorter
HO O
Noninsulin therapies
CH3
Thiazolidinediones NH
N N S
O
O
The thiazolidinediones (more conveniently Rosiglitazone O
known as glitazones or TZDs) act on the peroxi- CH3
NH
some proliferator-activated receptors (PPARs), CH3 O O S
particularly PPAR-. These nuclear receptors Troglitazone
CH3
regulate DNA expression including genes O
HO O
involved in lipid metabolism (160).
C2H5
Two different heterozygous mutations that CH3
damage the function of PPAR- have been identi- NH
S Pioglitazone
fied in patients with severe insulin resistance, N O
type 2 diabetes, and hypertension at an unusually O
early age. These loss-of-function mutations 161 Chemical structure of TZDs. All the members of
provide genetic evidence that this receptor is this class of drugs are derived from the parent compound
important in the control of insulin sensitivity and thiazolidinedione.
blood pressure.
The precise mechanism by which TZDs increase
insulin sensitivity in the peripheral tissues is
unclear.
It is known that they promote the TZDs (161) were introduced in the late 1990s,
development of mature adipocytes. but troglitazone was withdrawn in the UK in 1997
Subcutaneous fat is increased in comparison and the USA in 2000, due to adverse liver effects.
to visceral adiposity, although whether glita- Rosiglitazone was withdrawn in the UK in 2010
zones actually decrease visceral fat mass is over concerns about its cardiovascular safety;
less clear. in 2011 it was removed from the market in New
Concomitant with these changes there is a Zealand and its use in the USA has been severely
rise in serum adiponectin levels, which are restricted. Pioglitazone is still available.
usually decreased in type 2 diabetes and TZDs improve glycemic control in patients with
insulin resistance compared with the levels insulin resistance when used either as mono-
seen in nondiabetic subjects and the therapy or in combination with other antidiabetic
nonobese. agents in type 2 diabetes.
As monotherapy their glucose-lowering effect is
similar to that of other oral agents. In type 2
diabetes the addition of a glitazone to insulin
treatment can further reduce the HbA1c by about
160 PPARs. These are a group of receptor proteins found in 1%; in this situation particular care should be
the cell nucleus; three types (, , and ) have been identified. exercised because of fluid retention (see below)
PPAR- is linked to type 2 diabetes. and in the UK this combination is not licensed.
Noninsulin therapies
Tissue expression profile Liver, kidney, skeletal muscle, Ubiquitous Adipose tissues, skeletal muscle, heart,
brown adipose tissue liver, kidney, gut, macrophages, vascular
smooth muscle cells (VSMCs)
Isoforms 1, 2
160
20
140
0
2 8 16 26 38 52 12 24 36 48
Weeks of treatment Months on trial
162 TZDs and blood glucose. As monotherapy, the 163 TRIPOD study. Cumulative incidence rates of type 2
TZDs have been shown to reduce fasting plasma glucose diabetes in high-risk Hispanic women randomized to either
levels by around 3.3 mmol/l (60 mg/dl), with a longer-lasting placebo or troglitazone were significantly lower in the troglita-
effect than sulfonylureas. zone group. Adapted from Buchanan TA, et al, 2002.
Mivcrovilli
GLP-1 analogs
1.00
0.90
respectively from the K and L cells of the small
0.80 and large intestines are gut hormones that
enhance insulin secretion in a glucose-dependent
0.70 fashion in response to ingested food (166).
Acarbose GIP and GLP-1 are rapidly (within minutes)
Placebo
0.60 inactivated in vivo by the enzyme DPP-4.
Up to approximately 60% of postprandial insulin
0.50
secretion is due to the incretin effect (167). This
0
00
00
20
40
60
80
10
12
Days after randomization
accounts for the long-established observation that
insulin secretion is greater after ingestion of an
oral glucose load than after intravenous injection
165 Alpha-glucosidase inhibitors. Patients with impaired of an equivalent glucose load.
glucose tolerance assigned to acarbose in the STOP-NIDDM This effect is present, but diminished, in
randomized trial were 25% less likely to develop diabetes patients with type 2 diabetes.
than those on placebo.This effect was noted at 1 year and
continued throught the study. Adapted from Chiasson et al,
2002.
Insulin
signals: G
is due to the incretin effect. n al LP
mo -1
or ,G
H
IP
Neural signals
GUT
167 The incretin effect. Orally administered glucose
has a greater effect on insulin secretion than when it is given Pancreas
intravenously owing to the action of glucose on gut hormones.
Glucagon
IR insulin (nmol/l)
Incretin effect
0.3 0.3
0.2 0.2
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser
Exenatide
Amino acids that
Site of DPP-4 action differ from GLP-1
Amino acids essential
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg for receptor binding
GLP-1
168 GLP-1 analogs. Exenatide is a 39-amino acid peptide, GLP-1 is the best characterized of the incretins,
having 50% homology with human GLP-1. Comparative amino and in addition to enhancing insulin secretion it
acid sequences of exenatide and GLP-1, and the cleavage site suppresses production of the counter-regulatory
of DPP-4 (arrow) are shown. hormone glucagon, delays gastric emptying, and
induces a feeling of greater satiety. The net effect
of these actions is to help limit the extent and
duration of postprandial hyperglycemia.
GLP-1 analogs enhance insulin secretion GLP-1 secretion is decreased in type 2 diabetes,
and help reduce postprandial hyperglycemia. making it potentially a target for therapeutic
intervention.
Exenatide is a synthetic form of exendin-4, a
circulating meal-related peptide isolated original-
ly from the saliva of Heloderma suspectum (the
a Gila monster). It shares slightly more than 50%
Exenatide + sulfonylurea (SU) homology with human GLP-1 and binds to and
8.5
Exenatide + SU + metformin stimulates human GLP-1 receptors in vitro.
Exenatide + metformin Because of the difference at the site of DPP-4
HbA1c (%)
8.0
action, exenatide is not inactivated by the
enzyme, and therefore has a much longer half-life
7.5
than native GLP-1 (168).
Bydureon, a long-acting form of exenatide,
7.0
can be given once weekly and has fewer
initial side-effects.
Week 0 5 10 15 20 25 30 Liraglutide is an acylated form of GLP-1 given
once daily with comparable glucose-lowering
b
effects to exenatide, probably with less nausea.
Change in body weight (kg)
0
Subcutaneous injection of exenatide before meals
1
is associated with enhanced insulin secretion,
2 diminished glucagon secretion, and a decreased
3 postprandial glucose excursion in patients with
Noninsulin therapies
4 type 2 diabetes.
5 Clinical trials of exenatide in patients with
6
type 2 diabetes already treated with
metformin, sulfonylurea, or a combination of
Week 26 52 78 104 130 156 the two, achieved a mean drop in HbA1c of
approximately 1%, dependent on the initial
HbA1c, for example, from 8.5% (69 mmol/
169 Exenatide. In clinical trials, exenatide was effective in mol) to 7.5% (58 mmol/mol) (169).
lowering HbA1c by approximately 1%, when administered Short-term studies also confirm that
with sulfonylurea and/or metformin (a). Over a 3-year period it exenatide is effective in combination with a
was also shown to reduce body weight by around 5 kg (b). TZD, as is liraglutide.
151
12 12
Blood glucose (mmol/l)
10 10
8 8
Exenatide week 26 Insulin glargine week 26
6 6
ng st h h er er am ng st h h er er am
sti kfa nc nc inn inn 0 sti kfa nc nc inn inn 0
Fa rea
relu stlu ed std 3.0 Fa rea
relu stlu ed std 3.0
st-
b P Po Pr Po stb P Po Pr Po
Po Po
Glucose (mmol/l)
10.0
fasting glucose.
7.5
5.0
Placebo
GLP-1
2.5
150
remain on exenatide the weight loss may
continue, at least up to 3 years longer-term
100
data are not yet available.
Injection of exenatide also reduces an elevated
50
fasting glucose.
A randomized study comparing the addition
of exenatide with that of insulin glargine in
patients treated with oral hypoglycemic 20
Glucagon (pmol/l)
9.0
Inactive GLP-1
Placebo
Active DPP-4 8.5
S/100 mg
HbA1c (%)
8.0
M/500 mg
GUT PLASMA
M/1000 mg
7.5
GLP-1 action S/50 mg + M/500 mg
Inhibition of Excretion 7.0
DPP-4 by
k S/50 mg + M/1000 mg
idn
Active GLP-1
eys
Week 6 12 18 24
172 Action of DPP-4 inhibitors. The DPP-4 enzyme rapidly 173 Effectiveness of DPP-4 inhibitors. This 24-week study
inactivates and degrades GLP-1. Gliptins bind to DPP-4, found that a combination of sitagliptin (S) with metformin (M)
allowing the GLP-1 to remain active for longer and enhancing therapy significantly improved glycemic control in type 2
the endogenous incretin effect. diabetes patients. Adapted from Goldstein BJ, et al.
Bromocriptine Side-effects
The quick-release form of bromocriptine Nausea is a common side-effect, especially in the
(Cycloset), a dopamine-D2-receptor agonist, has first few weeks.
been approved by the FDA for the management Pramlintide is contraindicated in patients with
of type 2 diabetes. Though the exact mechanism confirmed gastroparesis and hypoglycemia
of its glucose-lowering effect is not known, unawareness.
several observations are noteworthy:
In patients with type 2 diabetes, it is believed Drugs on the horizon
that there is a decrease in dopaminergic
activity, and an increase in sympathetic Sodiumglucose cotransporter 2 (SGLT2)
activity (with concomitant increase in hepatic inhibitors
glucose output), in the early morning. Plasma glucose is normally filtered in the renal
In obese individuals, there is also an increase glomeruli and then reabsorbed via sodium-
in daytime plasma prolactin levels. dependent glucose cotransporters (SGLTs) in the
With the administration of Cycloset in the proximal tubules, mostly through SGLT type 2.
morning, the elevated prolactin levels are By inhibiting SGLT2, glucose reabsorption is
reduced, possibly reflecting a restoration of decreased, glucosuria is promoted, and plasma
dopaminergic tone, and a reduction in post- glucose levels are decreased.
prandial plasma glucose levels. Dapagliflozin is one such drug in this class. In
Bromocriptine is taken in the morning within two clinical studies, dapagliflozin in doses of 2.510
hours of awakening, with food. The initial dose is mg reduced HbA1c by 0.580.89% when used
0.8 mg per day and can be increased weekly, to a alone, by 0.670.84% when used with metformin,
maximum dose of 4.8 mg per day. and by 0.740.93% when used with insulin.
In these dose ranges and combinations, hypo-
Side-effects glycemia was reported in around 24% of
Bromocriptine may cause hypotension, may patients.
exacerbate psychotic disorders, and may increase In one study, the rate of hypoglycemia was
the risk of hypotension in patients with syncopal 56.6% in patients on insulin plus dapagli-
migraine. There is early evidence that cardio- flozin as compared to 51.8% in patients on
vascular events might be decreased in patients insulin plus placebo.
taking Cycloset compared to placebo. Urinary tract infections are one of the often-cited
concerns for this class of drugs; the frequency has
Pramlintide been reported to be about 57% in the first year,
Amylin is a hormone that is co-secreted with falling thereafter.
insulin by the pancreatic cells (see chapter 4);
it has been found to reduce glucagon levels after
meals, increase satiety, and delay gastric
emptying. It is reduced in patients with type 2
Noninsulin therapies
diabetes.
Pramlintide, an amylin analog, is given as a
premeal subcutaneous injection in patients on
prandial insulin. A reduction in prandial insulin is
recommended in patients with relatively good
control, to avoid hypoglycemia. Weight loss of
about 0.51.4 kg has been seen in studies.
155
CHAPTER 14
Insulin treatment
ate risk
High risk
Moder Ver y
high
ris
risk k
Low
A-chain Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn
B-chain Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Lys Pro Thr Insulin lispro
A-chain Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn
B-chain Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Asp Lys Thr Insulin aspart
A-chain Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn
B-chain Phe Val Lys Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Glu Thr Insulin glulisine
156
A-chain Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Insulin glargine
B-chain Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Arg Arg
A-chain Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn Insulin detemir
B-chain Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Myristic acid
Insulins with prolonged action 175 Insulin analogs. Comparative structures of long-acting
Protamine or zinc can be added to human and insulin analogues showing amino acid substitutions/additions.
animal insulins to promote formation of insulin Detemir differs from human insulin in that the B30 amino acid
crystals, which dissolve slowly after subcuta- threonine is omitted and a 14-carbon fatty acid chain
neous injection. These insulin preparations are myristic acid is attached to lysine at B29.
suspensions rather than solutions, so they are
cloudy in appearance, in contrast to regular/
soluble insulins and analog insulins (e.g. detemir, Insulin detemir is another modified insulin with
glargine), which are clear. less peak action than the older long-acting
NPH (neutral protamine Hagedorn) insulin, insulins. Its prolonged action is due to hexamer
known as isophane insulin, can be premixed with stabilization, hexamerhexamer interaction, and
soluble insulin to form stable mixtures. A range of binding to albumin.
these mixtures is available, but the combination Another very long-acting insulin insulin
of 30% soluble with 70% isophane is the most degludec is soon to be introduced. This forms
widely used. soluble multihexamer assemblies after injection,
Zinc insulins are prepared by precipitation of resulting in an ultra-long action profile, and only
insulin crystals with excess zinc, thus delaying needs to be injected three times a week.
absorption and prolonging duration of action The longer-acting insulins that are suspensions
proportional to the size of the crystals. Since an have to be thoroughly mixed prior to subcuta-
excess of zinc is present in the vial, these insulins neous injection to try and ensure uniform con-
(e.g. lente insulins including Humulin L) cannot centration in the vial. Even so, the intra-patient
be premixed with soluble insulin. variability in duration and strength of action of
Insulin glargine has its structure modified to these insulins from day to day is considerable.
reduce its solubility at physiological pH, thus pro-
longing its duration of action (175). It is injected
as a slightly acidic (pH 4) solution and then pre-
cipitates in the tissues, which have a pH of about
7.4. The precipitates then dissolve slowly from
the injection site, giving the preparation a NPH
virtually peakless action with a duration of Detemir
Plasma insulin level
Insulin action
In contrast, glargine and detemir have a more Alternative insulin delivery systems
consistent action profile, a point commented on There are alternative insulin delivery systems,
by many patients when they switch from one of including experimental routes:
the older insulins. Detemir, and probably Inhaled insulin.
glargine, is associated with less or no weight gain Buccal absorbed insulin.
compared with conventional insulin treatment. Intranasal insulin.
These different insulins can be categorized Implantable insulin pumps to infuse insulin
according to the time profile of their action (177). intravenously or intraperitoneally.
They can also be classified according to The need for injections has long been perceived
whether they can best provide basal coverage as a barrier to insulin treatment in type 2 patients;
(while the patient is in the fasting or post- it is fair to say, also, that most type 1 patients
absorptive state) or prandial coverage (while would welcome the option of insulin treatment
the patient is absorbing nutrients from meals) without injections.
(see p.159). Inhaled insulin. The first inhaled insulin
Funding agencies are concerned about the cost of (Exubera, Pfizer), an inhalation powder of human
insulin analogs. insulin of rDNA origin, was approved for use in
2006 but withdrawn in 2008 due to lack of com-
mercial success.
The time/action profile showed a similar
onset to that of the subcutaneously injected
rapid-acting analogs, but with a duration of
Exubera (8 mg) action more like that of regular insulin (178).
100
Insulin lispro (18 IU sc) The reproducibility of action was similar to
Regular insulin (18 IU sc)
80 those of subcutaneous insulin injections.
Maximal GIR (%)
Insulin treatment
60
40
20
Exubera was well accepted in clinical trials of Insulin spray. An insulin spray (Oral-Lyn,
both type 1 and type 2 diabetes, achieving equiv- Generex) which delivers human insulin for
alent glycemic control when substituted for absorption through the buccal mucous
premeal subcutaneous insulin or oral agents. membrane, but not the lungs, has been approved
Most trial participants expressed a preference for commercial marketing and prescription since
for remaining on inhaled insulin rather than 2005 in various countries (but not Europe or
reverting to their previous regimens. North America).
However, trial participants were often The peak insulin concentration occurs about
patients who specifically disliked injections, 25 minutes after administration, with onset of
so their preference was perhaps predictable. action occurring a little later and peaking at
When this insulin became available for about 45 minutes. There have been no post-
everyday prescription there was a very marketing reports of this buccal insulins
limited take up, leading the manufacturer long-term use.
to withdraw it on commercial grounds. The intranasal route and the implantable pumps
Hypoglycemia has been the most frequent for intraperitoneal/intravenous insulin delivery
adverse event, similar in frequency to that of are still under investigation.
subcutaneous insulin. Other forms of inhaled
insulin are in development. Indications for insulin treatment
Safety is a vital concern. Specific concerns with
inhaled insulin understandably relate to respira- In classical childhood- or adolescent-onset type 1
tory symptoms and pulmonary function. diabetes the need for insulin treatment is clear
Dry mouth, mild cough, and mild to and unequivocal.
moderate dyspnea all occurred more fre- When autoimmune diabetes develops later in life
quently than with comparator treatment in the extent of insulin deficiency is initially less
the clinical trials, but very few patients dis- severe. Patients are commonly misdiagnosed as
continued treatment because of these having type 2 diabetes, but many, though by no
symptoms. means all, progress to insulin treatment.
FEV1 (forced expiratory volume in 1 second) In type 2 diabetes there are no absolutes. There is
decreases by a mean of 11.5% in the first few no a priori reason not to use insulin as an initial
weeks of treatment, but thereafter stabilizes; therapy in type 2 diabetes, but few physicians
it is recommended that all patients should recommend that. Insulin treatment is generally
have assessment of pulmonary function recommended when the other alternatives have
(spirometry) before starting inhaled insulin. failed to achieve adequate glycemic control.
The treatment is not recommended for Many type 2 patients will at some stage
smokers, until they have quit for at least 6 benefit from insulin treatment as a part of
months, or for patients with asthma or their routine treatment.
chronic obstructive pulmonary disease. We have traditionally been too slow in con-
Another potential concern is whether prolonged, fronting the need for insulin in our patients,
repeated exposure of the bronchi and smaller due to a combination of patient anxiety about
airways to insulin would promote the formation insulin treatment and clinical inertia.
of granulomatous or mitotic disease.
It has been reported that a small number of
Insulin treatment
50
To establish an insulin regimen, a typical day can
be considered to comprise periods of basal
insulin production essentially the fasting and 25
postabsorptive states interspersed with bursts of
prandial and postprandial insulin production.
In healthy individuals, with normal glucose
0
tolerance and taking three meals a day, basal
insulin accounts for about 50% of the total. This 8.00 12.00 16.00 20.00 24.00 4.00
Time of day (hr)
will naturally be modified by physical activity and
normal diurnal fluctuations in counter-regulatory
hormone production. Mealtime or prandial
insulin makes up the other 50% of insulin 179 Insulin regimens. The pattern of physiological
secretion. Secretion of insulin in response to basalbolus insulin secretion (top), with peak action at
meals is rapid, with a relatively narrow peak, and mealtimes (arrows), can be mimicked by therapy schedules.
results in absorption of glucose in tissues, with These can use both rapid-acting and longer-acting (NPH)
Insulin treatment
excess glucose being stored as glycogen in the insulin or mixed (rapid/longer-acting) insulin or a single
liver and muscle or converted to lipid. injection of long-acting insulin with rapid-acting insulin at
While it makes sense to mimic this pattern, there mealtimes.
is no rule when it comes to the best regimen,
which should be tailored to suit individual needs
(179).
160
Regimens with multiple injections (180) are more Once the honeymoon period is over, patients
flexible, and the risk of hypoglycemia can be with type 1 diabetes who have a relatively normal
reduced by using long-acting insulin with body weight will typically require a daily insulin
minimal peak action for basal needs and rapid- dose of between 0.5 and 1.0 IU/kg.
acting insulin analogs for mealtime coverage. The precise distribution of the insulin dosages
The closest we can get to mimicking physiologi- will depend on a number of factors.
cal insulin production (apart from pancreas or If the basal coverage is supplied by an insulin like
islet cell transplantation) is with continuous sub- glargine or detemir that effectively has no peak,
cutaneous insulin infusion (CSII) pumps (181). then it is reasonable to apportion approximately
CSII could be suggested for most patients with 50% of the total daily dose to that.
type 1 diabetes, but specific reasons include: For glargine, this can usually be given as a
Poor metabolic control with hyperglycemia. single injection at approximately the same
Poor metabolic control with hypoglycemia. time each day, usually at bedtime, but chosen
Instability of metabolic control with swings to fit in with the individuals lifestyle.
from high to low glucose. In some people particularly adolescents
Patients who have a significant dawn pheno- and young adults with irregular work and
menon (a rise in blood glucose in the early leisure schedules, it may make more sense to
hours) since a pump can deliver insulin at split the glargine insulin dose in two to
different rates or doses at different times of ensure round the clock coverage.
the day. In a small percentage of patients, insulin
For a period (weeks to months) after type 1 glargine may not last the full 24 hours,
diabetes has been diagnosed, there will usually making a split-dose regimen more effective.
be some residual endogenous insulin secretion If the basal component is supplied by a long-
and less intensive insulin regimens may achieve acting insulin that does have a significant peak
excellent glycemic control at that time. such as isophane/NPH then that insulin will
Occasionally, insulin treatment can be tem- make a significant contribution to mealtime
porarily withdrawn and blood glucose levels coverage as well as basal requirements, so that
will remain normal. This remission of proportionately more basal and less prandial
diabetes is popularly referred to as the insulin will comprise the total dose.
honeymoon period and it is important to Insulin detemir probably lies somewhere
emphasize to patients that it is, regrettably, between glargine and isophane/NPH in this
a temporary phenomenon. respect, and both detemir and isophane/NPH
(plus in selected cases glargine) can be given
twice a day when used as basal insulin in
type 1 diabetes.
Common insulin regimens
d b a
181 CSII. In this sensor-augmented system, a sensor (a) 182 CSII. A tubeless, waterproof insulin pump in a patient
attached to a transmitter (b) communicates with the pump with type 1 diabetes.This device ataches directly to the skin via
(c), which delivers insulin via a cannula to the infusion set (d). a cannula and is managed by a wireless pocket computer.
Insulin is fed to the subcutaneous tissue from a Although patients can effectively forget about the
reservoir via a fine flexible catheter that is easily pump so far as basal insulin delivery is
inserted by the patient; this catheter is changed concerned once the settings are in place, the
every 2 or 3 days. same is not true of mealtime insulin boluses.
With careful attention to simple hygiene, and Pumps do not yet have sufficient technological
relocation of the infusion site each time, there sophistication to anticipate and respond to the
are very few problems with infection or other increased insulin needs that accompany eating,
local adverse effects, such as fibrosis or lipo- so the success or failure of pump therapy can rest
hypertrophy. on the individuals preparedness to manage
There is general consensus that a rapid-acting mealtime insulin.
insulin analog rather than soluble human insulin Modern pumps do offer programs that help
works best in the pump. calculate the appropriate dose in relation to
Pumps can be programmed to alter the basal rate the composition of the meal, and the choice
of infusion many times during a 24-hour period: of delivering the mealtime insulin as a single
Some patients find that a single basal rate bolus or a square wave delivery over a
over 24 hours works well. defined period, or a combination of the two.
Many patients do better with basal rates that This aspect of insulin pump therapy still
take account of such things as diurnal requires as much active input from the
changes in counter-regulatory hormones, patient as any insulin injection regimen, and
work patterns, and regular exercise. for this reason it should not be assumed that
The most sophisticated pumps offer the pump treatment will necessarily lead to better
ability to set alternative basal regimens on glucose control.
specific days to accommodate, for example, Several studies confirm that forgetting, or
Insulin treatment
the demands of shift work or change of neglecting, to deliver a mealtime bolus is one
activity at weekends compared to weekdays. of the commonest problems among (particu-
It is rare that basal rates greater than 1 IU/h are larly younger) pump-treated patients.
required, and many patients require considerably
less; this has to be worked out on an individual
basis. Advice from an experienced diabetes
educator and pump trainer can be invaluable.
162
Positive expectations of benefit can outweigh The choice of insulin treatment could, therefore,
reservations about insulin self-injection lie between augmenting basal and mealtime
(extending to needle phobia, hypoglycemia, and insulin levels, or a combination of the two.
weight gain). This was amply demonstrated by Consideration of the typical 24-hour glucose
the relative welcome that many patients gave profile in type 2 diabetes is useful in this respect
when offered a trial of the noninsulin injectable (185).
exenatide because of expectations that it would The major abnormality is that the elevated
promote weight loss. fasting glucose results in the entire glucose
Any insulin treatment brings with it a risk of profile shifting upwards; the postprandial
hypoglycemia, but risk of severe hypoglycemia is glucose excursions are greater in diabetes,
considerably less in patients with type 2 diabetes and increase as the fasting glucose increases.
than in those with type 1 diabetes. The entire area under the profile represents
This may be due partly to increased insulin the integrated glucose, corresponding to
resistance, and regimens that employ supple- HbA1c level; augmenting basal insulin and
mentation of basal insulin in the absence of reducing the fasting glucose towards normal
mealtime dosing are also less likely to cause effectively shifting the whole line
severe hypoglycemia. downwards should lead to a greater overall
Given that hypoglycemia is an unpleasant and reduction in glycemia and HbA1c than
potentially serious adverse effect of insulin, it targeting only the postprandial glucose peaks
makes sense to start with low doses that will be by giving mealtime insulin.
unlikely to cause hypoglycemia, and gradually Fasting and postprandial glucose are not
increase the dose thereafter; this is true whatever independent variables, however, and action
insulin regimen is selected in type 2 diabetes. taken to specifically change the one will have
There are two components to the insulin- a knock-on effect on the other, so either
secretory defect in type 2 diabetes: fasting insulin strategy can be expected to have success, and
and first-phase insulin response. an ideal strategy would be to target both.
Loss of first-phase insulin response to At this stage, patient choice, convenience,
ingested food is, perhaps, the earliest abnor- and economics come into play.
mality, and this defect is apparent in subjects
with fasting glucose levels higher than
normal but not yet at the level of 7 mmol/l
(126 mg/dl) which defines diabetes.
In these individuals, and also those with
recently diagnosed type 2 diabetes, the
fasting serum insulin level often appears
similar to, or even higher than, fasting insulin
levels in normal subjects, as insulin deficien-
Poor control
cy is relative to the higher glucose level and, Good control
in effect, at an early stage there is a defect in 15
Plasma glucose (mmol/l)
Normal
both mealtime as well as basal insulin glucose level
secretion.
10
Insulin treatment
Meals
185 24-hour glucose profile. As plasma glucose falls from
high towards normal levels, so the basal glucose falls and is an 0
9.00 12.00 15.00 18.00 21.00 24.00 3.00 6.00
indicator of glucose control. Adapted from Holman RR and Time of day (hr)
Turner RC, 1981.
165
a b
Fasting glucose (mg/dl)
Glargine 8.5
180
NPH
8.0
HbA1c (%)
160
7.5
140
7.0
120 6.5
4 8 12 16 20 24 4 8 12 16 20 24
Weeks of treatment Weeks of treatment
Basal insulin 186 Basal insulin treatment. Insulin glargine had similar
Isophane or NPH insulin at bedtime has been effects on fasting glucose (a) and HbA1c (b) in the Treat-to-
shown to be an effective means of reducing Target trial. Insulin dosages were titrated upwards on a weekly
fasting glucose and HbA1c in patients treated basis, depending on the fasting glucose level. Adapted from
with metformin or sulfonylurea as oral mono- Riddle MC, Rosenstock J, et al.
therapy, or metformin and sulfonylurea as dual
oral therapy.
The insulin action overnight has the effect of 1.4
Glargine
limiting hepatic glucose output, leading to 1.2
NPH
Events per patient/year
mean HbA1c was just under 7% (53 mmol/ regimens that have failed to achieve a satisfactory
mol), from a starting HbA1c of 8.7% HbA1c is now the most common pathway for the
(72 mmol/mol). introduction of insulin treatment in type 2
diabetes. This typically occurs after the patient
has been on a combination of two or three oral
agents, but it can be applied also when oral
A truly basal insulin has little or no peak action. monotherapy does not result in a satisfactory
HbA1c.
166
The ADA/EASD consensus treatment guidelines There is no single dosage algorithm that is nec-
make the point that insulin is potentially the most essarily better than another. Some studies have
effective next step after monotherapy fails to used 10 IU, or 0.5 IU/kg, or 0.1 IU/kg (young
achieve the goal. children) as a starting dose, with increases made
A single injection each day is easily accepted by weekly on the basis of the mean fasting glucose,
most patients when the potential benefits are while others recommend more frequent dose
explained to them. Administering the first increases, such as an additional single unit every
injection during the course of a routine clinic visit day until the target fasting glucose is being
often convinces even reluctant patients of the achieved fairly consistently. The important thing
ease of the treatment. is for the patient to recognize the need for insulin
With insulin glargine the timing of subse- adjustment and to participate in the process.
quent injections can be selected by the This strategy enables many patients to achieve
patient to fit in best with their daily routine HbA1c levels of <7% (IFCC 53 mmol/mol), but
and preferences. Many choose to give the inevitably some patients will start experiencing
injection first thing in the morning, while hypoglycemia, either nocturnal or daytime,
others prefer dinner time or bedtime; the before the target fasting glucose has been
important thing is consistency from day to achieved.
day. In that case the dose of the basal insulin
With isophane/NPH and insulin detemir should be reduced to eliminate the hypo-
bedtime injection is preferable. glycemia, and additional treatment
Regardless of which particular insulin is selected, mealtime insulin, exenatide or perhaps a
it makes sense to start with a relatively low dose gliptin will be required.
that would not be expected to cause hypo- It should be noted that addition of a gliptin in
glycemia, and then to titrate the dose gradually a patient on basal insulin treatment is not
but steadily, aiming ideally for fasting glucose (yet) approved by the regulatory authorities,
levels persistently in the range of 47 mmol/l but it is quite commonly done in the UK and
(about 70130 mg/dl). US and can be effective.
This needs to be explained and frequently
reinforced to patients, who will often become Mealtime insulin
concerned that the strategy may not be Targeting the postprandial rise in glucose is
working if, after a few weeks of steadily another potential means of improving all-round
increasing insulin dosage, the fasting glucose glycemia.
is still not at goal. Epidemiological studies suggest that postprandial
Because of the insulin resistance in type 2 glucose is a greater determinant of cardiovascular
diabetes the effective dose of basal insulin can risk than fasting glucose, so there is a school of
seem alarmingly high to patients; experience thought that it makes more sense to train our
suggests that patients start to get concerned when guns primarily on postprandial hyperglycemia.
the dose exceeds 3040 IU. The need for several injections per day makes this
It is therefore imperative that patients learn option less attractive as an initial insulin treatment
that there is no predetermined maximum for most type 2 patients, though it can be success-
dose of insulin, and that some patients ful in those who try it.
require much higher doses, sometimes well
Insulin treatment
150
t
im
as
convenient way of trying to provide both basal m
Lu
m inn m
dt 00
kf
90 90 D 90 e .
ea
+ + + B 3
Br
and mealtime insulin supplementation.
The most commonly used fixed ratios are
30/70% soluble and isophane/NPH or
25/75% rapid-acting/NPH. Metabolic instability on insulin
The obvious attraction is the convenience of
having both components in one premixed There are several factors surrounding insulin use
syringe or pen device, and injections are typically that might affect glucose control.
given before breakfast and before the evening Errors in insulin injection technique:
meal. The wrong dose or timing.
A randomized study comparing this approach Air in the syringe.
(using an aspart and isophane/NPH mixture) Poor injection technique.
with once-daily insulin glargine showed this to be Alterations in insulin pharmacokinetics:
successful in terms of reducing HbA1c, and there Injection into the wrong place (e.g. into area
is a particular benefit in lowering the postprandial of lipohypertrophy or intradermal or intra-
glucose after the evening meal (188). muscular injection) (common) (189).
A potential drawback is that this type of
regimen tends to sometimes give more
insulin than needed, with the pre-evening
meal injection heightening the risk of
nocturnal hypoglycemia even in comparison
to bedtime isophane/NPH (see 179).
A defect of the study was that on adding
insulin treatment all patients discontinued
sulfonylurea, while continuing whatever
metformin and/or TZD treatment they were
taking. It is arguable that patients randomized
to glargine, without the possible mealtime
boost of sulfonylurea, were thus disadvan-
taged. Not surprisingly, there was more
hypoglycemia in patients treated with
premixed insulin than with glargine.
Insulin treatment
8 80
6 60
4 40
2 20
0 // 6 7 8 9 10 0 // 6 7 8 9 10
HbA1c (%) HbA1c (%)
Common signs and symptoms of hypoglycemia and actions to be taken by the patient
Hunger, sweating, tremor, Autonomic response to Below 3.5 [63] Take glucose-rich sweets,
palpitations subnormal glycemia drink or food
atypical behavior, speech (brain deprived of glucose) drink or food; seek assistance
difficulty, uncoordination,
dizziness, drowsiness
Malaise, headache, nausea, Severe neuroglycopenia Below 2.0 [36] Third-party intervention required
reduced consciousness
Convulsions, coma Severe neuroglycopenia Below 1.5 [27] Medical intervention essential
170
Hypoglycemic unawareness
Many patients with long-standing insulin-treated Hypoglycemia
The following factors predispose to recurrent All patients and their close relatives and friends
hypoglycemia: should learn about the risks of hypoglycemia and
Overtreatment with insulin. Frequent hypo- to recognize and treat the symptoms.
glycemia impairs the response to further Patients should be warned that taking excessive
hypoglycemia within 2 weeks and lowers the carbohydrate could be counterproductive, since
blood glucose level at which symptoms this may cause rebound hyperglycemia; however,
develop. in practice it is notoriously difficult to avoid some
Endocrine causes, including pituitary insuffi- degree of overcorrection.
ciency, adrenal insufficiency, hypothyroid- The dangers of alcohol excess and of hypo-
ism, and premenstrual insulin sensitivity. glycemia while driving need to be emphasized.
Gastrointestinal causes, including exocrine
pancreatic failure, celiac disease, and diabetic Mild hypoglycemia
gastroparesis. Any form of rapidly absorbed carbohydrate will
Renal failure. The kidneys are important for relieve the early symptoms, and sufferers should
the clearance of insulin and oral hypo- always carry glucose or sweets.
glycemics, such as sulfonylureas, and also Drowsy individuals will be able to take
contribute to gluconeogenesis, which dimin- carbohydrate (15 g) in liquid form (e.g.
ishes with declining renal function. Lucozade).
Patients may manipulate their therapy or mis- It is also sensible to recommend a small
understand it. amount of less readily absorbed carbohydrate
Alcohol use has been implicated in up to 19% (30 g), particularly when an oral hypo-
of severe hypoglycemic episodes. Alcohol in glycemic drug or longer-acting insulin is
excess will suppress hepatic gluconeogenesis implicated as a cause of the hypoglycemia, as
and, particularly if taken late in the evening, a proportion of these patients will become
the effect may coincide with the nocturnal hypoglycemic again after treatment.
decline in cortisol, predisposing the patient to
severe nocturnal hypoglycemia. Severe hypoglycemia
Other recreational drug use. In a recent Patients should carry a card or wear a bracelet or
report, 10% of diabetic patients under the age necklace identifying themselves as diabetic, and
of 50 tested positive for illicit drugs at the time these should be looked for in unconscious
of a severe hypoglycemic episode. patients. The diagnosis of severe hypoglycemia
resulting in confusion or coma is simple and can
Treating hypoglycemia usually be made on clinical grounds, backed by
an on the spot finger-stick blood test.
Treatment depends on the severity of the hypo- If real doubt exists, blood should be taken for
glycemia. glucose estimation before treatment is given,
If it is practical to do so, it is useful to confirm the as long as this does not delay treatment for
diagnosis with a blood or plasma glucose estima- more than a short period (i.e. 12 minutes).
tion by finger-stick. However, if hypoglycemia Unconscious patients should be given either
may reasonably be assumed, it is important not to intramuscular glucagon (1 mg) or intravenous
delay treatment simply because of lack of glucose (2550 ml of 50% dextrose solution)
absolute certainty about the diagnosis. followed by a flush of normal saline to preserve
Insulin treatment
Administering treatment for hypoglycemia the vein (since 50% dextrose scleroses veins).
when in fact hypoglycemia is not present is Glucagon acts by mobilizing hepatic
potentially less harmful than delaying glycogen, and works almost as rapidly as
treatment to someone who is truly hypo- glucose. It is simple to administer and can be
glycemic, as long as there is adequate assess- given at home by relatives. It does not work
ment and follow-up over several hours. after a prolonged fast.
172
Allergy
Local or general
Dose-dependent
Hypoglycemia
Weight gain (due to the anabolic action of insulin)
Not dose-dependent
Lipohypertrophy (due to repeated injections at the
Insulin treatment
same site)
Lipoatrophy (rare now with purified insulin)
Insulin edema (especially just after the start of treatment)
195 Complications of treatment. Side-effects of insulin 196 Lipohypertrophy at insulin injection sites. Lipohyper-
treatment, such as allergic reaction, are rare, but they do occur trophy may lead to poor glycemic control, as insulin absorption
in some patients. can be significantly delayed.
173
CHAPTER 15
Low
considerations
risk
Ver y
high
ris k
Mortality (%)
30
admitted to the hospital for reasons other than 30
diabetes, the focus of treatment is the illness trig- 20
gering the admission. 20
Diabetic patients who have poor control before
10
admission may continue to have poor control in 10
the hospital. Patients who lack dietary discipline 0
may experience unexpected hypoglycemia and a 0
5
7
5.
6.
7.
8.
9.
1.
3.
6.
6.
4
>1
decrease in insulin requirements with imposed
4.
5.
6.
7.
8.
.0
.1
.9
10
11
13
dietary compliance caused by hospitalization. Mean glucose level (mmol/l)
Patients who were in good control before
admission now find themselves with elevated
blood glucoses since they are sick, and the dosing 197 Hyperglycemia in critically ill patients. Hyperglycemia
of their insulin is left to physicians who may not is associated with a significantly increased risk of mortality.
pay careful attention to their glycemic control. Adapted from Krinsley JS, 2003.
The risk of mortality and complications increases
as the level of hyperglycemia increases (197).
Mortality is higher in hyperglycemic versus
nonhyperglycemic patients.
30
Mortality in those without a previous Total inpatient mortality
diagnosis of diabetes (i.e. patients who have 25 NonICU mortality
Mortality (%)
In the critically ill, the use of insulin infusion Detemir or glargine 10 IU daily for insulin-nave
protocols in the intensive care unit has facilitated patients, or 0.15 IU/kg daily for patients with
the control of hyperglycemia. features of insulin resistance, is a typical starting
Morbidity and mortality are lower in intensively dose to provide patients with basal insulin in the
treated patients achieving excellent glucose hospital. However, many acutely ill patients will
control. require doses of 0.3 IU/kg or higher.
In one study of hyperglycemic patients Insulin pumps present a unique problem:
admitted to the surgical intensive care unit, patients with these are usually independent and
the use of an insulin infusion protocol to attuned to their insulin needs. However, if they
achieve blood glucose levels of <6.0 mmol/l are too ill to manipulate their pumps and
(108 mg/dl) was associated with significantly calculate insulin doses, it may be better to put
less mortality and less incidence of complica- these patients on basal and prandial subcuta-
tions (such as acute renal failure, critical care neous insulin if the hospital staff cannot operate
neuropathy, septicemia, and the need for the pump. This decision can be arrived at based
blood transfusions) compared to convention- on the patients clinical state and the individual
al treatment. Of note, only 13% of these hospitals policy, if any exists, regarding allowing
patients had a known history of diabetes. the patient to self-administer insulin.
The same study was performed in the
medical intensive care unit; in this group, Diabetes and surgery
intensive insulin infusion reduced morbidity
but not mortality. It is now accepted, and supported by clinical trial
In cardiothoracic surgery, the use of insulin results, that efforts to achieve near-normal
infusion protocols in diabetic patients imme- glycemia during and after major surgery, particu-
diately following coronary artery bypass graft larly cardiothoracic surgery, and in surgical
resulted in a reduced incidence of deep intensive care patients, will significantly decrease
sternal wound infection, and thus a mortality and postoperative infection, and may
decreased length of hospital stay. also decrease the need for transfusion, need for
Recent studies in critically ill patients suggest, dialysis, and critical care neuropathy (199).
however, that a tight glucose target of 4.46.1 When an emergency major surgical procedure
mmol/l (80110 mg/dl) may have to be re- is required in a diabetic patient it is, therefore,
evaluated. Studies such as the VISEP and NICE- mandatory to institute immediately an insulin
SUGAR show either no benefit, or a greater risk of infusion regimen that aims to achieve and
hypoglycemia and mortality, with tighter control. sustain near normal glucose levels (48 mmol/l
Insulin infusions are broadly recommended for [72144 mg/dl]) (200).
perioperative care and details of such manage- Relevant medical, nursing, and intensive care
ment are to be found in more specialized sources. staff should be trained in the use of an
In the noncritically ill patient on the regular algorithm-based insulin infusion regimen
hospital ward, the ongoing use of retroactive (201).
sliding scale insulin therapy, despite recommen- Experienced medical and nursing staff may
dations to the contrary, is one of the reasons why assume that hypoglycemia is the major risk to the
hyperglycemia is perpetuated. severely ill postoperative patient, but the adverse
The use of basal insulin (in the form of NPH consequences of hyperglycemia probably
[isophane] insulin, detemir insulin or glargine outweigh the minor risks posed by hypoglycemia
insulin) and, if necessary, prandial insulin, can in such patients.
prevent hyperglycemia, whereas sliding scales
Special management
considerations
100 100
Intensive treatment
Conventional treatment
96 96
94 94
92 92
90 90
88 88
50 100 150 50 100 150 200 250
Days after admission Days after admission
199 Intensive insulin therapy in critically ill patients. Insulin-treated diabetes regimen
In a study of 1548 patients, intensive therapy reduced both
ICU and general in-hospital mortality. Adapted from van den Stop long-acting and/or intermediate insulin the day
Berghe G, et al, 2001. before surgery, substitute short-acting insulin, and start
insulin infusion
10
Postoperatively, the infusion is maintained until the patient
8 is able to eat. Other fluids must be given through a
6 separate intravenous line
4
Monitor glucose and potassium levels and adjust amounts
2 in infusion while keeping the rate constant
0
<150 150175 175200 200225 225250 >250 When transitioning patient from infusion to subcutaneous
Average postoperative glucose (mg/dl) insulin the first injection of basal insulin should be adminis-
tered at least 2 h before the infusion is discontinued
Major surgery
For major surgery that is elective, rather than Diabetes management for surgery
emergency, efforts should be made to optimize
Management is by a team; liaison between the diabetes
glycemic control and electrolytes before team and the anesthetist is ideal
admission to hospital (202).
If that seems unlikely to be achieved on an Metabolic control should be optimized before the
operation. For emergency surgery, metabolic disturbances
outpatient basis, consider admitting the should be carefully managed
patient a day early for intensive insulin
management preoperatively. Use insulin therapy when in doubt
Tight glycemic control postoperatively should be
Special management
204 Management points. Optimization of blood glucose is 205 Management plan. Management of early pregnancy is
key to successful management. important to reduce the risk of congenital anomalies.
100 <1922
Diabetic mothers
45.1%
Infant mortality (%)
19241938
75 Macrosomia
Congenital
50 1969 malformations
8.8% 2.8%
Perinatal mortality
1972
25 1976
1972 1979
19561975 1973
0 1980 1976 2.6%
National data 10.0% 0.8%
DKA 250 200 150 100 50
Mean maternal blood glucose (mg/dl)
Special management
considerations
206 Infant mortality. A review of the major studies over the 207 Perinatal outcomes. Women with type 1 diabetes in the
last century revealed that as maternal blood glucose Netherlands in 19992000 showed a 34-fold greater risk of
concentrations decreased, infant mortality also decreased. obstetric complications compared to national data. Adapted
Adapted from Jovanovic and Peterson. from Evers IM, de Valk HW, et al. 2004.
178
Insulin dose
Prepregnancy 50.0 (23.2) 51.3 (25.1)
Units/day 105.0 (51.3) 120.4 (32.3)
Units/kg 1.2 (0.5) 1.4 (0.5)
Change 50.2 (35.7) 65 (49.0)
Cesarean section
Total 21/31 (68%) 14/30 (47%)
For suspected disproportion 8/31 (26%) 7/30 (23%)
Fructosamine (mol/l)
Trimester 2 250.4 (37.6) 240.3 (33.2)
Trimester 3 214.4 (27.2) 213.4 (32.8)
A randomized study with glucose targets 208 Glucose monitoring. In this study, 61 women with
identical to those in the above study, but type 1 diabetes were randomly assigned at 16 weeks gestation
carried out in type 1 diabetic women from 16 to preprandial or postprandial blood glucose monitoring
weeks gestation, showed that postprandial throughout pregnancy. Maternal age, parity, age of onset of
monitoring, as compared with preprandial, diabetes, number of previous miscarriages, smoking status,
was associated with greater success in social class, weight gain in pregnancy, and compliance with
achieving glycemic targets in the second and therapy were similar in both groups.The postprandial
third trimesters and significantly less likeli- monitoring group had a significantly reduced incidence of pre-
hood of pre-eclampsia (208). eclampsia and greater success in achieving glycemic targets.
There is now a consensus that in pregnancy the
aim should be to achieve glucose levels of less
than 7.8 mmol/l (140 mg/dl) 1 hour after meals.
Special management
considerations
Delivery
Type 1 diabetes patients
First missed
Prepregnancy counseling, with efforts to achieve period
Last Pre-eclampsia
near normal glycemia, and the planned introduc- menstrual
period
tion of folate 5 mg, should ideally be the rule at an UTI, heartburn, candidiasis
early stage in adult life.
Inevitably, many women become pregnant when
HbA1c is still elevated. Insulin therapy
An appreciation of the effect of pregnancy on
insulin needs is crucial. 1st trimester 2nd trimester 3rd trimester
During the first trimester insulin requirements are 0 5 10 15 20 25 30 35 40
Gestation (weeks)
fairly stable, though the actual diagnosis of
pregnancy will often lead to a change in the level
of self-care, and if dietary habits alter (i.e. calorie 209 Impact of diabetes on the mother. Insulin needs rise
intake decreases) there may be a need for rapidly in the second trimester.
adjusting the insulin dosage downwards. On the
other hand, in those women with elevated HbA1c
an alteration in the insulin dose (usually an In the sense that insulin therapy is a necessity
increase) will be required to optimize glycemic for women with type 1 diabetes, its safety in
control rapidly. pregnancy has been established through
Patients not already on an intensive insulin common usage; the outcome for both the mother
regimen of multiple injections or a subcuta- and the fetus would be clearly disastrous in the
neous insulin infusion pump should be absence of insulin therapy.
strongly advised to adopt one or the other. Insulin analogs, prescribed increasingly along
In the second trimester, insulin needs rise with or in preference to human insulin in non-
steadily, often to more than double the pre- pregnant diabetic patients, have not been specifi-
pregnancy dose, and then tend to level off or cally tested for safety in human pregnancy.
occasionally even fall slightly in the final few Inevitably, therefore, the package inserts of
weeks (209). analog insulins caution against the lack of safety
The precise cause of the increasing insulin data as to their use in pregnancy.
need is not known, but is probably related to With each new analog, concerns are raised
the rise in hormones like cortisol, proges- about potential for harm, for example
terone, and human placental lactogen. through affinity for placental receptors of
Management of glycemia during labor is best insulin-like growth factors. However, to date,
achieved by intravenous infusion of insulin and the lack of evidence for adverse effects
glucose, the aim being to maintain normal supports the emerging view that insulin
glucose levels. analogs are probably just as safe as human
Immediately postpartum the insulin resistance of and animal insulin.
pregnancy decreases, so the insulin dose may It is unlikely that the safety issue will ever be
decrease to low levels, even zero, for a few days; strictly tested in randomized controlled trials
thereafter, insulin should be resumed at a dosage in pregnancy, and probably true that the
appropriate for prepregnancy needs. majority of diabetologists with wide experi-
ence in pregnancy treatment would regard
current insulin analogs as safe for use.
Each woman and her partner need to make
an informed choice between the lack of
Special management
considerations
Type 2 diabetes patients Many diabetic women, on learning that they are
The rising prevalence of type 2 diabetes in pregnant, make a renewed effort with dietary
women of childbearing age has resulted in care and their general well-being. So, in theory at
increasing numbers of pregnant women with pre- least, since glycemia in type 2 diabetes is poten-
existing diabetes. tially more responsive to lifestyle change than in
Unless stringent glycemic control is readily type 1 diabetes, insulin requirements may be indi-
achieved through dietary management the vidually more variable.
consensus is that insulin treatment is appropriate. It is likely that some women with type 2 diabetes
Initial insulin needs are likely to be greater could maintain satisfactory control with oral
than in type 1 diabetes because of the pre- agents, but studies of this are limited.
existing insulin resistance associated with At present the use of oral agents is not
type 2 diabetes, but the principles of acknowledged as the standard of care,
treatment are essentially the same. though many patients with diabetes and
polycystic ovary syndrome are becoming
pregnant whilst on metformin, and results to
date suggest that the drug has no adverse
effect on the fetus.
A retrospective survey in South Africa found that,
despite the achievement of comparable glycemic
control when glibenclamide and metformin were
used rather than insulin, there were higher peri-
210 Oral glucose-lowering agents in pregnancy. natal mortality and stillbirth rates (210), but such
In an analysis of 379 women with type 2 diabetes using oral adverse effects from these oral agents have not
hypoglycemic agents (metformin and glibenclamide) sub- been confimed in other studies.
divided into three groups according to therapy, increased
perinatal mortality was associated with the use of sulfonylureas
or sulfonylureas plus metformin. Conversion from oral agents
to insulin was protective for perinatal mortality compared with
oral agents alone.
Birth weight (g) 3185.2 103.3 (n 90) 3259.0 52.3 (n 244) 3238.8 140.5 (n 29)
No. of outcomes/
no. of pregnancies
Perinatal mortality 11/88 (12.5%) 7/248 (2.8%) 1/30 (3.3%)
Stillbirth rate 8/88 (9.1%) 5/248 (2.0%) 1/30 (3.3%)
Neonatal death rate 3/87 (3.4%) 2/248 (0.8%) 0/30 (0.0%)
No. of outcomes/
no of pregnancies
Fetal anomaly 5/88 (5.7%) 5/248 (2.0%) 0/30 (0.0%)
Cesarean section 55/88 (62.5%) 146/244 (59.8%) 18/31 (58.1%)
Neonatal hypoglycemia 18/75 (24%) 37/196 (18.9%) 5/22 (22.7%)
Macrosomia 21/90 (23.3%) 44/245 (18%) 5/29 (17.2%)
Special management
Adapted, with permission, from Ekpebegh CO, Coetzee EJ, van der Merwe L, et al 2007.
182
50 Pre-existing diabetes
Gestational diabetes mellitus (GDM)
40 No diabetes
Rate (%)
30
20
10
Preterm birth Preterm birth Induced labor <37 Cesarian section Postnatal hospital stay
2031 wks 3236 wks wks >7 days
Risks to the diabetic mother 211 Pregnancy outcomes. The Australian Institute of Health
Theoretically the risk of maternal mortality is and Welfare analysis of National Perinatal Data Collection data
higher in the diabetic than nondiabetic pregnancy found that mothers with pre-existing diabetes have higher
(211, 212). This relates to: rates of adverse pregnancy outcomes than mothers without
Risk of ketoacidosis if appropriate attention diabetes or with GDM.
is not paid to glycemic control.
Increased labor risks if there is fetal macro-
somia. It is important to screen all pregnant diabetic
Increased risk of cardiac or renal failure in women for the presence of microvascular compli-
the presence of established advanced micro- cations as soon as pregnancy is diagnosed.
vascular or macrovascular disease. The pre-existence of complications is not neces-
Increased risk of pre-eclampsia. sarily a reason to advise against pregnancy, but
women with diabetes should be made aware that
microvascular complications can worsen
suddenly and considerably during pregnancy
Risks of diabetic pregnancy
despite improving glycemic control. Reasons for
MATERNAL RISKS strongly advising against pregnancy include:
Metabolic deterioration Clinical ischemic heart disease holds greatly
increased maternal risk of mortality, and,
Microvascular complications progress arguably with the increasing prevalence of
Macrovascular complications type 2 diabetes in younger patients, we may
expect to see more patients in that situation.
Risk of urinary tract infection increased Advanced nephropathy, particularly with
Risk of diabetes in later life increased 212 Pregnancy risks. Diabetes during pregnancy significantly
increases the risks to both mother and child.
183
280
HbA1c <8.5%
Major congenital
abnormalities
3.5%
Special management
considerations
Further reading
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Niskanen L, Al Hakim M, Madsen J, Rasmussen MF,
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Lean ME; NN80221807 Study Group (2009)
diabetes in the Collaborative Atorvastatin Diabetes
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a randomised, double-blind, placebo-controlled
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Resources
Glossary
Adiponectin A cytokine derived from adipocytes Autoantibody An antibody that reacts to the
that is associated with improved glycemic control and patients own cells or tissues. Islet cell autoantibodies
lipid profiles in patients with diabetes. are strongly associated with the development of
type 1 diabetes.
Advanced glycation end-product (AGE) Formed
when excess glucose combines nonenzymatically Autoantigen An antigen that is present in the
with tissue or circulating proteins. AGEs are increased endogenous tissue, and stimulates the production of
in diabetes, and contribute to microvascular compli- antibodies (autoantibodies).
cations.
Autonomic neuropathy Damage of the nerves that
Aldose reductase Some of the glucose that enters are not in the patients conscious control (such as
the cell is metabolized by this enzyme into sorbitol, nerves of the cardiovascular, gastrointestinal and
which in turn is implicated as a factor for some micro- genitourinary systems).
vascular complications.
B
Allele One of a pair of genes found in a specific Bariatric surgery Surgery to promote weight loss
location on a chromosome. by altering the gastrointestinal anatomy.
Body mass index (BMI) A measurement to estimate Double diabetes Diabetes with features of both
body fat, calculated by dividing a persons weight in type 1 and type 2 diabetes.
kilograms by their height in square meters (kg/m2).
A BMI of less than 18 is considered underweight, Dyslipidemia Derangement in lipid (cholesterol
18 to 24.9 is normal, 25 to 29.9 is overweight, and and triglyceride) levels and composition. Dyslipid-
30 and above is obese. emia contributes to atherosclerosis.
Diabetic ketoacidosis (DKA) Severe metabolic Glucagon A hormone produced by the alpha cells of
disturbance seen in diabetes, consisting of a triad of the islets of Langerhans; it has generally anti-insulin
hyperglycemia, ketonemia, and anion gap acidosis. effects and forms part of the feedback loop that stabi-
lizes glucose levels.
Dipeptidyl peptidase-4 (DPP-4) inhibitors A class
of diabetes drugs that inhibit dipeptidyl peptidase-4, Glucagon-like peptide-1 (GLP-1) A hormone
the enzyme that degrades glucagon-like peptide-1 released from the L cells of the distal end of the small
(GLP-1). This results in lowering of glucose levels, bowel and the proximal end of the large bowel,
especially during the mealtime excursions. usually in response to eating.
195
Glycemic index (GI) An estimation of the extent to Hyperinsulinemia Excessive levels of insulin in the
which a specific foodstuff will elevate plasma blood relative to the level of glucose.
glucose; sometimes taken to refer specifically to the
carbohydrate content of the foodstuff. Hyperosmolality Increased concentration of
solutes in a body fluid, e.g. blood, expressed as
Glycogen A polysaccharide; the principal storage osmoles of solute per kilogram of serum.
form of glucose in humans, found mainly in the liver
and muscles. Hyperosmolar nonketotic hyperglycemia
(HONK) Also known as hyperosmolar hyper-
Glycogenesis The process of glycogen synthesis glycemic state (HHS), this condition is seen more
from glucose. often in type 2 than in type 1 diabetes. It is associated
with extremely high plasma glucose, raised urea,
Glycogenolysis The process of breakdown of electrolyte disturbance, and severe dehydration.
glycogen to glucose.
Hypoglycemia An abnormally low level of plasma
Glycolysis The intracellular metabolic pathway that glucose and a common complication of insulin
converts glucose into high-energy compounds, prin- treatment. Hypoglycemia results from an imbalance
cipally ATP. between injected insulin or oral therapy and a
patients diet, activity, and metabolic requirements.
Glycosuria The presence of glucose in the urine.
This is usually indicative of impaired glucose
tolerance or diabetes.
196
Insulin A hormone produced by the cells of the Ketone/ketone body One of a family of organic
islets of Langerhans that is the principal hormone ketones or their organic acid forms, namely aceto-
regulating glucose, but is also important in regulating acetate, -hydroxybutyrate, or acetate.
fat and carbohydrate metabolism.
L
Insulin analog An altered, synthetic form of insulin, Lactic acidosis A metabolic acidosis with lactic acid
in which certain amino acids are modified to affect as the major anion involved.
the time course of the insulin action.
Latent autoimmune diabetes of adults (LADA)
Insulin deficiency Inability to produce sufficient A slow-onset form of diabetes occurring in adults,
insulin; the state of having insufficient insulin relative closely related to type 1 diabetes.
to the prevailing glucose level.
Leptin A hormone released almost entirely from
Insulin-like growth factor (IGF) A protein with a white adipose tissue, its absence causes insatiable
structure similar to insulin, and that may interact with hunger, reduction in metabolic rate, and infertility,
insulin receptors and share some actions with insulin. among other effects.
Insulin receptor A cell membrane receptor Lipoatrophy Atrophy of adipose tissue, which can
activated by insulin to initiate a signaling cascade that have a variety of causes, including subcutaneous
stimulates glucose uptake. insulin injection.
Insulin resistance A condition in which cells and Lipohypertrophy Hypertrophy of adipose tissue,
tissues respond suboptimally to insulin stimulation. usually as a consequence of chronic local insulin
Untreated insulin resistance can lead to type 2 injection.
diabetes.
Lipolysis Breakdown of fat, usually triglyceride,
Insulin secretagogue A substance which stimulates which can be either circulating or intracellular.
the secretion of insulin from the pancreas. Sulfonyl-
ureas, repaglinide, and nateglinide are all in this
category of drugs.
197
Lipotoxicity The concept that excess availability of Michaelis constant (abbreviated Km) The substrate
lipid (which may be of several forms) inhibits normal concentration at which a reaction obeying Michaelis
function of glucoregulatory mechanisms. Menton kinetics (a model which describes the rate of
enzymatic reactions) is at half-maximum rate.
Low-density lipoproteins (LDL) Circulating Different Km values of different glucose transporters
lipoproteins of density 1.0191.063 g/ml that (GLUTs) enable specific functions.
transport cholesterol from the liver to the tissues.
Cholesterol carried in LDL particles is especially Microalbuminuria Albuminuria of modest degree,
atherogenic and hence these are colloquially called not detectable with routine urine testing strips (<300
bad cholesterol lipoproteins. mg/l on a spot sample).
U
Ulcer (ischemic/neuropathic foot)
A break in the skin leading to wounds or open sores.
The result of peripheral neuropathy, peripheral
arterial disease, and other factors, foot ulcers are an
important complication of diabetes, as they may lead
to infection and amputation.
V
Vagal neuropathy A condition in which the vagal
nerve is damaged. The vagal nerve is involved in the
function of several organs, notably the stomach and
its acid production, so vagal neuropathy is associated
with abnormal clearance of food from the gut.
Index
Note: Page references in italic refer to angiotensin converting-enzyme (ACE) genetic defects 16
tables or boxes inhibitors 61, 823, 83, 109 immune-mediated destruction 39
renal dysfunction 115, 11617 MODY 18
A angiotensin receptor blockers (ARBs) 61, potassium channels 143
abciximab 76, 77 82, 83, 115, 11617 bicarbonate 125, 126
acanthosis nigricans 22 anhidrosis 93 biguanides
acarbose 57, 148, 149 anion gap 1245 lactic acidosis 130
accelerator hypothesis (double diabetes ankle reflexes 88
effect) 13 side-effects and contraindications
annual examination 60 1423
ACEI, see angiotensin converting- Anti-Hypertensive and Lipid-Lowering
enzyme inhibitors see also metformin
Treatment to Prevent Heart Attacks bile acid sequestrants 141, 153
acidbase balance, restoration 125 Trials (ALLHAT) 82
acidosis, high anion gap 1245 birth weight 46
anti-vascular endothelial growth factor
acute coronary syndrome 76, 145 (anti-VEGF) 110 bladder dysfunction 93, 95
adiponectin 55, 146 antidepressants, tricyclic 94 blood pressure 4950, 77
adipose tissue antihypertensive agents 823, 83 impairment of regulation 92
actions of insulin 34, 35 antipsychotic agents, atypical 121 metabolic syndrome 51
and insulin resistance 55 ARBs, see angiotensin receptor blockers blood pressure control 823, 83
adiposity, and TZD therapy 146, 147 arrhythmias 92 renal dysfunction 11617
advanced glycation endproducts (AGE) arterial thrombosis 129 surgery 176
79, 80 arthropathy, neuropathic 89 therapeutic targets 133
AfricanAmericans 47, 111 Asian populations 42, 43, 47, 111 type 2 diabetes 50
Afro-Caribbeans 47 aspart insulin 127, 155 body mass index (BMI) 51, 133, 134
age, and prevalence of diabetes 13 aspirin 75, 84, 86, 109 distribution in developed countries
air hunger 123 45
atherosclerosis 74, 163
airport security 70 bone loss 147
atorvastatin 84
albumin, urinary 11213, 113 brain, glucose use 28
atrial natriuretic peptide 50
albumin/creatinine ratio 113, 115 breast cancer 43, 158
autoantibodies 17, 39, 40
alcohol consumption 136, 171 brittle diabetes mellitus 130
screening 44
aldose reductase 80 bromocriptine 141, 154
autoimmune diseases 39, 40, 44
allergy, insulins 172 bullae 23
autonomic neuropathy 87, 87, 97
allodynia 90 buproprion 85
clinical manifestations 92, 97
alpha-adrenergic blockers 83 bydureon 150
aviation 69, 70
alpha-glucosidase inhibitors 141, 148, Bypass Angioplasty Revascularization
149 B Investigation (BARI) Trial 76
alprostadil, intracavernous injection 95 B lymphocytes 39 C
American Diabetes Association BABYDIAB study 40 C-peptide 31
HbA1C guidelines 86 bacterial overgrowth 93, 94 C-reactive protein (CRP) 74
tips for drivers 71 bariatric surgery 47, 138 CABG, see coronary artery bypass
treatment algorithm 131 Barker Hypothesis 46 grafting
amputations 102 basement membrane calcium-channel blockers 82, 83
risk factors 97, 100 glomerular 111, 112 callus formation 97, 98, 99
risk reduction 84 retinal vessels 106, 107 calorie intake 1334
amylin 54, 154 bedwetting 64 calorie restriction 134
analog (pramlintide) 141, 154 Bergamo Nephrologic Diabetes calpain 10, 36
amyotrophy, diabetic 92 Complications Trial (BENEDICT) 83 cancer risks 43, 158
anemia 147 beta-adrenergic blockers 83, 11617, 117 capsaicin 94
angina, symptoms 76 masking of hyperglycemia 117 carbamazepine 94
angioedema 153 cells 11, 25 carbohydrates, dietary 134, 135
angioplasty 102 deficiency in type 2 diabetes 49, 523,
140
202
cardiovascular disease congenital malformations 185, 185 diabetic ketoacidosis (DKA) 1218
diabetic autonomic neuropathy 923 consensus algorithms 131, 139 clinical features 124
and duration of diabetes 73 continuous ambulatory peritoneal differentiation from HONK 128, 129
and lipid-lowering drugs 84 dialysis (CAPD) 118 investigations 1245, 124
and physical activity 137 continuous subcutaneous insulin pathogenesis 1223
risk factors 81, 111, 163 infusion (CSII/insulin pump) 122, recurrent 130
128, 132, 1603
and sulfonylurea therapy 145 treatment algorithm 126
contraception 178
and TZD therapy 148 diabetic ketoacidosis (DKA) insulin
convulsions 169 pump therapy 162
carpal tunnel syndrome 91, 94
coronary artery bypass grafting (CABG) diagnostic criteria 1415
cataracts 105, 109 76
juvenile (snowflake) 109 dialysis (hemodialysis) 118
coronary artery revascularization 75, 76
senile 109 diarrhea 93, 142
cost-benefit assessment, management of
treatment 110 diabetes 59 treatment 94
catecholamine response 93, 170 costs of diabetes 23 diet 82, 1326
central nervous system (CNS), actions of cotton-wool spots 107 calorie intake 1334
insulin 35 cranial nerve palsies 91, 105 carbohydrates 134
cerebral edema 127 ocular nerves 109 childhood diabetes 64
cesarean section 179, 181 creatine kinase (CK) 75 ethnic minorities 68
Charcots arthropathy 89, 98, 103 creatinine, serum 61, 112, 115, 116, 118, fats 1345
cheiroarthropathy 22 143 patient advice 1323
chemokines 39 metformin therapy 143 and prevention of diabetes 56, 57
children 624 critically-ill patient 1734 protein restriction 117
clinical presentation 63 CSII, see continuous subcutaneous recommendations 1356, 135
common issues in diabetes 64 insulin infusion (insulin pump) and recurrent ketoacidosis 130
incidence of diabetes 37 Cycloset (bromocriptine) 141, 154 in renal dysfunction 117
insulin pump therapy 162 cyclosporins 117 type 2 diabetes 1326, 139
management of diabetes 634 cytokines 39, 74 dipeptidyl peptidase-4 (DPP-4) inhibitors
self-management 63 66, 1524
sulfonylurea therapy 144 D benefits 141
type 2 diabetes 13, 62 Da Qing study 57 colesevelam 141, 153
types of diabetes 62, 62 dapagliflozin 154 mode of action 152, 153
cholecystitis, emphysematous 21, 21 dawn phenomenon 160 side-effects/risks 141, 153, 154
cholesterol levels 50, 51, 153 DCCT, see Diabetes Control and sitagliptin 66, 1523
Complications Trial diphenonoxylate 94
management 76, 845, 117
De Fronzo hypothesis 49 disseminated intravascular coagulation
Cholesterol and Recurrent Events (CARE)
trial 76 deep venous thrombosis 127 129
classification of diabetes 15, 16 definitions diuretics
clinical inertia 139 diabetes mellitus 11, 13 loop 116
clinical presentation 1920 insulin resistance 52 thiazide 82, 83
elderly patients 65 metabolic syndrome 51 DKA, see diabetic ketoacidosis
young children 63 dehydration 1223, 128, 129 DNA mutations 33, 36, 144
colesevelam 141, 153 demyelination 88 domperidone 94
Collaborative Atorvastatin Diabetes Study dermopathy 23 Doppler ultrasound 101
(CARDS) 84 detemir insulin 67, 127, 1567, 157 dot and blot hemorrhages 107
coma diabetic in-patient 174 double diabetes 38, 38
causes 124 type 2 diabetes 165 DPP-4 inhibitors, see dipeptidyl
DKA 124 dextrose infusion 127, 175 peptidase-4 (DPP-4) inhibitors
hyperosmolar, nonketotic 65, 67 diabetes insipidus 11 DREAM trial 57
hypoglycemic 169, 169 Diabetes Control and Complications Trial dressings, ulcers 102
community care 68 (DCCT) 63, 78, 85, 86, 109, 116, 168, driving 69, 69, 701
169 ADA tips 71
complications 11, 203
Diabetes Mellitus Insulin Glucose drug interactions 144
elderly patients 65 Infusion in Acute Myocardial
ethnic minorities 67, 81 Infarction (DIGAMI) study 75, 163 drug therapy
mortality 43 Diabetes Prevention Program (DPP) 57, combination 152
pregnancy 182 142 elderly patients 65, 667, 67, 143, 144
risks in pregnancy 182 diabetic autonomic neuropathy (DAN) hypertension 823, 83
screening 601 934 stepwise increase 86
see also individual complications
203
glomerular basement membrane (GBM) pregnancy 176, 177, 1789, 179, 185 and microvascular disease 77, 789,
111, 112 in renal disease 116 86
glomerular filtration rate (GFR) 112, 115, surgical in-patient 174 mild 27
118 and survival rates 66 MODY subgroups 18
estimated (eGFR) 66 glycemic index (GI) 134 oxidative stress 79
glomerular particle filtration 112 glycogenesis 27 symptoms 19, 267
glomerulosclerosis 113 glycogenolysis 27 Hyperglycemia and Adverse Pregnancy
GLP-1 analogs, see glucagon-like glycolysis 28, 79 Outcome (HAPO) study 183
peptide-1 (GLP-1) analogs hyperhidrosis 93
glycoproteins 25
glucagon 25, 122 hyperinsulinemia 49, 53
glycosuria 20
and exenatide therapy 151 hyperosmolar nonketotic hyperglycemia
glycotoxicity 54, 55
intramuscular 171 (HONK) 12830
granuloma annulare 22, 23
glucagon-like peptide-1 (GLP-1) 138, 149 hypersensitivity reactions 153
growth, childhood diabetes 64
glucagon-like peptide-1 (GLP-1) analogs hypertension 4950, 77
66, 14952 gustatory sweating 93
ethnic minorities 67
benefits 141, 14951 gut peptides 138, 149
management 823, 83, 117, 176
side-effects 141, 1512 renal dysfunction 11617
H
glucagon response 170 Hypertension Optimal Treatment (HOT)
hands, diabetic cheiroarthropathy 22
glucokinase gene 48, 81 trial 82
hard exudates 107
glucokinase (hexokinase type IV) 30, 32 hyperventilation 123
healthcare expenditure 23
gluconeogenesis 27, 122 hypoglycemia 26, 16870
heart failure 148
glucose development 168, 169
heart rate 92, 93
biological roles 25, 28 in elderly 667
hemiparesis 169
intracellular levels 79 insulin secretagogues 145
hemodialysis 66, 118
intravenous 171 metformin 142
hemoglobin A1c (HbA1c) 15, 75, 856
oral 32, 149 neonatal 181, 184
accuracy 86
glucose (blood levels) 267 nocturnal 167, 170
and DPP-4 inhibitors 152, 153
diagnostic 14, 14 oral therapies 66
and GLP-1 analog therapy 150
fasting 51, 151, 164, 165 and physical activity 69, 136
guidelines 86
HONK 128 prevention/avoidance 172
insulin pump therapy 162
ketoacidosis 121, 122 recurrent severe 1701
insulin secretagogue therapy 144, 145
and physical activity 69, 136 SGLT2 inhibitors 154
metformin therapy 139, 142
postprandial 26, 166 signs and symptoms 1689, 169
and oral therapies 140
pregnancy 1789, 179 sulfonylureas 144
pregnancy 178, 179, 185
treatment targets 133, 133 treatment 1712
renal dysfunction 116
see also glycemic control; hyper- type 2 diabetes 164, 165
and retinopathy 169
glycemia; hypoglycemia unawareness 93, 170
sulfonylurea therapy 144
glucose metabolism hypotension
therapeutic target 133
elderly patients 65 bromocriptine therapy 154
and vascular disease risk 75, 86
normal 25, 278 DKA 127
hemorrhages, retinal vessels 107
glucose monitor, implantable 163 orthostatic/postural 92, 93
hepatic disease 143, 144
glucose monitoring hypothermia 127
hepatic glucose output (HGO) 34, 35
self-monitoring 132, 133
hepatic ketogenesis 122 I
glucose resistance 28
hexokinases 30 identification, medical 71, 171
glucose transporters (GLUTs) 2830, 29,
33, 36 HGO, see hepatic glucose output IDF, see International Diabetes
glucose uptake 2830 high-density lipoprotein (HDL) 50, 51, Federation
117 IFG, see impaired fasting glycemia
insulin-dependent 29
histocompatibility leukocyte antigens IGT, see impaired glucose tolerance
insulin-independent 28
(HLA) 38, 401
glucose-6-phosphate 27, 30 illness 1734
holidays 70
glulisine insulin 127, 155, 157 and HONK 128
HONK, see hyperosmolar nonketotic
GLUTs, see glucose transporters hyperglycemia insulin therapy 121
glycemic control hospitalized patient 1736 and ketoacidosis 130
elderly patient 66 hyaline membrane disease 184, 185 immune-mediated disease 16, 39, 40, 44
and eye disease 109 hyperesthesia 91 impaired fasting glycemia (IFG) 14, 14
insulin pump therapy 162 hyperglycemia impaired glucose tolerance (IGT) 14, 14,
and macrovascular disease 756 56
critically-ill patient 1734
and microvascular disease 779, 86 acarbose treatment 148, 149
DKA 123
children/adolescents 62
205
lispro insulin 127, 155, 157 pregnancy 181, 181 neonates 19, 1845
liver 25, 27, 32 in renal dysfunction 116 autoantibody screening 40
actions of insulin 35 side-effects and risks 141, 1423 hypoglycemia 181, 184
liver disease 143, 144 surgery 143 mortality rates 177, 181
Long-Term Intervention with Pravastatin synergy with TZDs 147 sulfonylurea therapy 144
in Ischemic Disease (LIPID) trial 76 methanol poisoning 125 nephropathy
loperamide 94 metoclopramide 94 diagnosis 114
losartan 117 Michaelis constant 29 link with hypertension 49
Losartan Intervention for Endpoint Micro-HOPE study 83 non-diabetic causes 114
Reduction (LIFE) study 117 microalbuminuria 51, 111, 11213 overt clinical 113, 116
low-density lipoprotein (LDL) cholesterol diagnosis 113, 114 risk in pregnancy 182
50, 84, 117
screening 61 treatment/management 11417
lung cancer risk 158
microaneurysms, retinal vessels 107 neuroendocrine disorders 93
lung function, inhaled insulin 158
microvascular disease 7786 neuroglycopenia 26, 169
M modifiable factors 77 neuropathy
macroalbuminuria 112, 113 pathogenesis 7780 acute motor 92
macrophages 39, 74 risk reduction 816 acute sensory 901
macrosomia 181, 184 treatment and management 81 assessment chart 89
macrovascular disease 737 unmodifiable factors 81 autonomic 87, 87, 923, 92
pathogenesis 74 midodrine 94 chronic sensory 89
risk factors 59, 73 miglitol 148, 149 classification 87, 87
treatment and management 757 migrant populations 42, 47 diagnosis 88, 89
macular edema 108, 110 monofilament testing 88, 89 foot 89, 97
maculopathy 105, 108 mononeuritis, ocular nerves 109 prevalence 87
treatment 110 mononeuritis multiplex 90 sensorimotor 87, 87, 97
major histocompatibility complex (MHC) mononeuropathies 901, 94 treatment and management 946
401 morphological associations 45 niacin 84, 85
malformations, congenital 185, 185 mortality 13 NICE guidelines 86
Malm study 57 diabetic in-patient 173 NICE-SUGAR study 173
management DKA 123 nitric oxide synthase, endothelial (eNOS)
childhood diabetes 624 HONK 130 80
elderly diabetic patient 657 macrovascular disease 73 nocturnal hypoglycemia 167, 170
ethnic minorities 678 motor neuropathy 92, 97 nonesterified fatty acids (NEFA) 25, 26,
goals of 59 mucormycosis, rhinocerebral 21, 21 50, 55
treatment targets 132, 133 Multiple Risk Factor Intervention Trial NPH (neutral protamine Hagedorn)
(MRFIT) 81 insulin 156, 157, 159
maturity onset diabetes of the young
(MODY) 1718, 30, 48 muscle wasting 92 type 2 diabetes 165, 166
management 62, 145 myocardial infarction 92, 145, 163 nuclear factor- B (NF B) 79, 80
subgroups 18 risk 148 O
mealtimes silent 127 obesity 52, 82, 132
and insulin levels 30, 33 treatment of diabetes 756 android type 45
insulin therapy 159, 161, 166 myositis, risk 117 association with forms of diabetes 17
metabolic responses 26 myristic acid 156 central 51
mesenteric artery occlusion 129
N children 62
metabolic acidosis 1223
NADPH 80 dietary management 1326
correction 125
nateglinide 145 frequency in developed countries 45
metabolic syndrome 49, 502, 59, 73
benefits 57, 141 and insulin resistance 52
definitions 51
chemical structure 145 surgical management 138
metformin 86, 1413
side-effects/risks 141, 145 ocular nerve palsies 109
benefits 57, 141, 142
Native Americans 47 OGTT, see oral glucose tolerance test
cautions 66
nausea olanzepine 121
comparison with lifestyle
DKA 122 ophthalmoplegia 91
modification 142
oral therapies 142, 152 ophthalmoscopy 601
effects on long-term HbA1c levels
139 NAVIGATOR trial 57 non-proliferative retinopathy 107
hospitalized patient 176 necrobiosis lipoidica 22 proliferative retinopathy 108
lactic acidosis 130 necrotizing fasciitis/cellulitis 21 optic nerve, neovascularization 107
mode of action 30, 141 NEFA, see nonesterified fatty acids oral contraceptive pill 178
207
oral glucose tolerance test (OGTT) 14 PPARs, see peroxisome proliferator- reactive oxygen species (ROS) 79, 80
gestational diabetes 183, 183 activated receptors recreational drugs 171
oral therapy 13940 pramlintide 141, 154 Reduction of Endpoints in NIDDM with
choice of initial agent 140 pravastatin 76 the Angiotensin II Antagonist
hospitalized patient 176 prayer sign 22 Losartan (RENAAL) Trial 116
lactic acidosis 130 pre-eclampsia 179, 181 renal disease
pregnancy 181, 181 pregabalin 94 end-stage (ESRD) 113, 117
prevention/delay of diabetes 57, 142, pregnancy 17684 metformin therapy 143
147, 148, 149 eye examination 106 natural history 11113
orlistat 57, 57 fetal and neonatal risks 181, 182, pathophysiology 111
osmolal gap 125 1845 rate of progression 118
osmolality, serum 128, 129, 130 glycemic control 1789, 179 risk factors 81
osteomyelitis 101 insulin therapy 162 screening 61
osteopenia 22 labor/delivery 177, 180, 184 sulfonylurea therapy 144
otitis externa, malignant 21, 21 management plan 177 type 2 diabetes 111
ovarian cancer 43 maternal risks 182 renal function, assessment 66
oxidative stress 79, 80 type 1 diabetes 180, 185 renal papillary necrosis 114
type 2 diabetes 181, 181 renal replacement therapy 11819
P preproinsulin 31 renal transplantation 119
pain, neuropathic 90, 94 prescription charges 69 repaglinide 141, 145
pancreas 11, 25 prevalence 1213 resistance training 82
exocrine disease 16 prevention, type 2 diabetes 567, 142, respiratory distress syndrome, neonate
transplantation 119 147, 148, 149 184
see also cells priapism 95 respiratory symptoms, inhaled insulin
pancreatitis, acute 152 PROactive study 147, 148 158
papaverine, intracavernous injection 95 progesterone-only contraceptive pill 178 retinal detachment 108
pathophysiology 11 proinsulin 31, 36, 155 retinal ischemia 107
patient education 68 prolactin 154 retinal laser photocoagulation 110
pegaptanib 110 proprioceptive deficits 89 retinopathy 105
penile implant surgery 96 prostaglandin E-1 95 examination 61
percutaneous transluminal coronary protein intake 135 and hypoglycemia 169
angioplasty (PTCA) 76 restriction 117 non-proliferative 1067, 106
perinatal outcomes 177, 181 protein kinase C-beta (PKC-) 80 pathophysiology 80
peripheral arterial disease 98, 101 proteinuria prevalence 105
peripheral nerve palsies 91 development 11113 proliferative 106, 108
peroxisome proliferator-activated diagnosis 114 risk factors 78, 81
receptors (PPARs) 55, 146, 146 overt 113, 116 treatment and management 10910
phenformin 130 prurigo, nodular 23 rhinocerebral mucormycosis 21, 21
phentolamine 95 pseudohypoxia 80 risperidone 121
phosphodiesterase type-5 (PDE5) puberty 64 ROS, see reactive oxygen species
inhibitors 95 rosiglitazone 57, 146, 148
pulses, foot 98, 100
physical activity, see exercise rotator cuff syndrome 22
pupillary disorders 93
Pima Indians 45, 47, 81 roux-en-Y gastric bypass 138
pyelonephritis, emphysematous 21
pioglitazone 146, 147 rubeosis iridis 105
pyruvate 28
Pittsburgh Epidemiology of Diabetes
Complications study 43 Q S
plantar pressure 102 quadriceps muscles, wasting 92 salicylate poisoning 125
platelet IIb/IIIa inhibitors 767 saline, normal 125
podiatrist 98, 99 R salt intake 136
polymorphisms 33, 36, 41 RabsonMendenhall syndrome 33 salt restriction 82
polyol pathway 79, 80 race, see ethnicity saxagliptin 66
polyuria 19, 129 radiculopathy 91, 94 screening
population risk 38 radiography, diabetic foot 101, 103 complications of diabetes 601
postural hypotension 92, 93, 94 radiological contrast 143 type 1 diabetes 40, 44
potassium channels, ATP-sensitive 32, Ramadan 678 type 2 diabetes 56
143 ramipril 83 second messenger systems 36
gene mutations 144 Randle cycle hypothesis 54 secondary diabetes 16, 18, 47
potassium chloride 175 rash 144
potassium, serum levels 115, 125, 126