41

Diabetes Mellitus
Benjamin J. Miller

http://evolve.elsevier.com/Banasik/pathophysiology/
• Review Questions and Answers • Case Studies
• Glossary (with audio pronunciations for selected terms) • Key Points Review
• Animations

KEY QUESTIONS
• Which hormones are involved in the regulation of serum glucose
level, and under what physiologic conditions would each be
secreted?
• What are the differentiating characteristics of type 1 and type 2
diabetes?
• How do the pathophysiologic processes differ among the various
types of diabetes?
• What clinical findings are associated with hyperglycemia, and
how do they differ from those of hypoglycemia?
• How is diabetes mellitus diagnosed, monitored, and managed?
• What are the acute and chronic complications of diabetes
mellitus?

CHAPTER OUTLINE
Regulation of Glucose Metabolism, 816 Neuropathic Complications, 827
Hormonal Regulation, 816 Complications in Pregnancy, 827
Neural Regulation, 817 Treatment and Education, 827
Exercise, 818 Nutrition, 828
Stress, 818 Obesity and Eating Disorders, 828
Glucose Intolerance Disorders, 820 Exercise, 829
Classification of Glucose Intolerance Disorders, 820 Pharmacologic Agents, 829
Prediabetes, 820 Oral Antidiabetic Agents, 829
Impaired Glucose Tolerance and Impaired Fasting Glucose Incretin Enhancers, Incretins, and Amylins, 830
Tolerance, 820 Insulin, 830
Diabetes Mellitus, 821 Stress Management, 831
Type 1 Diabetes Mellitus, 821 Assessment of Efficacy, 831
Type 2 Diabetes Mellitus, 823 Pediatric Considerations, 833
Other Specific Types of Diabetes, 824 Goals of Therapy, 834
Gestational Diabetes Mellitus, 824 Acute Complications, 834
Screening for Diabetes, 824 Chronic Complications, 834
Clinical Manifestations and Complications, 825 Treatment, 834
Acute Hyperglycemia, 825 Geriatric Considerations, 834
Diabetic Ketoacidosis, 825 Goals of Therapy, 835
Nonketotic Hyperglycemic Hyperosmolar Syndrome, 826 Acute Complications, 835
Chronic Hyperglycemia, 826 Chronic Complications, 835
Vascular Complications, 826 Treatment, 835
Macrovascular Complications, 826
Microvascular Complications, 826

815
816 Unit XI Endocrine Function, Metabolism, and Nutrition
The public health impact of diabetes mellitus is enormous. According
to the Centers for Disease Control (CDC) (2017) more than 30 million
persons (over 9% of the population) have diabetes mellitus, although it
is estimated that only 72% are aware of their diagnosis. Should this trend
continue unabated, worldwide the number of persons with diabetes will
rise to 439 million by 2030. The annual cost of diabetes to the U.S. medical
care system was estimated to be $245 billion in 2012 (41% increase
from 2007), with almost half of the total cost attributed to inpatient
diabetes care. The American Diabetes Association (2016) estimates the
cost may be closer to $322 billion per year. Diabetes mellitus is the
seventh leading cause of death and is a major cause of disability in
the United States, as well as a major risk for heart disease, end-stage renal
disease, blindness, amputation, and complications of pregnancy. The
disease disproportionately affects non-Caucasian and elderly individuals.
REGULATION OF GLUCOSE METABOLISM
Because diabetes mellitus affects the utilization of all energy nutrients,
it is helpful to review energy nutrient metabolism to understand the
disease process. The energy requirements of humans are predominantly
met by glucose and fats. Produced from endogenous glycogen stores
in the muscles and liver or manufactured from such substrates as amino
acids and lactate, glucose is supplied to the bloodstream from the
gastrointestinal tract and liver. Glucose is typically present in greater
quantities in extracellular fluid than within cells.
Cells are variously permeable to glucose, and the diffusion of glucose
into them is accomplished by glucose transporters (GLUT 1 to 4) specific
to each tissue. GLUT 1 to 3 transporters are insulin independent; they
remain in the plasma membrane whether or not insulin is present.
GLUT 1 is the major glucose transporter at the blood–brain barrier,
and GLUT 3 is the dominant glucose transport molecule for neurons.
GLUT 2 is the primary glucose transporter in the liver and is present
in small quantities in the pancreatic β cells. GLUT 1 and GLUT 3 are
the predominant glucose transport molecules in the pancreatic β cells.
GLUT 4, found in muscle and adipose cells, is insulin dependent.
In the absence of insulin GLUT 4 is sequestered in vesicles located
within the cell. When insulin binds to insulin receptors, an intracellular
signaling cascade occurs that causes the vesicles with GLUT 4 in their
membranes to move (translocate) to the plasma membrane, enabling
glucose entry into the muscle cell or adipocyte. When insulin no longer
binds to its receptor, GLUT 4 is removed from the plasma membrane.
Hormonal Regulation
Protein and fat metabolism is regulated by the anabolic effects of insulin.
Insulin is synthesized in the pancreas by the β cells of the islets of
Langerhans. The islets are groups of cells dispersed throughout the
pancreas. Within the islets can be found β cells that produce insulin in
the form of proinsulin, α cells that produce glucagon, δ cells that produce
somatostatin, and F cells that produce pancreatic polypeptide. The
primary stimulus for release of insulin from the pancreatic β cells is
glucose. Glucose enters the β cells by facilitated diffusion through GLUT
1 and GLUT 3 carriers in the plasma membrane (Fig. 41.1). The
concentration of glucose in the extracellular fluids determines how
much enters the cell. Glucose within the β cell triggers a cascade of
events that results in exocytosis of vesicles containing insulin (see Fig.
41.1). Proinsulin is produced and packaged into vesicles along with
enzymes that cleave proinsulin into insulin and C-peptide (Fig. 41.2).
Insulin binds to its receptor on insulin-sensitive cells and triggers glucose
uptake through GLUT 4 carriers (Fig. 41.3). These carriers are sequestered
within the cell when insulin levels are low and then sent to the plasma
membrane to transport glucose when insulin levels are higher. Insulin
mediates other effects besides glucose uptake. Insulin appears to increase
the uptake and to decrease the release of amino acids by skeletal muscle,
Glucose
GLUT 1
1
Glucose
2 Glucokinase
Glucose-6-phosphate
Oxidation
3
Closes
ATP K+
4 K+
5
Depolarization
7
2+
Opens
[Ca ] 6 Ca2
+
8
Exocytosis
Insulin and amylin
FIG 41.1 Processes of glucose-stimulated exocytosis of insulin from
β cells of the pancreas. Glucose enters the β cells by facilitated diffusion
through GLUT 1 in the plasma membrane. Glucose triggers production
of ATP, which closes ATP-sensitive K+ channels and promotes depolariza-
tion of the cell. Depolarization triggers opening of voltage-sensitive Ca2+
channels, allowing calcium ions to enter the cell. Calcium ions interact
with release-site proteins and trigger exocytosis of stored insulin and
amylin.
thus inducing protein synthesis and preventing muscle breakdown. The
amount of stored fats in the form of triglyceride is potentiated by the
action of insulin in preventing fat breakdown and inducing lipid forma-
tion. Insulin also appears to have a role in growth by stimulating the
secretion of insulin-like growth factor 1 (somatomedin).
Normal glucose metabolism is usually described in reference to the
fed and fasting (or absorptive and postabsorptive, respectively) states.
The fed state occurs after ingestion of a meal and is characterized by
utilization and storage of ingested energy nutrients. The fasting state
is characterized by utilization of stored nutrients for the energy needs
of the body.
In the fed state, glucose from ingested food provides the primary
energy source (Fig. 41.4). The postprandial rise in blood glucose level
and the presence of certain gastrointestinal hormones stimulate the
production of insulin. Initial stimulation produces a brief rise in insulin
secretion, termed the first phase. The continued presence of increased
concentration of glucose produces the second phase of insulin secretion,
a state characterized by insulin synthesis. Amylin is a peptide hormone
produced by pancreatic β cells and cosecreted with insulin. Amylin acts
on the area postrema (AP) in the brain to inhibit gastric emptying,
 CHAPTER 41 Diabetes Mellitus 817

52 51 50 49 48
53 47
54 46
55 Gln Leu Gly Gly Leu Gly 45
56 Leu Ala Gly 44
57 Ala Gly
Leu Leu 43
58 Glu Connecting peptide Glu 42
59
Gly Val
41
60 Pro Ala
61 Pro 40
Gly
62 Gln 39
Ala
Lys
63
Arg Gln 38
1 Gly Pro 37

2 IIe Asn 36

3 Val Gln 35
COOH
NH2 Asn
4 Glu Ala 34
21
Cys
5 Gln Glu
Phe S Tyr 20 33
1
Cys S 19 Arg
Val 6 Asn
2 A Chain 32
Cys Glu 18 Arg
Asn 7 Thr Leu
3 Ser Gln 17 31
Gln IIe Cys Ser Leu Tyr Ala
S 8 16 S
4 9 15 Lys 30
His 10 11 12 13 14
5 S Pro 29
Leu
Thr 28
6 Cys Tyr
Gly S Phe 27
7
Ser Phe 26
8 B Chain 25
His Gly
9 Leu Arg 24
Val Glu Glu 23
10 Ala Leu Tyr Leu Val Cys Gly 22
11 21
12
13 14 19 20
15 16 17 18
FIG 41.2 Structure of proinsulin. The blue-colored amino acids represent the insulin that is released when
the C-peptide (connecting peptide) segment is cleaved.

induce satiety, and prevent postprandial spikes in blood glucose levels.
Suppression of glucagon release by amylin is from a paracrine effect
within the pancreatic islets and does not require any participation by
the AP.
The ingestion of nutrients stimulates the release of incretin hormones,
which include glucose-dependent insulinotropic polypeptide (GIP) and
glucagon-like peptide 1 (GLP-1) from cells in the intestine. Both
hormones stimulate production of insulin in the presence of glucose,
promote proliferation of β cells, and inhibit apoptosis. The presence
of these hormones and their effect on blood glucose level is known as
the incretin effect. With parenteral nutrition, the incretin effect is not
observed. In addition, GLP-1 delays gastric emptying, inhibits glucagon
production, and increases satiety.
The presence of insulin stimulates the diffusion of glucose into
adipose and muscle tissue and inhibits the production of glucose by
the liver. After diffusion into the cell, glucose may be oxidized for the
energy needs of the cell, a process termed glycolysis. Most ingested
glucose is utilized in glycogenesis (production of glycogen in the muscle
and the liver) (see the Metabolic Syndrome section in Chapter 42).
In the fasting state, glucose is produced by glycogenolysis (breakdown
of stored glycogen) in the liver and muscles and by gluconeogenesis
(production of glucose from amino acids and other substrates) in the
liver (Fig. 41.5). Insulin levels, no longer stimulated by an influx of
ingested glucose, fall to a basal level. The catabolic effects of the absence
of insulin are evident in the stimulation of glycogenolysis and are
accompanied by a rise in glucagon levels. If insulin is the hormone
that dominates the fed state, glucagon dominates the fasting state.
Glucagon-stimulated glycogenolysis and gluconeogenesis are responsible
for up to 75% of glucose production in the fasting state. The primary
source of energy to muscle tissue in the fasting state is free fatty acids
produced by lipolysis (breakdown of fat from adipose tissue). Lipolysis
is stimulated by the decline in plasma insulin levels.
Other hormones referred to as counterregulatory hormones have a
role in glucose metabolism in the fasting state. Corticosteroids stimulate
gluconeogenesis and counteract the hypoglycemic action of insulin.
Growth hormone increases peripheral insulin resistance and prevents
insulin from suppressing hepatic glucose production. Catecholamines
augment glucose production by prompting hepatic glycogenolysis and
gluconeogenesis.
Neural Regulation
There is a strong connection between the neural regulatory pathways
and the enteric function of digestion, motility, secretion, absorption,
and defense. Neural influences from the sympathetic and parasympathetic
nervous system are directly involved with carbohydrate metabolism
and glucose utilization. There are glucose-sensitive receptors in the
brain, mouth, and pancreatic β cells and also in the hepatic portal vein.
Once food is placed in the mouth, there is stimulation of the parasym-
pathetic nervous system with stimulation of the β cells for insulin release.
This is referred to as first-phase insulin release. Glucose-sensitive cells
are located in many areas of the brain. These are activated by a decline
in glucose levels (glucose-inhibited neurons [GI neurons]) or by a rise
in glucose concentrations (glucose-excited neurons [GE neurons]).
Under the control of the vagus pathway, the parasympathetic nervous
818 Unit XI Endocrine Function, Metabolism, and Nutrition

Insulin
Glucose

Insulin receptor  

GLUT-4  

P P

P P IRS-1 P
CBL

P IRS-2 P

P IRS-3 P

GLUT-4 P IRS-4 P
vesicle
P GAB-1 P

P13K MEK/ERK

AKT MAP kinase

pathway

Increased glycogen/lipid/protein synthesis

Decreased lipolysis
Cell growth and differentiation
FIG 41.3 The insulin receptor is a protein kinase receptor that triggers an enzyme cascade within the cell.
One effect of insulin binding to its receptor is the translocation of sequestered GLUT 4 transporters to the
cell surface. The GLUT 4 carriers are passive and transport glucose down its concentration gradient. Dotted
lines are indirect pathways of activation. AKT, Protein kinase B; CBL, Casitas B lineage proto-oncogene; GAB,
alpha-1-B glycoprotein associated binding protein; IRS, insulin receptor substrates; MAP, mitogen activated
protein; MEK/ERK, extracellular-regulated kinase; PI3K, phosphatidylinositol 3-kinase.

system not only stimulates the release of insulin but also can influence
the secretion activity and β-cell mass.
Glucagon is predominantly regulated by the sympathetic nervous
system in response to hypoglycemia. The hepatoportal vein contains
glucose-sensitive nerve fibers; when stimulated they release norepi-
nephrine and, along with epinephrine released from the adrenals, activate
α cells to release glucagon.
Exercise
Increasing activity requires increased fuel for muscle tissue. At the onset
of exercise, insulin levels drop and glucagon and catecholamine levels
initially rise and increase the production of free fatty acids, the primary
energy source of resting muscle (Fig. 41.6). Falling insulin levels and
increased glucagon levels stimulate glycogenolysis. Under the influence
of catecholamines, muscle tissue shifts from using primarily fatty acids
for fuel to using stored glycogen. The relative absence of insulin and
the increased production of glucagon also stimulate hepatic glycogenolysis.
Glucose released by the liver increasingly meets the energy needs of
muscle tissue while exercise continues. After 10 to 40 minutes of exercise,
blood glucose use by muscle tissue increases 7 to 20 times. The interac-
tions of hormones thus produce the mixture of glucose and free fatty
acids used by muscle tissue during exercise.
Muscle tissue is affected not only by the influence of hormones but
also by exercise itself. The resulting increase in insulin sensitivity can
last as long as 16 hours. Thus in normal metabolism, increased insulin
sensitivity allows normal blood glucose values in the presence of lower
levels of circulating insulin.
Stress
During stress such as injury, illness, and pain, stress hormones, including
corticosteroids and catecholamines, interact to ensure continuous supplies
of glucose. Corticosteroids increase the production of glucose in the
liver and elevate the production of glucagon. Glucocorticoids also decrease
the utilization of glucose by muscle tissue by diminishing the effect of
insulin on glucose transporters and by generating a decline in the number
of insulin receptors and their function.
Catecholamines increase plasma glucagon levels, increase glucose
production by the liver, and decrease the use of glucose by muscle and
fat tissue. The production of fatty acids that is triggered by the action
of catecholamines further inhibits glucose uptake in the periphery. The
series of events produced by traumatic stress is referred to as stress
hyperglycemia.
Psychological stress can produce metabolic changes comparable with
those of physical stress. Deterioration in metabolic control has been
 CHAPTER 41 Diabetes Mellitus 819

G Neural tissue

Gastrointestinal tract

Insulin

Bloodstream Pancreas

G
G
G
G Muscle tissue
(glycogenesis and
glycolysis)
Liver
(glycogenesis)
G

Adipose tissue

FIG 41.4 Energy metabolism in the fed state. G, Glucose.

Neural tissue

Gastrointestinal tract

Glucagon

Bloodstream Pancreas

FFA

G
G
Muscle tissue

Liver
(glycogenolysis and FFA
gluconeogenesis)
Adipose tissue

FIG 41.5 Energy metabolism in the fasting state. FFA, Free fatty acid(s); G, glucose.
820 Unit XI Endocrine Function, Metabolism, and Nutrition
Gastrointestinal tract
Bloodstream
G
G
Liver
(glycogenolysis and
gluconeogenesis)
FIG 41.6 Energy metabolism during exercise. FFA, Free fatty acid(s); G, glucose.
noted in stressed diabetic subjects. However, the response is by no
means universal. An increase in blood glucose levels has frequently
been observed during acute stress reflecting responses to psychological
stress (e.g., disordered eating).
KEY POINTS
• Plasma membrane permeability to glucose is determined by the type and
density of glucose transport proteins in the membrane. In some tissues,
particularly muscle and fat, the density of facilitative glucose transporters
is regulated by insulin. Insulin binding to receptors on the cell surface results
in translocation of glucose transporters to the cell surface. Glucose enters
the cell passively by facilitated diffusion. Neurons, endothelial cells, and
erythrocytes have glucose transporters that do not require insulin.
• The metabolic effects of insulin include enhancing protein synthesis and
inhibiting gluconeogenesis, enhancing fat deposition and inhibiting lipolysis,
and stimulating cellular growth by enhancing somatomedin secretion. Insulin
is synthesized in pancreatic β cells as proinsulin. Proinsulin is stored in
granules, where it is cleaved into insulin and C-peptide. A postprandial rise
in the levels of glucose and other substrates stimulates the release of
insulin into the bloodstream. During fasting, when blood glucose levels fall,
the decrease in insulin production and the increase in glucagon secretion
lead to lipolysis, glycogenolysis, and gluconeogenesis.
• Exercise has complex effects on glucose metabolism. The decrease in produc-
tion of insulin and the increase in secretion of glucagon and catecholamines
lead to elevated blood glucose levels. However, exercising muscle has
increased insulin sensitivity, which facilitates glucose uptake.
• A number of hormones released during stress increase blood glucose levels
and oppose the effects of insulin. Catecholamines, glucocorticoids, and
glucagon may precipitate stress hyperglycemia.
Neural tissue
Glucagon
Pancreas
FFA
FFA
G
G Muscle tissue
FFA
FFA
Adipose tissue
GLUCOSE INTOLERANCE DISORDERS
Classification of Glucose Intolerance Disorders
Diabetes mellitus is not a single disease entity; as many as 30 different
disorders may be called diabetes. Criteria for diagnosing the different
conditions, all associated with glucose intolerance, were established by
the Expert Committee on the Diagnosis and Classification of Diabetes
Mellitus in 2011.
Classifications include two prediabetes classes and four clinical classes
(Box 41.1). Prediabetes classes are impaired glucose tolerance and
impaired fasting glucose tolerance. The four clinical classes are type 1
diabetes mellitus, type 2 diabetes mellitus, other specific types of diabetes
mellitus, and gestational diabetes mellitus (GDM).
Prediabetes
Impaired Glucose Tolerance and Impaired Fasting
Glucose Tolerance
Guidelines for diagnosing the categories of impaired glucose tolerance
(IGT) and impaired fasting glucose tolerance (IFG) are listed in Box
41.2. IGT and IFG are intermediate stages between normal glucose
metabolism and the onset of diabetes. The pathophysiology of pre-
diabetes is complex with a distinct relationship of elevated glucose
levels and the development of insulin resistance. Glucose release is
stimulated by the mass of metabolically active tissues, including fat-
free mass and fat mass. The signals to stimulate gluconeogenesis are
greater than the counterregulatory effects, resulting in hepatic insulin
resistance.
When glucose levels remain high, the fat-free tissues such as muscle
become supersaturated with glucose and start to down-regulate the
glucose transporters, accelerating systemic insulin resistance.
 CHAPTER 41 Diabetes Mellitus 821

BOX 41.1 Classifications of Glucose Metabolism Disorders

Prediabetes (Increased Risk for Diabetes Mellitus) c. Glucagonoma
Impaired fasting glucose levels d. Pheochromocytoma
Impaired glucose tolerance e. Hyperthyroidism
f. Somatostatinoma
Type 1 Diabetes Mellitus g. Aldosteronoma
Type 1A: Immune mediated h. Others
• Polygenic 5. Drug or chemical induced
• Monogenic a. Pyriminil (Vacor)
• Latent autoimmune diabetes in adults b. Pentamidine
Type 1B: Idiopathic c. Nicotinic acid
d. Glucocorticoids
Type 2 Diabetes Mellitus e. Thyroid hormone
Other Specific Types of Diabetes f. Diazoxide
1. Genetic defects of β-cell function g. β-Adrenergic agonists
a. Chromosome 12, HNF1A (formerly MODY3) h. Thiazides
b. Chromosome 7, glucokinase (formerly MODY2) i. Phenytoin (Dilantin)
c. Chromosome 20, HNF4A (formerly MODY1) j. Interferon-α
d. Chromosome 13, insulin promoter factor 1 (IPF-1, MODY4) k. Others
e. Chromosome 17, HNF-1β (MODY5) 6. Infections
f. Chromosome 2, NeuroD1 (MODY6) a. Congenital rubella
g. Mitochondrial DNA b. Cytomegalovirus
h. Others c. Others
2. Genetic defects in insulin action 7. Uncommon forms of immune-mediated diabetes
a. Type A insulin resistance a. Stiff-man syndrome
b. Leprechaunism b. Anti–insulin receptor antibodies
c. Rabson–Mendenhall syndrome c. Others
d. Lipoatrophic diabetes 8. Other genetic syndromes sometimes associated with diabetes
e. Others a. Down syndrome
3. Diseases of the exocrine pancreas b. Klinefelter syndrome
a. Trauma/pancreatectomy c. Turner syndrome
b. Neoplasia d. Friedreich ataxia
c. Cystic fibrosis e. Huntington chorea
d. Hemochromatosis f. Laurence–Moon–Biedl syndrome
e. Fibrocalculous pancreatopathy g. Myotonic dystrophy
f. Pancreatitis h. Porphyria
g. Others i. Prader–Willi syndrome
4. Endocrinopathies j. Others
a. Acromegaly
b. Cushing syndrome Gestational Diabetes Mellitus

Data from American Diabetes Association: Standards of medical care for diabetes, Diabetes Care 2016;39(Suppl 1):S13–S23.
Dib S, Gomes M: Etiopathogenesis of type 1 diabetes mellitus: prognostic factors for the evolution of residual beta cell function, Diabet Metab
Syndrome 2009;1(1):25.

into three subcategories. Polygenic type 1 diabetes involves two or more

Diabetes Mellitus
Type 1 Diabetes Mellitus
Type 1 diabetes mellitus is, by definition, characterized by destruction
of the β cells of the pancreas. Type 1 diabetes can occur at any age, but
peaks at the ages of 2, 4 to 6, and 10 to 14 years of age. Type 1 diabetes
accounts for 10% of all diabetes and affects 1.25 million people in the
United States and approximately 10 to 20 million people globally. The
incidence is 1 in every 300 to 600 children and adolescents. Caucasian
populations are more susceptible to type 1 diabetes mellitus than are
African American, Hispanic, Asian, or Native American populations.
Little gender difference is noted in the incidence of type 1 diabetes
mellitus in children younger than age 15. However, more men than
women are affected in the population.
Etiology. The two forms of type 1 diabetes are type 1A immune-
mediated diabetes, which is the most common, and type 1B idiopathic,
which is rare. Immune-mediated type 1A can be further delineated
genetic loci and accounts for 80% to 90% of type 1 cases. Monogenic
causes of type 1 diabetes are rare and associated with IPEX syndrome
(immune dysfunction, polyendocrinopathy, enteropathy, X-linked). The
final subgroup of type 1 diabetes is latent autoimmune diabetes in
adults (LADA). LADA is linked to the development of T-cell reactivity
to islet antigens and autoantibodies to glutamic acid decarboxylase 65
(GADA65). LADA accounts for 2% to 12% of all cases of diabetes and
is typically diagnosed after the age of 35. Often initially misdiagnosed
as type 2 diabetes, LADA involves destruction of the pancreatic β cells,
resulting in insulinopenia.
Type 1A diabetes is the result of an autoimmune attack on the β
cells of the pancreas. A strong association with the presence of a gene
or genes in the major histocompatibility complex (MHC) on chromosome
6 has been observed. Genes in the MHC are responsible for the creation
of cell-surface proteins (human leukocyte antigens, or HLAs) influencing
the lymphocytes to stimulate or suppress antibody production. Recent
822 Unit XI Endocrine Function, Metabolism, and Nutrition

BOX 41.2
Diagnosis of Prediabetes
Fasting plasma glucose 100 to 125 mg/dL (IFG)
2-hr plasma glucose in the 75-gm oral glucose tolerance test (OGTT) 140 to
199 mg/dL (IGT)
HbA1C: 5.7%–-6.4%
Diagnosis of Diabetes
FPG ≥126 mg/dL. Fasting is defined as no caloric intake for at least 8 hours.*
OR
Symptoms of hyperglycemia and a casual plasma glucose ≥200 mg/dL. Casual
is defined as any time of day without regard to time since last meal. The
classic symptoms of hyperglycemia include polyuria, polydipsia, and
unexplained weight loss.
OR
2-hour plasma glucose ≥200 mg/dL during an OGTT. The test should be performed
as described by the World Health Organization, using a glucose load containing
the equivalent of 75 g of anhydrous glucose dissolved in water.*
OR
HbA1C greater than 6.5%. The test should be performed in a laboratory using
a method that is NGSP certified and standardized to the DCCT assay.
From American Diabetes Association: Diagnosis and classification of
diabetes mellitus, Diabetes Care 2012;35(Suppl 1):S64–S71, doi:
10.2337/dc12-s064.
DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma
glucose; IFG, impaired fasting glucose; IGT, impaired glucose
tolerance; NGSP, National Glycohemoglobin Standardization Program;
OGTT, oral glucose tolerance test.
*In the absence of unequivocal hyperglycemia, criteria 1 to 3 should
be confirmed by repeat testing on a different day.
evidence demonstrates that two primary loci (DR and DQ) confer a
genetic predisposition, whereas other loci may have a protective effect
on the development of type 1 diabetes mellitus.
Viral infection or exposure to a toxic agent may be the responsible
environmental influence for triggering the autoimmune process in
susceptible individuals. The immune system activation is a complex
process of antigen recognition (please see Chapter 9 for a detailed
explanation).
The etiologic progression of type 1B diabetes mellitus is not known.
Idiopathic diabetes is associated with β-cell destruction without
autoimmune markers or HLA association.
Pathogenesis and clinical manifestations. Type 1A diabetes is the
result of destruction of the pancreatic β cells. The process is mediated
by macrophages and T lymphocytes with detectable autoantibodies to
various β cells. The T lymphocytes infiltrate the islets and destroy the
β cells through the secretion of cytokines (CD4 cells) and direct cytotoxic
action (CD8 cells). The preclinical β-cell autoimmunity is variable and
precedes the clinical diagnosis. Specific antibodies that develop against
GADA65, insulinoma-antigen 2, or insulin frequently appear early in
the onset of immune-mediated diabetes. Antibodies may be present
for as long as 13 years before diagnosis, and the order of antibody
appearance is not significant; however, the presence of multiple antibodies
is highly predictive of type 1A diabetes. The presence of these antibodies
results in the destruction of the pancreatic β cells. The presence of
hyperglycemia indicates that autoimmune destruction of β cells has
reached the point at which insulin secretion is inadequate.
Type 1A and 1B diabetes mellitus are characterized by an absolute
insulin deficiency, and thus glucose cannot enter muscle and adipose
tissue (Fig. 41.7). Production of glucose by the liver is no longer opposed
by insulin. Overproduction of glucagon by pancreatic α cells stimulates

KA

Neural tissue
G

Gastrointestinal tract

Glucagon

Bloodstream Pancreas
(no insulin produced)

FFA
KA FFA

KA KA
Muscle tissue
G

G
Liver
(glycogenolysis and FFA
gluconeogenesis)
FFA
Adipose tissue

FIG 41.7 Pathophysiology of energy metabolism in type 1 diabetes mellitus. FFA, Free fatty acid(s); G,
glucose; KA, ketoacid(s).

glycogenolysis and gluconeogenesis. Plasma blood glucose levels rise.
When the maximal tubular absorptive capacity of the kidney is exceeded,
glucose is lost in the urine, and the resulting glycosuria and osmotic
fluid loss eventually lead to profound hypovolemia. Tissues dependent
on insulin for glucose transport do not have glucose available as a
substrate. Neural tissue in the brain responds to this emergency by
promoting eating behavior. The increased thirst (polydipsia), increased
urination (polyuria), and increased hunger (polyphagia) resulting from
the aforementioned processes are the classic symptoms of diabetes.
Type 2 Diabetes Mellitus
Etiology. Individuals with type 2 diabetes mellitus are resistant to
the action of insulin on peripheral tissues. Type 2 diabetes mellitus
affects 90% to 95% of individuals with diabetes in the United States.
Non-Caucasian and elderly populations are disproportionately affected.
The prevalence of diabetes is 7.1% in the non-Hispanic white population,
12.6% in non-Hispanic blacks, and 11.8% in Hispanic/Latino Americans.
The age-adjusted prevalence of diabetes in Native American populations
ranges from 5.5% among Alaska Native adults to 33.5% in American
Indians in southern Arizona. Overall, close to 26.9% of American
individuals older than 65 years have diabetes mellitus. In people under
the age of 20, diabetes affects 25.6 million people in the United States,
or 11.3% of the population. The greatest at-risk population is adolescent
Native Americans.
Risk factors include aging and a sedentary lifestyle, but the most
powerful predictor is obesity. Excessive abdominal (visceral) fat introduces
a greater threat of diabetes mellitus (and cardiovascular disease) than
does lower-body obesity. The initial symptoms of polydipsia, polyuria,
polyphagia, and weight loss may be subtle or absent in type 2 diabetic
patients.
Epidemiologic studies indicate a strong genetic component, but
no specific HLA type has been identified. When one identical twin
G
Gastrointestinal tract
Bloodstream
G G
G Muscle tissue
Liver
(glycogenolysis and
gluconeogenesis)
FIG 41.8 Pathophysiology of energy metabolism in type 2 diabetes mellitus. G, Glucose.
CHAPTER 41 Diabetes Mellitus 823
is affected, there is close to a 100% chance the other twin will be
affected.
Pathogenesis and clinical manifestations. Type 2 diabetes is
characterized by a relative lack of insulin. The processes instrumental
in producing the relative lack of insulin are insulin resistance and β-cell
dysfunction (Fig. 41.8).
The insulin resistance of type 2 diabetes mellitus is defined as a
requirement for more insulin for the same biological action, along with
lowered glucose utilization at all levels of insulin concentration. A
decreased number of insulin receptors and such postreceptor defects
as decreased action of glucose transporters are associated with insulin
resistance. Impaired glycogen synthesis may also be a factor in the
development of type 2 diabetes. Impaired production of insulin by the
pancreatic β cells that intensifies as the disease progresses is also present
in type 2 diabetes mellitus. Individuals with this condition ultimately
have an absent first-phase insulin response and a diminished second-
phase response.
Basal insulin secretion may be higher than normal in type 2 diabetes.
Glucagon secretion is increased absolutely or relatively (relative to insulin
levels). The incretin effect, stimulation of insulin secretion by GLP-1 and
GIP, is diminished in type 2 diabetes. Individuals with this condition may
be predominantly insulin resistant or predominantly insulin deficient.
Type 2 diabetes mellitus is a progressive disease characterized by the
development of insulin resistance, at first compensated for by increased
insulin production and hyperinsulinemia. Decompensation occurs as
the impaired β cells are unable to produce sufficient insulin to overcome
insulin resistance. Insulin levels, however, remain elevated above normal
until later in the progression of the disease. Relatively decreased insulin
levels, continued insulin resistance, and hyperglucagonemia result in
the hyperglycemia of diabetes. Hyperglycemia itself may then increase
insulin resistance and further diminish insulin secretion. The latter
process has been termed glucose toxicity.
Neural tissue
↓ Insulin
Glucagon
Pancreas
Insulin resistance
Insulin resistance
G
Adipose tissue
824 Unit XI Endocrine Function, Metabolism, and Nutrition
Other Specific Types of Diabetes
• Genetic defects of β cells: The genetic defects of β cells follow an
autosomal-dominant pattern of inheritance and are characterized
by a defect in the production of insulin. Affected individuals are
identified before they reach 25 years of age, The disorder is also
referred to as mature-onset diabetes of the young (MODY). MODY is
a monogenetic disorder affecting approximately 1% of people with
diabetes and tends to be seen in families of people with the condition.
MODY is caused from a mutation in a single gene and passed on to
offspring. Six genes have been identified that cause MODY: HNF1A,
GCK, HNF1B, HNF4A, IPF1, and NEUROD1. Because of the genetic
variation, some people with MODY are treated with insulin, whereas
other people respond to diet, exercise, and oral agents.
• Genetic defects in insulin action: The disorders listed in Box 41.1
result in relatively rare, genetically determined defects of the insulin
receptor.
• Diseases of the exocrine pancreas: Diseases of the pancreas can
affect the insulin-producing capability of the organ (see Box 41.1).
• Endocrinopathies: Excessive production of insulin antagonists (e.g.,
cortisol, growth hormone, glucagon, and epinephrine) affects glucose
metabolism (see Box 41.1).
• Drug- or chemical-induced diabetes: Many chemicals can affect
the ability of the pancreas to produce insulin (see Box 41.1).
• Infections: Destruction of the β cells of the pancreas has been linked
to various infectious agents (see Box 41.1).
• Uncommon forms of immune-mediated diabetes: Certain auto-
immune disorders are linked to glucose intolerance (see Box 41.1).
• Other genetic syndromes sometimes associated with diabetes:
Certain genetic syndromes are linked to glucose intolerance (see
Box 41.1).
Gestational Diabetes Mellitus
GDM is, by definition, a disorder of glucose intolerance of variable
severity with onset or first recognition during pregnancy. Approximately
4% (may range from 1% to 14% depending on population) of pregnancies
are affected by GDM. GDM represents 90% of all pregnancies complicated
by diabetes.
Etiology. In its pathophysiologic characteristics, GDM closely
resembles type 2 diabetes mellitus. As in type 2 diabetes, tissue insulin
resistance is present during normal pregnancy. Insulin resistance in
normal pregnancy is most likely precipitated by the presence of placental
hormones: human chorionic somatomammotropin, estrogen, and
cortisol. The weight gain of pregnancy is also responsible for an increase
in insulin resistance. During pregnancy, women require two to three
times as much insulin as they do in the nonpregnant state. Women
with gestational diabetes are unable to produce sufficient insulin to
meet their needs during pregnancy.
Risk factors for GDM include severe obesity, history of gestational
diabetes, previous offspring weighing more than 9 lb at birth, presence
of glycosuria, or a strong family history of type 2 diabetes. High-risk
individuals should be screened as soon as possible after confirmation
of pregnancy. Because insulin needs rise sharply in the twenty-fourth
to twenty-eighth weeks of pregnancy, it is recommended that all pregnant
women older than 25 years be screened for gestational diabetes during
the twenty-fourth to twenty-eighth weeks of gestation with either a
one-step or a two-step screening strategy. Younger pregnant women
who are obese, have a first-degree relative with diabetes, are members
of an ethnic/racial group with a high prevalence of diabetes (e.g., African
American, Hispanic, Asian, Native American), have a history of abnormal
glucose tolerance, or have a history of poor obstetric outcome should
also be screened (Table 41.1). Untreated gestational diabetes can result
TABLE 41.1 Diagnosis of GDM With a
One-Step or Two-Step Test*
TWO STEP
One Step
75-g Glucose 50-g Glucose 100-g Glucose
Load (Fasting) Load (Nonfasting) Load (Fasting)
Fasting 92 mg/dL NA 95 mg/dL
1 hour 180 mg/dL ≥140 mg/dL 180 mg/dL
2 hours 153 mg/dL NA 155 mg/dL
3 hours NA NA 140 mg/dL
Data from American Diabetes Association: Diagnosis and classification
of diabetes mellitus, Diabetes Care 2015;38(Suppl 1):S8–S16.
*Two or more blood glucose level determinations must be equal to
or greater than these values to establish the diagnosis. The test
should be done in the morning after an overnight fast of between 8
and 14 hours and after at least 3 days of unrestricted diet (150 g of
carbohydrate per day) and unlimited physical activity. The subject
should remain seated and should not smoke throughout the test.
in metabolic abnormalities and stillbirth. However, the most common
complications are macrosomia and neonatal hypoglycemia. Macrosomia
(birth weight greater than 4000 g or >90% for gestational age) is a
result of increased glucose, free fatty acids, and amino acids delivered
to the fetus. Neonatal hypoglycemia is due to increased production of
insulin by the fetal pancreas in response to the chronic stimulation of
hyperglycemia while in utero.
Treatment. Management of GDM includes education regarding
appropriate dietary choices, implementation of an exercise regimen,
and observation of blood glucose and urine ketone levels. If hypergly-
cemia persists, insulin therapy should be initiated. Only glyburide does
not cross the placenta to cause fetal hypoglycemia; this sulfonylurea
may be used in GDM.
Glucose tolerance will return to normal after parturition in 97% of
women with GDM. Women with this condition have a markedly increased
risk for the development of type 2 diabetes mellitus or impairment in
glucose tolerance later in life, especially within the first 5 years post-
partum. In subsequent pregnancies, recurrence varies between 30%
and 84% in women with a history of GDM.
Screening for Diabetes
Because of the high prevalence of undiagnosed type 2 diabetes mellitus,
current recommendations are to screen all adults older than age 45 for
diabetes at least every 3 years. There is some controversy regarding
screening individuals with asymptomatic disease. Individuals who are
obese with risk factors should be screened at more frequent intervals
(Box 41.3).
Screening for gestational diabetes is discussed in the Gestational
Diabetes Mellitus section. It is not recommended that routine screening
for type 1 diabetes mellitus be performed. No agreement has been
reached on the blood level of immune markers that represents a risk
for type 1 diabetes or on treatment after identification of the presence
of such markers.
KEY POINTS
• Diabetes mellitus is an endocrine disorder diagnosed by the presence of
chronic hyperglycemia. Diabetes may be diagnosed based on the fasting
(8-hour caloric fast) plasma glucose level ≥126 mg/dL (7.0 mmol/L) or the
2-hour oral glucose tolerance test ≥200 mg/dL (11.1 mmol/L) repeated on
separate days. In the presence of symptoms of hyperglycemia, a single

random plasma glucose level greater than 200 mg/dL would confirm a
diagnosis of diabetes. The glycosylated hemoglobin level (HbA1C) may be
used to confirm a diagnosis of diabetes when the HbA1C ≥6.5% (48 mmol/
mol). The test should be performed in a laboratory using a method that is
certified and standardized.
• The classification of diabetes mellitus includes two broad categories: (1)
actual glucose intolerance and (2) risk of glucose intolerance. Disorders of
actual glucose intolerance include type 1, type 2, other specific types, and
gestational diabetes. Prediabetes categories include individuals with impaired
glucose tolerance and those with impaired fasting glucose tolerance. Individu-
als at risk for glucose intolerance include those with a history of glucose
intolerance and those with a positive family history, obesity, or other risk
factors.
• Persons with type 1 diabetes have an absolute insulin deficiency caused
by pancreatic β-cell failure. Immune-mediated type 1A diabetes is associated
with a specific HLA genetic makeup and is autoimmune. Idiopathic type 1B
diabetes is not an autoimmune process. Type 1 diabetes may affect people
of any age. Classic manifestations include polyuria, polydipsia, polyphagia,
and weight loss.
• Persons with type 2 diabetes have a relative insulin deficiency caused by
decreased tissue sensitivity and decreased responsiveness to insulin. A
decreased number of insulin receptors or abnormal translocation of glucose
transporters is suspected. As the disease progresses, pancreatic insulin
production may become impaired. Obesity, female gender, family history,
older age, and lack of exercise are risk factors.
• Gestational diabetes is a disorder of glucose intolerance that is diagnosed
during pregnancy. Placental hormones and weight gain are contributing
factors. High infant birth weight and neonatal hypoglycemia are common
complications. Gestational diabetes is a risk factor for the later development
of type 2 diabetes.
BOX 41.3 Screening for Diabetes
Testing should be considered in all adults who are overweight (BMI ≥25 kg/
m2) and have additional risk factors:
• Physical inactivity
• First-degree relative with diabetes
• Members of a high-risk ethnic population (e.g., African American, Latino,
Native American, Asian American, and Pacific Islander)
• Women who delivered a baby weighing >9 lb or were diagnosed with GDM
• Hypertension (≥140/90 mm Hg) or receiving therapy for hypertension
• HDL cholesterol level <35 mg/dL and/or triglyceride level >250 mg/dL
• Women with polycystic ovarian syndrome
• IGT or IFG on previous testing
• Other clinical conditions associated with insulin resistance (e.g., severe
obesity and acanthosis nigricans)
• History of CVD
In the absence of these criteria, testing for prediabetes and diabetes should
begin at age 45 years.
If results are normal, testing should be repeated at least at 3-year
intervals, with consideration of more frequent testing depending on
initial results and risk status.
Data from American Diabetes Association: Standards of medical care
in diabetes, Clin Diabetes 2016;34(1):3–21.
CVD, Coronary vascular disease; HDL, high-density lipoprotein; IFG,
impaired fasting glucose; IGT, impaired glucose tolerance.
CHAPTER 41 Diabetes Mellitus 825
CLINICAL MANIFESTATIONS
AND COMPLICATIONS
Acute Hyperglycemia
Etiology. Acute hyperglycemia is most commonly caused by altera-
tions in nutrition, inactivity, inadequate use of antidiabetic medications,
or any combination of these factors. Persistent fasting hyperglycemia
can occasionally be attributed to the dawn phenomenon, which is a
rise in blood glucose concentration in the early morning hours attributed
to increased growth hormone, cortisol, glucagon, and epinephrine release.
Complications. A primary concern both of health care providers
and of individuals with diabetes is avoiding the acute and chronic
complications. Acute complications of diabetes include the signs and
symptoms of hyperglycemia—polydipsia, polyphagia, and polyuria—and
concomitant metabolic and fluid problems. Prolonged insulinopenia
can result in ketoacidosis and nonketotic hyperglycemic coma with the
accompanying more severe electrolyte and fluid derangements.
Acute complications of diabetes also include infections, most com-
monly of the skin, urinary tract, and vagina. Infections that particularly
affect elderly diabetic patients include malignant otitis externa, necrotiz-
ing fasciitis, and persistent candidal infections. Tuberculosis infection
and reactivation can be a particular problem in diabetic residents of
extended care facilities.
Nausea, fatigue, and a generally decreased sense of well-being fre-
quently accompany hyperglycemia. Blurred vision is a common short-
term problem of acute hyperglycemia. These symptoms can be quite
distressing and uncomfortable. Acute complications are directly linked
to hyperglycemia and recede as euglycemia is approached.
Diabetic Ketoacidosis
Continued insulin deficiency and other hormonal influences (increased
levels of catecholamines, cortisol, glucagon, and growth hormone, in
part caused by hypovolemia, physical stress, or insulin deficiency itself)
lead to lipolysis in body tissues. As the catabolic process continues,
metabolism of fats stored in adipose tissue leads to the production of
fatty acids. The resulting fatty acids undergo transformation to ketoacids
in the liver. Hepatic gluconeogenesis in response to tissue glucose depriva-
tion is also responsible for the increased production of ketoacids. Under
normal circumstances, ketoacids can be used by neural and muscle tissue
in energy metabolism. When the normal pathway is saturated, the pH
falls (6.8 to 7.3) and ketone bodies are present in the urine, thus sharply
increasing osmotic fluid loss. Metabolic acidosis ensues as the bicarbonate
concentration decreases, and diabetic ketoacidosis results. In response
to the metabolic acidosis, extracellular hydrogen ions are transported
intracellularly. Physiologically, potassium is constantly leaking into the
vascular space through diffusion and is transported intracellularly via
the sodium–potassium pump. This active transport mechanism requires
insulin, and in the presence of ketoacidosis, the absence of insulin results
in hyperkalemia. Serum potassium levels rise (transient hyperkalemia)
and excess potassium is excreted into the urine, eventually leading to a
net potassium loss. Losses of sodium, magnesium, and phosphorus also
occur as the amount of total body water decreases. Serum levels of the
ions may be normal or elevated due to hypovolemia. Hypovolemia and
dehydration also account for increased values of the following: hematocrit,
hemoglobin (Hb), protein, white blood cell count, creatinine, and serum
osmolality (Table 41.2). Lactic acidosis, or an excessive amount of lactate,
a product of glucose metabolism, can also be present because of hypo-
volemia and possibly reduced uptake of lactate by the liver as a result of
acidosis. Hypovolemia and muscle catabolism are present in persons
with ketoacidosis and often at diagnosis of type 1 diabetes. Hypovolemic
shock can lead to death if the patient is not promptly treated.
826 Unit XI Endocrine Function, Metabolism, and Nutrition
TABLE 41.2 Diabetic Ketoacidosis and
Nonketotic Hyperglycemic Hyperosmolar
Syndrome
Nonketotic
Hyperglycemic
Diabetic Hyperosmolar
Parameter Ketoacidosis Syndrome
Glucose >300 mg/dL >600 mg/dL
Urine ketones Moderate to high None
pH 6.8 to 7.3 Normal
Na+, K+ Low, normal, or high Low, normal, or high
Hct, Hb, protein, WBC High High
count, Cr, BUN,
serum osmolality
BUN, Blood urea nitrogen; Cr, creatinine; Hb, hemoglobin; Hct,
hematocrit; WBC, white blood cell.
Respiratory compensation for the metabolic acidosis in the form
of deep, labored respirations that are “fruity” in odor (Kussmaul respira-
tions) results in lowered Pco2 values (compensatory respiratory alkalosis).
Ketoacidosis may be the initial symptom of a new diagnosis of type 1
diabetes. Other factors that may precipitate ketoacidosis are intercurrent
illness and inadequate treatment. The need for hospitalization for diabetic
ketoacidosis is greatest for individuals less than 45 years of age (39.7
per 1000 individuals with diabetes).
Nonketotic Hyperglycemic Hyperosmolar Syndrome
The relative lack of insulin seen in individuals with type 2 diabetes
mellitus leads to similar but not identical sequelae as the absolute lack
of insulin of type 1 diabetes mellitus. The initial symptoms of polyuria,
polydipsia, and polyphagia may be present, possibly in a more subtle
form. Ketoacidosis is an uncommon occurrence in type 2 diabetes. The
presence of endogenous insulin in type 2 diabetes suppresses the lipolysis
that leads to the production of ketone bodies and subsequently keto-
acidosis. More common in type 2 diabetes mellitus, especially in older
individuals, is nonketotic hyperglycemic hyperosmolar syndrome
(NHHS), characterized by severe hyperglycemia with no or slight ketosis
and striking dehydration. NHHS is more likely to occur in institutional-
ized patients, especially patients unable to recognize or respond
appropriately to thirst. Diabetic ketoacidosis and NHHS can be life-
threatening events, especially in the elderly. Seventy percent of all cases
of NHHS coma occur in individuals older than 64 years. The mortality
rate is approximately 11%.
Chronic Hyperglycemia
Chronic complications associated with diabetes are extensive and are
generally placed into two categories: vascular and neuropathic. The
vascular complications are further subdivided into macrovascular and
microvascular components. Microvascular complications affect the
capillaries, and macrovascular complications involve damage to large
vessels.
Vascular Complications
Macrovascular Complications
Macrovascular complications of diabetes mellitus are defined as damage
to the large blood vessels providing circulation to the brain, heart, and
extremities. Although atherosclerosis is an age-dependent process, the
presence of diabetes results in accelerated atherosclerosis. These complica-
tions include cardiovascular disease and stroke (38.1% of all individuals
with diabetes mellitus over the age of 35), as well as peripheral arterial
disease. The presence of heart and blood vessel disease is increased
twofold to fourfold in individuals with diabetes and is responsible for
more than half of all deaths. Ischemic cerebrovascular accidents (strokes)
are more prevalent in individuals with diabetes and are associated with
poorer outcomes. Cerebrovascular accidents are responsible for almost
1% of hospitalizations of individuals with diabetes mellitus.
Several studies have investigated whether intensive glycemic control
(HbA1C <6.5%) would result in a decrease in cerebrovascular events,
cardiovascular events, and all-cause mortality. The ACCORD study was
the only study to suggest an increase in overall mortality but a significant
reduction in nonfatal coronary events. Other studies have demonstrated
improved overall mortality with aggressive glycemic control (mean
HbA1C of 6.5%) and a 14% reduction in cardiovascular events for a
1% decrease in HbA1C. Despite the reduced mortality, the risk of severe
hypoglycemic events significantly increased.
Diabetes is an independent risk factor for coronary artery disease.
However, several important risk factors—dyslipidemia, hypertension,
and impaired fibrinolysis—are present in uncontrolled diabetes and
decrease with improved blood glucose level control. The latter risk
factor may be linked to the presence of the compensatory hyperinsu-
linemia of type 2 diabetes mellitus. Reduction of insulin resistance by
such hygienic measures as caloric restriction and exercise, and possibly
by pharmacologic means, may be of principal importance in reducing
the incidence of macrovascular complications. Conventional measures
of risk reduction, including measures to control dyslipidemia and
hypertension, continue to be considered essential. Improved glycemic
control is thought to affect the microvasculature rather than the
macrovascular complications.
Microvascular Complications
The microvascular complications of diabetes—retinopathy and
nephropathy—are thought to result from abnormal thickening of the
basement membrane in capillaries. Capillary basement membrane
thickening has been shown to increase with the length of time after
diagnosis and with persistent hyperglycemia.
Hyperglycemia has been shown to disrupt platelet function and
growth of the basement membrane. The presence of proteins altered
by high glucose levels (advanced glycation end products) is also believed
to play a part in the pathogenesis of microvascular complications.
Thickening of capillary basement membranes has been shown to decrease
with improved glycemic control. Other risk factors for microvascular
disease include hypertension and smoking.
Retinopathy is evident in less than 10% of those diagnosed with
diabetes for less than 5 years. However, more than 50% of patients
diagnosed with diabetes for more than 20 years are found to be suffering
with some degree of retinopathy. Because of the prevalence of long-
standing undiagnosed diabetes mellitus, as many as 21% of individuals
with newly diagnosed type 2 diabetes are affected by retinopathy.
Retinopathy is the primary cause of new cases of blindness in adults
in the United States. The incidence of diabetic retinopathy appears to
correlate with the duration of diabetes. Retinopathy is a progressive
disease involving three stages: background retinopathy, preproliferative
retinopathy, and proliferative retinopathy. Background retinopathy is
characterized by microaneurysms and small hemorrhages in the
retinal capillaries. Background retinopathy usually does not affect visual
acuity. Preproliferative and proliferative retinopathies involve further
damage to retinal capillaries, with the latter condition characterized by
capillary neovascularization. The small new capillaries are particularly
prone to hemorrhage. Proliferative retinopathy is managed with laser
photocoagulation.
Nephropathy affects 20% to 40% of individuals with type 1 diabetes.
Fewer individuals with type 2 progress to end-stage renal disease. Diabetic

nephropathy accounts for 40% of cases of end-stage renal disease. Ethnic
origin is a risk factor in the development of diabetic nephropathy, with
African American, Hispanic, and Native American diabetic individuals
experiencing an increased rate of end-stage renal disease compared
with Caucasians. The characteristic lesion of diabetic nephropathy is
glomerulosclerosis, or thickening and hardening of the basement
membrane of capillaries in the glomeruli. Filtration, an essential
component of kidney function, occurs in the glomerulus. The first stage
of diabetic nephropathy is an increase in the glomerular flow rate, or
the rate of blood flow through the glomerulus. This increased flow rate
leads to hyperfiltration in the glomerulus, or a rise in the rate at which
blood is filtered. The mechanisms leading to the increase in glomerular
flow rate are unclear but are evidently related to poor glycemic control.
As hyperfiltration progresses, the glomeruli become damaged. The
resulting glomerulosclerosis leads to blockage and leaking of the capil-
laries. Protein is characteristically seen in the urine, at first in small
amounts (microalbuminuria) and then grossly. As diabetic nephropathy
advances, the glomerular filtration rate drops and chronic kidney disease
ensues. Hypertension is an important contributing factor to diabetic
nephropathy. Management of hypertension with medications that inhibit
angiotensin-converting enzyme has been shown to reduce the rate of
chronic kidney disease, end-stage renal disease, and mortality.
Neuropathic Complications
Diabetic neuropathy produces symptoms in 60% to 70% of individuals
with diabetes and is responsible for 6.8 per 1000 diabetic population
hospitalizations. Neuropathic complications are divided into autonomic
dysfunction and sensory dysfunction. Autonomic complications include
gastrointestinal disturbances, bladder dysfunction, tachycardia, postural
hypotension, and sexual dysfunction. Approximately 35% to 50% of
men with diabetes experience erectile dysfunction. Sensory disturbances
include carpal tunnel syndrome and paresthesias or lack of sensation
in the feet and lower legs. Neuropathy is largely responsible for the
increased risk of serious foot problems in individuals with diabetes.
The rate of lower extremity amputation in individuals with diabetes is
15 to 40 times higher than in nondiabetic individuals. More than 60%
of all nontraumatic amputations in the United States are performed
on individuals with diabetes.
Diabetes in humans and experimentally induced diabetes in animals
are associated with decreased levels of myoinositol in peripheral nerves.
Myoinositol is a cell membrane component normally found in abundance
in nerve tissue. Several theoretical explanations have been proposed for
the myoinositol link to neuropathy. Glucose appears to compete with
myoinositol in transport into the cell. Degradation of glucose to sorbitol
and fructose (the polyol pathway) occurs in the nerves in the presence
of hyperglycemia and insulinopenia. Increased activity of the polyol
pathway also appears to be linked to reduced amounts of myoinositol
in the peripheral nerves. Focal ischemic lesions of the nerves may also
have a role in diabetic neuropathy. Pathologic findings include degeneration
or loss of nerve fibers resulting in decreased nerve function.
Glycemic control has been shown to improve nerve function in
animals and in humans and to decrease perceived pain. In addition to
hyperglycemia, hypertriglyceridemia, obesity, smoking, and hypertension
are modifiable vascular risk factors for the development of neuropathy.
Other risk factors associated with neuropathy include male gender,
white race, older age, and possibly height >175.5 cm. In addition, the
elderly, non-Hispanic blacks, and Mexican Americans are dispropor-
tionately affected. Strong evidence linking prolonged hyperglycemia to
neuropathy and the microvascular complications of diabetes was provided
by the Diabetes Control and Complications Trial, a 9-year multicenter
prospective study designed to examine the effect of intensive insulin
therapy on the development of retinopathy. Renal and neurologic indices
CHAPTER 41 Diabetes Mellitus 827
were also examined. Subjects in this trial were individuals with type 1
diabetes and no or mild retinopathy at baseline. The experimental group
was intensively treated with three or more insulin injections daily or
with insulin delivered by a pump. The incidence of initial retinopathy
was reduced by 76%, and progression of existing retinopathy was reduced
by 54% in the experimental group. Indices of beginning nephropathy
such as microalbuminuria and albuminuria were reduced in the
experimental group by 39% and 54%, respectively. Symptomatic
neuropathy was reduced by 60% in the experimental group. Dilemmas
presented by the Diabetes Control and Complications Trial include the
presence of a significant increase in severe hypoglycemia in the experi-
mental group and some question about the validity of extrapolating
all results to individuals with type 2 diabetes. A large study on the effect
of lowering blood glucose level in type 2 diabetes has also yielded data
on decreased morbidity and mortality with improved glycemic control
(United Kingdom Prospective Diabetes Study).
Complications in Pregnancy
Pregnancy in women with type 1 diabetes has been complicated by an
increased risk for perinatal infant mortality and congenital anomalies.
Metabolic control during pregnancy reduces the risk of perinatal
mortality to a rate approximating that of the general population. An
increased rate of congenital malformations continues to attend pregnan-
cies in women with type 1 diabetes. Because the affected organs develop
early in the first trimester, excellent glycemic control before conception
is recommended. Untreated maternal hyperglycemia can result in
increased rates of macrosomia, shoulder dystocia, and preeclampsia,
as well as death, fractures, and nerve palsies.
KEY POINTS
• The acute complications of diabetes are hyperosmolar coma, ketoacidosis,
and infection. Hyperglycemia may be associated with nausea, fatigue, and
blurred vision.
• Ketoacidosis occurs primarily in type 1 diabetes mellitus as a result of
increased lipolysis and conversion to ketone bodies. Excessive ketones
result in metabolic acidosis, which is recognized by a fall in pH and bicarbon-
ate levels. Ketoacidosis may occur in patients with type 2 diabetes mellitus
under severe stress, such as concomitant sepsis, stroke, or myocardial
infarction. Acidosis-induced hyperkalemia and compensatory hyperventilation
(Kussmaul respirations) resulting in reduced levels of arterial carbon dioxide
are associated findings.
• Nonketotic hyperosmolar syndrome is more common in type 2 diabetes
because endogenous insulin suppresses ketone formation and thus prevents
ketoacidosis. Hyperglycemia may go untreated for a time and result in
persistent glycosuria with osmotic diuresis. Dehydration may be manifested
as high osmolality and hemoconcentration of erythrocytes, proteins, and
creatinine.
• The chronic complications of hyperglycemia are primarily caused by vascular
and neuropathic dysfunction. Individuals with diabetes are prone to vascular
complications, including coronary artery disease, stroke, and peripheral
arterial disease. These complications are related to dyslipidemia, hyperten-
sion, and impaired fibrinolysis. Retinopathy and nephropathy are thought
to be due to hyperglycemia-induced thickening of retinal and glomerular
basement membranes. Neuropathy is manifested as pain and loss of sensa-
tion. Excessive glucose is thought to interfere with myoinositol in neurons.
TREATMENT AND EDUCATION
The usual treatment goals in diabetes are achieving metabolic control
of blood glucose levels and preventing acute and chronic complications.
The American Diabetes Association recommends as goals a preprandial
828 Unit XI Endocrine Function, Metabolism, and Nutrition
blood glucose level between 70 and 130 mg/dL and a postprandial blood
glucose level less than 180 mg/dL for adults with diabetes. A glycemic
control algorithm to guide treatment is presented in Fig. 41.9. The goals
of treatment are accomplished by diet, exercise, medication, and such
hygiene practices as daily foot care and smoking cessation. Each treatment
involves lifestyle changes that are difficult to accomplish initially and
challenging to maintain. Treatment must be individualized to the type
of diabetes and the unique traits of each patient.
Nutrition
Nutrition has often been called the cornerstone of diabetes therapy.
Ideas about the optimal dietary prescription have been far from constant
throughout recorded history. From wheat, fruit, and beer in ancient
Egypt through blood pudding and rancid meats in nineteenth-century
France to more recent investigations of fiber and fat, nutritional con-
troversies are far from over.
FIG 41.9 Algorithm to achieve glycemic control for type 2 diabetes mellitus in adults. ER, Extended release
(Reprinted with permission from the Texas Diabetes Council, Texas Department of State Health Services.
www.tdctoolkit.org.)
In a position statement, the American Diabetes Association has listed
four recommendations for nutritional therapy in patients with diabetes
(Box 41.4). Accomplishing the goals can involve changes in composition
of the diet, meal patterns and timing, and caloric consumption. All the
energy nutrients—carbohydrates, fats, and protein—have an essential
role in optimal nutrition. Obesity and eating disorders such as bulimia
have an important impact on nutritional status.
Obesity and Eating Disorders
Obesity is the strongest risk factor for type 2 diabetes, in addition to
being a risk factor for cardiovascular disease in women. Obesity is
defined as a body mass index (BMI) of greater than 30 kg/m2. BMI
is calculated by dividing body weight in kilograms by the square of
the height in meters. Increased risk for health problems occurs at a
BMI equal to or greater than 25.2 kg/m2. A BMI of 18.5 to 24.9 kg/m2
is considered normal. Weight management is a chronic and difficult
 CHAPTER 41 Diabetes Mellitus 829

BOX 41.4 American Diabetes Association TABLE 41.3 Oral Antidiabetic Agents
Recommendations for Nutritional Therapy Category Class Drugs
1. To promote and support healthful eating patterns, emphasizing a variety of Sensitizers Biguanides Metformin
nutrient-dense foods in appropriate portion sizes, in order to improve overall Thiazolidinediones (TZDs) Pioglitazone, rosiglitazone
health and specifically Secretagogues Sulfonylureas First generation: carbutamide,
a. Attain individualized glycemic blood pressure and lipid goals chlorpropamide, tolbutamide,
b. Achieve and maintain body weight goals tolazamide
c. Delay or prevent complications of diabetes Second generation: glyburide,
2. To address individual nutritional needs based on personal and cultural glipizide, glimepiride
preferences, health literacy and numeracy, access to healthful food choices, Meglitinides Nateglinide, repaglinide,
willingness and ability to make behavioral changes, and barriers to change mitiglinide
3. To maintain the pleasure of eating by providing positive messages about DDP-4 inhibitors Linagliptin, saxagliptin,
food choices while limiting food choices only when indicated by scientific sitagliptin, vildagliptin
evidence Other α-Glucosidase inhibitors Acarbose, miglitol
4. To provide the individual with diabetes with practical tools for day-to-day Gliflozins (SGLT-2 Canagliflozin (Invokana),
meal planning rather than focusing on individual macronutrients, micronu- inhibitors) dapagliflozin (Farxiga), and
trients, or single foods empagliflozin (Jardiance).
Data from American Diabetes Association: Nutrition
recommendations and interventions for diabetes, Diabetes Care
2016;39(Suppl 1):S20–S30.
continued insulin sensitivity can result in hypoglycemia as long as 24
hours after activity.
problem for many individuals. No single strategy has been shown to be Hyperglycemia and ketosis may be a result of exercise under insu-
effective for all individuals. Current recommendations for management linopenic conditions. Safeguards must be built into exercise programs
of obesity include the use of a nutritionally complete diet, a maintenance to prevent hypoglycemia, ketoacidosis, injury, cardiac compromise, and
routine, and an exercise program. A modest weight loss of 2 to 8 kg exacerbation of diabetic complications.
may provide significant clinical benefits in those with type 2 diabetes. The exercise prescription is as essential in diabetes management as
Consult Chapter 42 for additional nutritional risk factors related to the medication or nutrition prescription. The CDC recommends an
obesity. exercise program of moderate intensity for at least 30 minutes, 5 or
Eating disorders such as bulimia and anorexia may be more common more days per week or vigorous intensity for 20 minutes, 3 or more
in women with type 1 diabetes. Inducing weight loss by reducing insulin days per week (with no more than 2 consecutive days without exercise).
levels has also been noted. In order for clinicians to be aware of eating All individuals should be encouraged to reduce sedentary time by
disorders in their patients, careful assessment is necessary. breaking up extended amounts of time (>90 min) spent sitting.
Exercise should be avoided if ketosis is present, because it can indicate
Exercise an acute shortage of insulin. Exercise under the latter conditions can
Exercise, one of the oldest treatments for diabetes, was prescribed in lead to increased hyperglycemia. Exercise when blood glucose values
India in 500 BC. Exercise can have a role in both type 1 and type 2 are greater than 250 mg/dL is safe if ketosis is not present.
diabetes to lower blood glucose levels and promote health maintenance.
Exercise lowers such cardiovascular risk factors as high blood pressure Pharmacologic Agents
and dyslipidemia, increases work capacity, reduces stress, prevents bone Oral Antidiabetic Agents
loss, and improves reaction time. Exercise may also be beneficial in Along with diet and exercise as an initial treatment of type 2 diabetes,
weight reduction. numerous medications may be used. A patient-centered approach should
The effects of exercise on fuel utilization and insulin sensitivity are be used to guide the choice of pharmacologic agents. Considerations
comparable to exercise-induced changes in normal metabolism. As include efficacy, cost, potential side effects, weight, comorbidities,
glucose production increases and plasma insulin levels drop, the reduction hypoglycemia risk, and patient preferences.
in tissue insulin resistance can result in a net decline in blood glucose Current guidelines call for timely implementation and titration of
levels. Exercise has the potential to decrease insulin requirements in oral agents as well as insulin to achieve euglycemia. Sulfonylurea drugs
type 1 diabetes, decrease and possibly eliminate the need for pharma- have been used in the management of type 2 diabetes for more than
cologic agents in type 2 diabetes, and reduce the risk for heart disease 40 years. These drugs have been joined by other agents with different
in all persons with diabetes. It has been shown to prevent the onset of mechanisms of action. Table 41.3 includes a list of common antidiabetic
type 2 diabetes in persons who are genetically at risk. agents.
Although the benefits of exercise are numerous, there are associated Metformin, classified as a biguanide, suppresses hepatic gluconeo-
risks. Individuals with type 1 diabetes are at risk for hypoglycemia and genesis and enhances glucose uptake by peripheral tissues without
ketoacidosis. Exercise in individuals with type 2 diabetes can be associated causing hypoglycemia. Metformin, if not contraindicated and if tolerated,
with hypoglycemia, cardiac dysfunction, orthopedic injury, and worsening is the first-line drug for type 2 diabetes. Metformin has been used alone
of some complications. and in combination with other oral agents and is associated with
When insulin or an oral hypoglycemic agent is used in the manage- improvement in dyslipidemia and weight loss. Side effects include nausea
ment of diabetes, the usual fuel metabolism of exercise is disturbed. and diarrhea. Serious side effects of metformin include acute renal
Inappropriately high insulin levels result in decreased hepatic glucose injury and metabolic acidosis. In a large review of several thousand
production and increased tissue insulin sensitivity. The latter processes patient-years, the incidence of metformin-associated lactic acidosis is
can lead to hypoglycemia. Replacement of expended glycogen and rare and most commonly associated with acute kidney injury. Caution
830 Unit XI Endocrine Function, Metabolism, and Nutrition
should be employed when using metformin in patients with liver disease.
Administration of radiographic iodine dyes has potential risk for causing
acute renal injury. Patients who are taking metformin have an increased
risk of developing metabolic acidosis. Depending on the creatinine
clearance value, some patients should hold their metformin for 24 hours
before and 48 hours after receiving IV contrast medium.
Sulfonylureas are often second-line antihyperglycmeic agents and
exert their hypoglycemic effect by binding to the adenosine triphosphate
(ATP)–dependent potassium channels on the cell membrane of β cells.
This inhibits efflux of potassium, resulting in a rise in intracellular
calcium concentration and the secretion of proinsulin. Sulfonylureas
are effective in augmenting the action of insulin in glucose disposal,
diminishing insulin clearance by the liver, and reducing hepatic glucose
production. Because sulfonylureas are ineffective in the management
of type 1 diabetes, stimulation of β cells is known to be a crucial factor
in the action of these oral agents. Enhanced insulin secretion appears
to be a short-term effect, possibly caused by a reduction in insulin
requirements as a result of the other hypoglycemic activities of sulfo-
nylurea agents.
The so-called first-generation agents (those formulated earliest) are
tolbutamide, chlorpropamide, and tolazamide. Second-generation agents
include glyburide, glipizide, and glimepiride. Use of first-generation
agents is not recommended unless patients have a well-established history
of previous use with good results. Second-generation agents are more
potent than first-generation agents, possibly because of increased capacity
to bind to the plasma membrane of the β cell. In addition, they are
more predictable, have fewer side effects, and represent more convenient
dosing.
The side effects of sulfonylureas include hypoglycemia, nausea,
dizziness, headache, allergic reactions, and flushing with alcohol use
(disulfiram effect). Sulfonylureas that are metabolized to inactive com-
pounds by the liver are considered safer for use in renal disease. Duration
of action is another safety issue. After insulin, sulfonylureas are the
major cause of severe hypoglycemia caused by a drug. The longer-acting
sulfonylureas, chlorpropamide and glyburide, are responsible for the
majority of cases of severe hypoglycemia and fatal hypoglycemic coma.
Acarbose and miglitol, α-glucosidase inhibitors, diminish postprandial
hyperglycemia by delaying carbohydrate absorption. They can be used
alone and in combination with sulfonylurea drugs, metformin, or insulin.
Side effects include symptoms related to decreased gastrointestinal
absorption (e.g., flatulence and diarrhea). They do not cause hypoglycemia
but can complicate its management if used in combination with a
sulfonylurea. Sulfonylurea-induced hypoglycemia cannot be managed
with sucrose when acarbose is being used because of drug-induced
delayed sucrose absorption.
Thiazolidinedione drugs increase tissue sensitivity to insulin and
inhibit hepatic gluconeogenesis. Thiazolidinediones are thought to
decrease insulin resistance, increase glucose uptake, and redistribute
fat. In addition, they are believed to preserve β-cell function, decrease
vascular inflammation, and minimally decrease hepatic glucose produc-
tion. Currently pioglitazone is the only commercially available thiazoli-
dinedione; rosiglitazone is available only through selective distribution
points because of the cardiovascular risks.
When prescribed along with an appropriate meal plan, oral antidiabetic
agents can be very effective in the management of type 2 diabetes mellitus.
Primary failure of the drug is considered to have occurred when initiation
of oral agent therapy does not result in a significant decline in blood
glucose levels. Primary failure can be due to misdiagnosis of type 1
diabetes mellitus or inadequate adherence to the diet and exercise regimen.
Secondary failure, or hyperglycemia after an effective initial response
to the drug, is often due to dietary nonadherence but may also be due
to the progressive β-cell dysfunction of type 2 diabetes mellitus.
Incretin Enhancers, Incretins, and Amylins
A newer group of oral agents for management of diabetes are the
incretins, incretin enhancers, and amylins. If noninsulin monotherapy
at the maximum tolerated dose does not achieve or maintain the HbA1C
target over 3 months, then a GLP-1 receptor agonist may be added.
Dipeptidylpeptidase-4 (DPP-4) is a widely expressed enzyme that
is responsible for rapidly degrading GLP-1 and GIP. Both of these
substances are critical factors in the development and treatment of type
2 diabetes. DPP-4 inhibitors block the secretion of DPP-4, causing
sustained action of incretin hormones that results in satiety, lower serum
glucose levels, and enhanced β-cell mass and function. DPP-4 inhibitors
prevent the release of glucagon from α cells through the release of
incretin while increasing insulin secretion. Medications in this class
include sitagliptin, saxagliptin, linagliptin, and vildagliptin.
The incretin class of medications focuses on GLP-1. GLP-1 mimetics
delay gastric emptying, inhibit release of glucagon, and increase satiety.
These drugs are injectable medications with the common side effects
of nausea and hypoglycemia. Exenatide can be used alone or in combina-
tion with sulfonylureas, metformin, or thiazolidinediones. Medications
in this class include exenatide, liraglutide, and lixisenatide.
Pramlintide is an amylin analog and can be used in conjunction
with insulin for the management of glycemia. It may not be mixed with
insulin and should be injected separately. Insulin requirements are
usually decreased by 50% with pramlintide; in addition, minimum
carbohydrate and caloric intake is required for its use. It is contraindicated
in patients with hypoglycemia unawareness or gastroparesis. Both incretin
and amylin mimetics have been effective in weight loss and lowering
HbA1C values when used in conjunction with metformin or a sulfonylurea
(both) or insulin (pramlintide only).
Gliflozins are the newest class of antihyperglycemic agents that inhibit
reabsorption of glucose in the kidney. In normal renal physiology, the
kidneys filter glucose out of the blood then reabsorb glucose back into
the blood through the sodium–glucose cotransportor 2 receptor (SGLT2).
During states of hyperglycemia, the SGLT2 receptors are at capacity,
and excessive glucose is excreted in the urine. SGLT2 inhibitors prevent
renal reabsorption of glucose, resulting in increased renal excretion
and thus reducing serum glycemia. Currently three SGLT2 inhibitors
are approved in the United States: canagliflozin (Invokana), dapagliflozin
(Farxiga), and empagliflozin (Jardiance). This group of medications
has no effect on the pancreatic β cells and has a minimal risk of
hypoglycemia.
Insulin
Insulin therapy is required in all persons with type 1 diabetes mellitus
and in 35% of persons with type 2 diabetes mellitus. Persons with type
1 diabetes mellitus require replacement of the deficient hormone in a
manner that most closely resembles normal physiologic mechanisms.
The role of insulin in type 2 diabetes mellitus is more complex.
Because type 2 diabetes mellitus is a progressive disease, many (if
not most) individuals will need insulin at some time, either because of
increasing insulin resistance or because of β-cell dysfunction. Glucose
toxicity, a phenomenon in which insulin resistance and decreased
production of insulin are worsened by hyperglycemia, may respond to
insulin therapy. Insulin may be necessary in type 2 diabetes intermittently
during times of physiologic stress that increase insulin requirements
(e.g., concomitant illness, surgery, inactivity, weight gain). However,
with resolution of the stress, the individual may be able to discontinue
insulin use.
Types of insulin are classified by a variety of features, but from
a practical standpoint are grouped according to the duration of
action: rapid acting, short acting, intermediate acting, and long acting

(Table 41.4). The most commonly used insulins in the ultra rapid-acting
category are aspart, glulisine, and lispro. Regular insulin is considered
short acting. Intermediate-acting agents include isophane. Glargine and
detemir are in the long-acting, or basal insulin group. Advances have been
made with the delivery of insulin, including Technosphere insulin (TI),
which is a fast-acting form of insulin delivered via an inhaled powder.
TI was approved for the management of type 1 diabetes mellitus with
concomitant use of basal insulin, with an onset of action and peak of
30 and 53 minutes, respectively. This new form of insulin delivery has
added benefits, including reduced social stigma and decreased pain from
injections. Novel forms of insulin and incretins are being developed,
including oral insulin tablets, oral insulin spray, and oral incretins.
Patterns of insulin use vary with the type of diabetes and the degree
of desired metabolic control. For patients with type 1 diabetes mellitus,
a minimum of two or more daily injections of rapid-acting and long-
acting insulins has been used to control postprandial and fasting
hyperglycemia. A popular regimen includes use of long-acting glargine
with preprandial injections of a rapid-acting insulin.
In the management of type 2 diabetes, insulin is initiated early in
the course of the disease to achieve and maintain glycemic control. It
can be used concomitantly with other antidiabetic agents. The intensity
of the regimen is based on the needs of the patient. A benchmark of an
HbA1C of 7% has been suggested as the target. In patients who have
confounding variables, this target may be adjusted down to an HbA1C
of 6.5% or less or increased to 7.5% or more. Variables to consider are
risks associated with hypoglycemia, disease duration, life expectancy,
established vascular complications, patient attitudes, and patient resources.
Long-acting insulin or rapid-acting insulin can be used to improve
fasting or postprandial glycemia, respectively, depending on the
patient’s needs. Normally, fasting glucose is targeted first; if HbA1C
goals are not met, prandial insulin is initiated. Mixed formulations
are beneficial and require only one to two injections per day in type 2
diabetes.
The action of insulin is affected by many elements, including climate,
alteration in blood flow, tobacco use, and the injection site. Insulin is
absorbed most rapidly from the abdomen, less rapidly from the arm,
and most slowly from the legs and buttocks. Insulin is absorbed more
rapidly from areas that are exercised or massaged after injection.
Hypoglycemia complications. Hypoglycemia is the most common
complication of hyperglycemic therapy and the most hazardous. Neural
tissue depends on a constant supply of glucose for normal function.
When insufficient food intake, unplanned activity, or an inappropriate
insulin or sulfonylurea dose lowers the blood glucose concentration
excessively, counterregulatory mechanisms are activated to ensure a
continued supply of glucose to the brain. The counterregulatory
mechanism that commences with the activation of the sympathetic
nervous system is a response to hypoglycemia that results in the release
of glucagon, corticosteroids, and growth hormones.
Symptoms of hypoglycemia produced by counterregulatory mecha-
nisms include pallor, tremor, diaphoresis, palpitation, and anxiety.
Neuroglycopenic symptoms noted in hypoglycemia are hunger, visual
disturbance, weakness, paresthesias, confusion, agitation, coma, and
death. In long-standing diabetes, neuropathy can alter the counterregula-
tory mechanisms. Hypoglycemic unawareness, in which the diabetic
patient does not experience counterregulatory symptoms, can be
the result.
Other complications of insulin therapy. Another typical complication
of insulin therapy is lipodystrophy. Lipoatrophy has been linked to the
use of insulin from animal and human sources and is manifested as
hollows in the surface of the skin caused by the destruction of subcutane-
ous adipose tissue. The exact mechanism is not clear but is suggested
to be derived from an immune-mediated response. Lipohypertrophy
CHAPTER 41 Diabetes Mellitus 831
is characterized by an increase in subcutaneous tissue because of insulin-
stimulated growth of adipose tissue at the injection sites. Avoiding
repeated injections at the same site is recommended to prevent
lipodystrophy.
An acute complication of insulin use can be insulin edema, or a
localized or generalized accumulation of fluid. Weight gain can accom-
pany initiation of insulin therapy, especially when glycemic control is
improved. A third complicating factor in insulin therapy is insulin
resistance. Insulin resistance is exacerbated by obesity and can necessitate
the use of large insulin doses. An appropriate diet and exercise program
is as important to insulin-treated individuals as it is to other patients
with diabetes.
Stress Management
Living with diabetes can be stressful. The tasks of blood glucose monitor-
ing, medication administration, meal planning, and implementing
preventive care to avoid complications can be demanding. Fearing the
onset of complications and their impact in addition to living with
complications are parts of the psychological impact of diabetes. Depres-
sion is more likely to be diagnosed in individuals with diabetes and is
correlated with deterioration of glycemic control. Stress management
can have an important role in diabetes care by improving quality of
life and reducing the possible impact of stress on glycemic control.
Assessment of Efficacy
Clinicians use several measures to determine the adequacy of glycemic
control. One indirect but very useful indication of blood glucose levels
is the level of glycated hemoglobin. Hemoglobin becomes glycated when
glucose is nonenzymatically attached to one of its terminal amino acids.
Four glycated hemoglobin products are formed: HbA1a1, HbA1a2, HbA1b,
and HbA1C. The latter is produced in the largest quantity and is used
in most assays.
Because erythrocytes are freely permeable to glucose, the quantities
of glycated hemoglobin formed are proportional to the quantity of
glucose in the blood plasma. Glycated hemoglobin values will reflect
mean blood glucose levels for the life of the average erythrocyte (100
to 120 days). Highly significant correlations have been found between
HbA1C levels and mean blood glucose level. The presence of abnormal
hemoglobins or hemolytic anemia can skew results. The normal value
for HbA1C varies with the laboratory technique, but is usually less than
7%. Results of the A1C-Derived Average Glucose Trial published in
2008 correlated an HbA1C number to average glucose levels rather than
a percentage. This change has little impact on clinical management;
however, it decreases patient confusion regarding glycemic control.
HbA1C values are used clinically to estimate long-term control and
to establish and evaluate therapeutic goals. Values of less than 7% or
as close to normal as possible without adverse effects are considered
desirable. Depending on individual circumstances and life expectancy,
less stringent goals may be appropriate. HbA1C values cannot be used
for daily management of therapy.
Assessment of glycemia on a daily basis was attempted in the past
by the use of testing for glycosuria. However, the blood glucose level
at which glucose is measurable in the urine, the glycemic threshold,
varies from individual to individual, is usually unacceptably high, and
cannot be used to establish the presence of hypoglycemia.
The First and Second Consensus Development Conference on Self-
Monitoring of Blood Glucose, convened by the American Diabetes
Association and other involved agencies, formulated several goals for
the use of capillary blood glucose monitoring. The goals included use
of capillary blood glucose monitoring to achieve and maintain a specific
level of glycemic control, prevent and manage hypoglycemia, avoid
severe hypoglycemia, adjust care in response to changes in lifestyle in
832 Unit XI Endocrine Function, Metabolism, and Nutrition

TABLE 41.4 Insulin and Other Injectable Antihyperglycemic Medications

RX Or
Drug Class Action Brand Name Generic Name Appearance OTC Drug Type
Noninjectable insulin Rapid Insulin Human, Afrezza Powder Rx Technospehere insulin
Inhalation inhalation
Insulin Rapid Humalog Insulin lispro Clear Rx Insulin analog

NovoLog Insulin aspart Clear Rx Insulin analog

Apidra Insulin glulisine Clear Rx Insulin analog

Short Humulin R Regular insulin; injectable Clear OTC Regular insulin; injected
Novolin R
Intermediate Humulin N Isophane insulin Cloudy OTC Isophane insulin
Novolin N

Long Levemir Insulin detemir Clear Rx Long-acting insulin analog

Lantus Insulin glargine Clear Rx Long-acting insulin complex

Combination Humulin 70/30 70% isophane/30% Cloudy OTC NPH and regular
products Novolin 70/30 regular combination
NovoLog 70/30 70% aspart Cloudy Rx NPH-like and rapid-acting
protamine/30% aspart combination
Humalog mix 75/25 75% lispro Cloudy Rx NPH-like and rapid-acting
protamine/25% lispro combination
Humalog mix 50/50 50% lispro Cloudy Rx NPH-like and rapid-acting
protamine/50% lispro
Humulin 50/50 50% isophane/50% Cloudy OTC NPH and regular
regular combination

Noninsulin Injectables
Incretin mimetic Adjunct therapy Byetta Exenatide Clear Rx GLP-1 analog

Adjunct therapy Victoza Liraglutide Clear Rx GLP-1 analog

Amylin analog Symlin Pramlintide Rx Amylin analog

individuals requiring pharmacologic therapy, and determine the need presence of ketones in the urine can be an indication of diabetic
for initiating insulin therapy in women with GDM. ketoacidosis and may be harmful to a developing fetus in pregnancy
Capillary blood glucose monitoring has been shown to be an accurate complicated by diabetes. All individuals with diabetes should be tested
reflection of venous blood glucose level when performed by health for ketonuria when blood glucose values are greater than 300 mg/dL,
professionals and by individuals with diabetes. Accuracy can be affected during concomitant illness, during pregnancy, and in the presence of
by such performance errors as underloading or overloading of the strip, symptoms of diabetic ketoacidosis (nausea, vomiting, abdominal pain).
incorrect placement of the sample, and improper handling of the sample.
Training improves performance.
KEY POINTS
Diabetic individuals using capillary blood glucose monitoring have
• The mainstays of diabetic treatment are diet, exercise, and drug therapy.
frequently reported enthusiasm and increased insight into the relationship
Education is an integral part of treatment, enabling individuals with diabetes
between blood glucose level and such factors as diet, exercise, and stress
to follow the diabetic regimen and avoid complications. The efficacy of therapy
and have expressed increased feelings of well-being. Capillary blood
can be assessed by monitoring blood glucose and HbA1C levels. Blood glucose
glucose monitoring has been associated with improved glycemic control.
monitoring is useful for assessing short-term efficacy. HbA1C is a better
Monitoring of capillary blood glucose levels is simply a feedback
measure of the long-term efficacy of therapy. A mean blood glucose level
mechanism that provides immediate information on the effects of a
less than 170 mg/dL (HbA1C level of 7% or less) is desirable.
change in therapy.
• Exercise has several benefits for an individual with diabetes. Insulin require-
In the replacement of testing for glycosuria with capillary blood
ments may be reduced, weight loss facilitated, and the risk of cardiovascular
glucose monitoring, testing for ketonuria should not be neglected. The
 CHAPTER 41 Diabetes Mellitus 833

Onset (in Hours Peak Duration Compatible Storage/

Unless Noted) (Hours) (Hours) Mixed With Expiration Typical Dosing/Comments
15–30 min 1 hr 2.5 hr NA Refrigerate/ 10 days Black box warning for people with asthma and COPD for
at room temp risk of bronchospasm
15–30 min 1–2 3–4 NPH Refrigerate/28 days 15 min before meal or immediately after meal
at room temp
15–30 min 1–2 3–5 NPH Refrigerate/28 days 5–10 min before meal
at room temp
15–30 min 1–2 3–4 NPH Refrigerate/28 days 15 min before or within 20 min after meal
at room temp
0.5–1 2–3 3–6 NPH Refrigerate/28 days 30 min before meal
at room temp
2–4 4–6 8–12 Insulin analogs/ Refrigerate/28 days One, two, or three times daily
injectable at room temp
regular insulin
2 6–9 14–24 None Refrigerate/42 days Once or twice daily
at room temp
4–5 Peakless 22–24 None Refrigerate/28 days Once daily, at same time each day
at room temp
30 min 1.5–16 24 None Refrigerate/28 days 30 min before meal
at room temp
15 min 1–4 24 None Refrigerate/28 days 15 min before meal
at room temp
15 min 1–6.5 24 None Refrigerate/28 days 15 min before meal
at room temp
15–30 min 1–13 14–24 None Refrigerate/28 days 15 min before meal
at room temp
30 min 2–5.5 24 None Refrigerate/28 days 30 min before meal
at room temp

2 10 None Refrigerate/30 days Within 60 min before morning and evening meals
after opening *When initiating, taking close to meals may minimize side
effects
8–12 13+ None Refrigerate/30 days Initial dose is 0.6 mg subQ daily × 1 week, then 1.2 mg
after opening subQ daily
20 min 3 None Refrigerate/28 days Immediately before each major meal (≥250 kcal or 30 g of
at room temp or carbohydrate)
refrigerated

complications decreased. Exercise may precipitate hypoglycemia, so insulin • Hypoglycemia is the most common complication of pharmacologic therapy.
injections or dietary intake may have to be adjusted. Oral antidiabetic agents Symptoms are mediated primarily by activation of the sympathetic
may be successfully used in type 2 diabetes. The sulfonylureas exert their nervous system stress response. Secretion of catecholamines, glucagon,
effects primarily by stimulating the release of endogenous insulin. They corticosteroids, and growth hormone rises in an attempt to increase blood
also reduce insulin degradation and suppress the release of glucose from glucose levels. Pallor, tremor, diaphoresis, weakness, and decreased
the liver. Metformin suppresses hepatic gluconeogenesis and enhances consciousness are the usual manifestations of hypoglycemia.
glucose uptake by peripheral tissue; thiazolidinediones enhance glucose
uptake by peripheral tissue; and acarbose delays absorption of ingested
carbohydrate. Newer agents such as incretin mimetics, incretin enhancers,
and amylin analogs will also be affected by exercise. PEDIATRIC CONSIDERATIONS
• Insulin replacement therapy is required in all patients with type 1 diabetes
Diabetes has been diagnosed in approximately 176,500 children and
and in about one third of patients with type 2 diabetes mellitus. Insulin is
adolescents younger than 20 years. One in every 400 to 600 children
classified according to its onset, peak, and duration of action. A combination
and adolescents has type 1 diabetes, and 18 new cases per population
of insulins may be given to produce optimal control. Long-acting insulin
of 100,000 are diagnosed yearly. The overwhelming majority have type
(glargine or detemir) and a rapid-acting insulin (aspart, lispro, glulisine) are
1 diabetes, with an approximate 5% prevalence of genetic defects in β
commonly used to mimic basal and prandial insulin levels, respectively.
cells.
834 Unit XI Endocrine Function, Metabolism, and Nutrition
Type 1 diabetes is characterized by destruction of the β cells of the
pancreas with resulting insulinopenia. Type 1 diabetes in children is
often manifested acutely as diabetic ketoacidosis when insulin secretion
falls below insulin needs. A condition termed the honeymoon period
can develop if the diagnosis occurs during a time of increased insulin
needs, such as during a viral illness. When the illness is resolved, insulin
needs can fall below residual insulin production and normoglycemia
results without the use of exogenous insulin. The honeymoon period
rarely lasts more than 1 year and is usually shorter.
Goals of Therapy
Goals of therapy for children include achieving normal growth and
development, avoiding acute and chronic complications of diabetes,
addressing psychosocial issues, and educating children regarding self-care.
Acute Complications
Whenever children with type 1 diabetes mellitus experience hyper-
glycemia, the resulting glycosuria can precipitate dehydration. The
threat of dehydration is especially severe during episodes of diabetic
ketoacidosis. Supplemental fluids and insulin may be necessary during
these times.
Diabetic ketoacidosis can occur when insulin administration is
inadequate for needs. Diabetic ketoacidosis frequently accompanies the
diagnosis of type 1 diabetes mellitus. Avoiding diabetic ketoacidosis
involves knowledge of appropriate care during times of increased insulin
need, such as during concomitant illness. To ensure early detection of
incipient diabetic ketoacidosis, children and adolescents should be tested
for ketonuria when the blood glucose concentration is greater than
240 mg/dL and during concomitant illness.
Hypoglycemia can be difficult to detect in very young children.
Caregivers should be alert for behavioral changes such as lethargy, pallor,
and sleep disturbances.
Chronic Complications
Chronic complications of diabetes are rarely manifested during ado-
lescence. Screening for neuropathy and nephropathy and determinations
of serum lipid levels should occur on a regular basis. Pregnant adolescent
girls must be counseled on the importance of maintaining excellent
metabolic control.
Treatment
Insulin requirements are approximately 1.0 unit/kg per day. An intensive
regimen of at least three injections per day is recommended to prevent
chronic complications. The administration of very small doses of insulin
in infants and children may necessitate the use of a diluent.
Insulin needs increase during times of physiologic stress, such as
during concomitant illness or puberty. Children who are inadequately
treated with insulin will not grow or mature normally.
Children are usually able to begin administering insulin and perform-
ing capillary blood glucose monitoring with supervision when they are
of school age. The age may vary with different children. When administer-
ing insulin, the abdomen is the least preferred site because of insufficient
abdominal subcutaneous fat.
Diabetic teaching of such self-management skills as insulin injection,
capillary blood glucose monitoring, and recognition and treatment of
hypoglycemia should include all caregivers. Babysitters and teachers
will need information on prevention, recognition, and management of
hypoglycemia. All educational materials used with children should be
age appropriate.
Children must be provided with a caloric intake adequate to meet
needs for energy expenditure, growth, and maturation. Caloric intake
is usually calculated as 1000 calories/day plus 100 added calories for
each year until age 11 years. From ages 11 to 18 years, an additional
100 calories is added for girls and an additional 200 calories for boys.
Growth should be plotted at each medical appointment to assess adequate
nutrition and adequate insulinization. After the age of 2 years, recom-
mended dietary guidelines for percentage of fat, carbohydrate, and
protein intake are the same as those for adults.
Exercise is encouraged, with careful attention to adequate nutritional
intake. Insulin doses may need to be adjusted to plan for unusual levels
of activity, such as during long-distance bike riding or hiking.
Following a regimen designed to prevent acute and chronic complica-
tions of diabetes is difficult under the best of conditions. The goals of
treatment are best accomplished when meals, medication, exercise, and
blood glucose monitoring are consistent. Achieving consistency while
also achieving developmental goals of separation and independence is
very difficult. Peer pressure during adolescence can lead to poor adherence
to therapeutic regimens. Concern regarding weight can lead to omission
of insulin injections or the manifestation of eating disorders.
The child and family need support and counseling to develop effective
strategies for achieving desired goals. Disturbed family functioning can
have an impact on children and adolescents with diabetes and can lead
to an increased frequency of hospitalization for diabetic ketoacidosis.
Genetic defects of the β cell are usually diagnosed in individuals
younger than 25 years. These individuals are not likely to become ketotic.
Management is identical to that of type 2 diabetes in young adults.
KEY POINTS
• Children and adolescents with diabetes overwhelmingly have type 1 diabetes
mellitus (5% have genetic defects of the β cell). In type 1 diabetes, insulin
is required at diagnosis or shortly thereafter.
• Goals of therapy for children include achieving normal growth and develop-
ment, avoiding acute and chronic complications of diabetes, addressing
psychosocial issues, and educating children regarding self-care.
• Acute complications of diabetes in children and adolescents include
hyperglycemia leading to dehydration, possible diabetic ketoacidosis, and
hypoglycemia. Hypoglycemia may manifest differently in children than in
adults.
• Chronic complications in children and adolescents are rare. Screening for
complications should nevertheless be initiated. Adolescent girls should be
counseled on issues regarding diabetes and pregnancy.
• Insulin needs will vary according to growth stages, exercise, and concomitant
illness. Regular capillary blood glucose monitoring is crucial for determining
the efficacy of treatment. The age at which children can perform insulin
measurement and administration, as well as capillary blood glucose monitoring
independently, will vary. Nutritional needs are calculated at 1000 calories/
day, with 100 added calories per year until age 11 and then an additional
100 calories for girls and an additional 200 calories for boys ages 11 to 18.
• Education in self-care activities should be appropriate for age and include
other family members. Support both for the person with diabetes and for
the family is important. Counseling may be helpful in some circumstances.
GERIATRIC CONSIDERATIONS
The prevalence of type 2 diabetes mellitus increases with age. Adults
older than 60 years constitute nearly 50% of the diabetic population
of the United States. The prevalence of diabetes in the elderly is almost
21% for individuals age 60 or older and more than doubles that of
younger adults ages 40 to 59.
The increase in risk for type 2 diabetes in older adults is multifactorial.
Aging often involves increased adiposity and a decrease in lean body
mass and activity levels. The latter factors contribute to insulin resistance.
Insulin secretion also diminishes with age. The risk of diabetes in the
elderly is likewise increased by surgery, illness, and the use of such
medications as steroids and diuretics.

Diabetes in the elderly can be difficult to diagnose because of fluctuat-
ing blood glucose values in response to food intake and activity and
because of inconsistent or absent symptoms of hyperglycemia. Chronic
complications of diabetes such as neuropathy and retinopathy are
frequently present at diagnosis and indicate glucose intolerance of long
duration.
Goals of Therapy
Goals of treatment for the elderly include prevention of acute complica-
tions, prevention and management of chronic complications, attention
to psychosocial issues, and education regarding self-care.
Acute Complications
Uncontrolled hyperglycemia in the elderly may be asymptomatic or
may produce such classic symptoms as polyuria and fatigue. Polydipsia
is less common because of decreased thirst perception. Hyperglycemia
can result in increased perception of pain and slowing of intellectual
processes. The risk of infection is greater when blood glucose values
are greater than 200 mg/dL. Such infectious disease processes as malignant
otitis externa and reactivation of chronic tuberculosis are linked to
hyperglycemia. Elderly individuals with diabetes are two times as likely
to be hospitalized for kidney infections as elderly individuals without
diabetes.
Chronic hyperglycemia can cause mild to moderate dehydration in
the elderly that can be exacerbated by age-related changes in kidney
function and water conservation. The resulting postural hypotension
and electrolyte imbalances can increase the risk of falls.
Elderly people with type 2 diabetes mellitus are not prone to ketosis,
but they are at risk for nonketotic hyperglycemic hyperosmolar coma.
Particular risk factors include impaired thirst recognition, polypharmacy,
dementia, and concurrent illness. Profound dehydration can occur and
lead to a significant mortality rate for this complication (10% to 50%).
Older individuals with type 2 diabetes mellitus must be instructed
in care during periods of concomitant illness and advised to perform
capillary blood glucose monitoring on a regular basis to avoid undetected
hyperglycemia.
Hypoglycemia can occur when an elderly individual with diabetes
is treated with a sulfonylurea or insulin. Hypoglycemia can occur
atypically with symptoms of lethargy or focal neurologic dysfunction.
Elderly individuals may have age-related decreases in counterregulatory
function or an inability to report hypoglycemic symptoms. Glycemic
targets for these individuals may be higher. The risk of injury during
a hypoglycemic episode warrants careful observation of blood glucose
values and regular evaluation of treatment of all elderly individuals
with diabetes.
Chronic Complications
The increased prevalence of heart and blood vessel disease, kidney disease,
eye disease, and foot disease in patients with diabetes overlaps with the
increased prevalence of these conditions in the general elderly population.
Diabetes increases the incidence and severity of these diseases.
Aging-related changes can present a particular problem in the
performance of diabetic foot care. Orthopedic deformity, loss of protective
subcutaneous fat, and atherosclerotic changes are all common problems
of the elderly. Inspection of the feet and nail care can be compromised
by changes in visual acuity and joint function. Assistance with foot care
is often necessary to minimize the risk of diabetic complications involving
the feet.
Treatment
Oral antidiabetic agents must be chosen carefully to avoid age-related
adverse effects. Oral agents with a shorter duration of action are prefer-
able. Elderly individuals with diabetes should be evaluated for changes
CHAPTER 41 Diabetes Mellitus 835
in renal and hepatic function. Oral agents metabolized in an impaired
system should be avoided. Metformin is not appropriate for individuals
with decreased liver and renal function because of the increased risk
of lactic acidosis.
Insulin is safe to use with caution in the elderly. Thin elderly individu-
als can be highly sensitive to insulin and may require very small amounts
to control hyperglycemia. Some elderly individuals are quite sensitive
to regular insulin. Daily or twice-daily dosing of long-acting insulin
may be preferable.
Age- or illness-related changes in vision, manual dexterity, and
cognition can diminish the ability to measure and administer insulin.
Magnification devices and the use of prefilled syringes can be of assistance.
Exercise is of benefit to individuals of all ages. Exercise plans must
often be modified to account for orthopedic or other mobility problems.
Armchair exercise can be an excellent way for elderly individuals to
stay active.
Appropriate food intake can help control hyperglycemia and reduce
the risk of chronic complications in the elderly, as in all individuals
with diabetes. The quality and quantity of nutrients must be assessed
carefully in the elderly. Elderly individuals may be obese, malnourished,
or both. Increasing the nutritional value of a meal plan that is low in
calories because of choice or a desire to lose weight is an important
and difficult goal. Dental and other oral disease or dysfunction can
have an impact on nutritional intake.
Education of the elderly in diabetic self-care practices can be chal-
lenged by age-related changes in vision, hearing, and cognition. Simple,
clearly written educational materials and less complex therapeutic
regimens can be of assistance. Caretakers and family members should
be included in education sessions if possible. Family or other assistance
can ensure safe performance of diabetic self-care activities while
maintaining as much independence as possible.
KEY POINTS
• The increased prevalence of type 2 diabetes mellitus in the elderly is
multifactorial and due to increased adiposity, decreased lean body mass,
decreased activity levels, decreased insulin secretion, the hyperglycemic
effect of certain medications, concurrent illness, and surgery. Varying blood
glucose values can lead to difficulty in diagnosis.
• Goals of treatment for the elderly include prevention of acute complications,
prevention and management of chronic complications, attention to psycho-
social issues, and education regarding self-care.
• Acute complications of diabetes in the elderly include hyperglycemia, often
asymptomatic, which can lead to dehydration; increased risk of infection;
and nonketotic hyperglycemic hyperosmolar coma. Hypoglycemia can occur
atypically and may lead to injury.
• Heart and blood vessel disease, foot problems, visual disabilities, and kidney
disease have a significant presence in the aging population in general, as
well as being chronic complications of diabetes. Avoiding foot problems
can be particularly challenging given the frequent presence of orthopedic
deformity and other common aging-related changes, as well as the decreased
ability to perform appropriate foot care.
• Oral antidiabetic agents should be carefully chosen with consideration of
renal and hepatic function. Short-acting agents are preferable. When insulin
treatment is necessary, visual or orthopedic and other changes may hinder
measurement of insulin. Adaptive devices can be helpful. Exercise should
be encouraged and may have to be modified for people with limited mobility
or other limiting factors. Meal planning for elderly individuals should
emphasize appropriate amounts of foods with high nutritional value.
• Simple, clearly written educational material can be helpful for individuals
with visual or cognitive impairments. Caretakers or family members should
be included in education sessions if necessary.
836 Unit XI Endocrine Function, Metabolism, and Nutrition
SUMMARY
Diabetes mellitus, the most common endocrine disorder, affects mil-
lions of Americans. Diabetes is characterized and diagnosed by chronic
hyperglycemia, the result of a relative or absolute deficiency of insulin;
however, the metabolism of all energy nutrients is altered. Of the four
clinical classes of diabetes, the most common are type 2 and type 1
diabetes. Type 2 diabetes is characterized by insulin resistance and a
reduction in insulin production leading to a relative insulin deficiency.
Type 1 diabetes is the result of destruction of the insulin-producing β
cells of the pancreas because of an autoimmune or idiopathic process.
Sequelae of insulin deficiency include the acute and chronic complica-
tions of diabetes. Acute complications include diabetic ketoacidosis in
type 1 diabetes and nonketotic hyperglycemic hyperosmolar coma in
type 2 diabetes. Chronic complications include cardiovascular disease,
retinopathy, nephropathy, and neuropathy.
The goals of treatment are glycemic control and prevention of
complications. Treatment is individualized and encompasses an
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