DIABETES_ LECTURE

PROF. DR. DOINA CATRINOIU

 Diabetes Mellitus
 One of the most common non-
communicable diseases
 Fourth leading cause of death in most
developed countries
 More than 194 million people with diabetes
worldwide
 Incidence of diabetes is increasing –
estimated to rise to 333 million by 2025
• To more than double in Africa, the Eastern
Mediterranean and Middle East, and South-East Asia
• To rise by 50% in North America, 20% in Europe, 85%
in South and Central Americas and 75% in the Western
Pacific
: International Diabetes Federation website
 Types of Diabetes Mellitus
 Type 1 diabetes (insulin-dependent
diabetes)
• mainly in childhood/early adult life
• 10-20% of cases
Type 2 diabetes (non-insulin-dependent
diabetes)
• usually develops in the middle-age/elderly
• incidence increasing at a younger age
• 80-90% of cases
 At least 50% of all people with diabetes
are unaware of their condition
: International Diabetes Federation website
CLASSIFICATION OF DIABETES
Impaired glucose tolerance without
diabetes (IGT)
Primary diabetes mellitus
• Insulin dependent (IDDM or Type 1)
• Noninsulin dependent (NIDDM or Type 2)
Malnutrition-related diabetes mellitus
(MRDM)
Secondary diabetes mellitus
• Pancreatic disease
• Endocrine disorders
• Drug therapy
• Inherited disorders
 SynthesisSecretia
of insulin de insulina
Synthesis of insulin

Proinsulin (86aa) Insulin (21 + 30aa)

NH2 HOOC NH2  - chain
S S S S

S S S S

HOOC HOOC NH2  - chain

S S S S

C - peptide (35aa)
ESR10-08 ESR10-0
 os e
Gluc
 Basal-bolus therapy attempts to re-
create physiological insulin secretion
Rapid-acting insulin
Predicted plasma insulin concentration

Basal insulin

Total
profile (mU/l)

Time of day
 Diabetes is defined biochemically
by the following criteria
 A fasting venous plasma glucose
level greater than 7.8 mmol/litre
(126 mg/dl) on more than one
occasion;

or A 2-hour (plus one other)

venous plasma glucose level in
excess of 11.1 mmol/litre (200
mg/dl) in a formal 75 g oral
glucose tolerance test (GTT).
 Clinical features of diabetes at
diagnosis 
Type 1 Type 2
Polyuria and thirst ++ +
Weakness or fatigue ++ +
Polyphagia with weight loss++ –
Recurrent blurred vision + ++
Vulvovaginitis or pruritus + ++
Peripheral neuropathy + ++
Nocturnal enuresis ++ –
Often asymptomatic – ++
 A diagnostic algorithm for diabetes
mellitus

Blood glucose > 200 mg/dl

Classical
Symptoms* + Blood glucose 100 -200 mg/dl

DIABETES

A Fasting plasma glucose

S > 126 mg/dl
Y
2-h Plasma glucose after
M Fasting plasma glucose "OGTT" > 200 mg/dl
P 109-125 mg/dl and/or
T Fasting plasma glucose >
126 mg/dl
O
postprandial plasma
M
glucose > 200mg/dl
A
T Blood glucose > 200 mg/dl
I "occasionally"
C
 INVESTIGATIONS

 Blood glucose is the key to diagnosis in

diabetes.
 Glycosylated haemoglobin and other
proteins: measurement of these proteins
reflects the degree of diabetic control in
the previous 4-6 weeks and is of value in
long-term management and control .
 INVESTIGATIONS

 Urine testing for glucose-glucose will

be found in the urine only when it rises
above the renal threshold (usually about
10 mmol/l
 Urine testing for ketone bodies the
presence of ketones suggests loss of
control.
 Proteinuria is a reflection of the
development of renal complications and
is an early indicator of diabetic renal
disease Multiple test strips allow rapid
testing for all these substancesin urine.
 INVESTIGATIONS

 Proteinuria is a reflection of the

development of renal complications and
is an early indicator of diabetic renal
disease Multiple test strips allow rapid
testing for all these substancesin urine.
 Microalbuminuria is a very sensitive
marker of early and potentially reversible
renal impairment; it is the term given to
the presence of protein below the level of
detection with the stick methods, that is
200 mg/litre.
 INVESTIGATIONS
 Serum electrolytes, blood gases,
osmolality and anion gap are all of
value in metabolic crises if there is
loss of water, sodium and potassium
and acidosis is developing, or if there
is a hyperosmolar state.
 Lipid profile: elevations in serum
cholesterol are common, and
elevation of serum triglycerides is a
reflection of poor glycaemic control,
which usually reverts to normal when
euglycaemia is achieved.
 PRESENTING FEATURES OF DIABETES
 Acute: the typical presentation of the young
patient with IDDM; features include polyuria,
polydipsia and weight loss of short duration,
often associated with, or apparently
precipitated by, a viral infection;visual
disturbance or impairment of the conscious
level associated with severe ketoacidosis
 Chronic: the typical presentation of a patient
with NIDDM; the symptoms have usually been
present for some months and often include
weight loss, thirst, excess urine volume, genital
and skin infections
 PRESENTING FEATURES OF DIABETES
 Coincidental discovery: routine
screening for urine or blood glucose as
part of a pre-employment medical, during
pregnancy or in local campaigns
 Complications: visual disturbance or
overt retinopathy, neuropathy,
nephropathy or after major thrombotic
events such as premature stroke or
myocardial infarction
PRESENTING FEATURES OF DIABETES
 Drug-related diabetes may develop in
patients on long-term steroids or thiazide
diuretics
 Disease-related as in acromegaly,
Cushing's syndrome, phaeochromocytoma,
thyrotoxicosis, pancreatitis,
haemochromatosis, cystic fibrosis,
carcinoma or surgical removal of the
pancreas
 Gestational: pregnancy may unmask
diabetes in a woman who is predisposed.
A full history and clinical examination are
essential to detect any of the causative
diseases and document the consequences.
Type 2 diabetes
PRESENTING FEATURES OF DIABETES

Patients with type 2 diabetes may

or may not have characteristic
features.

The presence of obesity or a

strongly positive family history
for mild diabetes suggests a high
risk for the development of type
2 diabetes.
DM Kendall et al. Eur J Intern Med 20, ( 2009) S329–S339
Prin amabilitatea Prof. Dr. N. Hâncu
 The Progression from CV Risk Factors to
Endothelial Injury and Clinical Events
LDL-C BP Risk factors Diabetes Smoking Heart failure

Oxidative stress

Endothelial dysfunction

NO Local mediators Tissue ACE-Ang II

VCAM Endothelium Growth factors Proteolysis

PAI-1
matrix
ICAM cytokines

Vascular lesion
Thrombosis Inflammation Vasoconstriction Plaque rupture
and remodelling

Clinical endpoints

NO Nitric oxide
Gibbons GH, Dzau VJ. N Engl J Med 1994;330;1431-1438.
 The Metabolic Syndrome and
Associated CVD Risk Factors
Hypertension

Abdominal obesity
Atherosclerosis
Hyperinsulinaemia
Insulin Diabetes
Resistance
Hypercoagulability

Dyslipidaemia
Endothelial
• high TGs Dysfunction
• small dense LDL
• low HDL-C

Deedwania PC. Am J Med 1998;105(1A);1S-3S.

 NCEP ATP III: The Metabolic
Syndrome
Recommends a diagnosis when 3 of these risk factors are present

Risk Factor Defining Level

Abdominal obesity
(Waist circumference)
Men >102 cm (>40 in)
Women >88 cm (>35 in)
TG 150 mg/dL (1.7 mmol/L)
HDL-C
Men <40 mg/dL (1.0 mmol/L)
Women <50 mg/dL (1.3 mmol/L)
Blood pressure 130/85 mm Hg
Fasting glucose 110 mg/dL (6.0 mmol/L)

NCEP, Adult Treatment Panel III, 2001. JAMA 2001:285;2486-2497.

WHO: The Metabolic Syndrome

A working definition is glucose intolerance, IGT or

diabetes mellitus and/or insulin resistance together
with two or more of the following:
• Raised arterial pressure 160/90 mmHg
• Raised plasma triglycerides (1.7 mmol/L, 150
mg/dL) and/or low HDL-C (men <0.9 mmol/L,
35 mg/dL; women <1.0 mmol/L, 39 mg/dL)
• Central obesity
• Microalbuminuria (UAER 20 g/min or
albumin: creatinine ratio 20 mg/g)

Alberti KGMM for the WHO. Diabet Med 1998:15;539-553.

 TREATMENT
 Type 1 diabetes ONLY INSULIN – is a
replacement therapy

 Type 2 diabetes ORAL DRUGS+/-

INSULIN THERAPY
NPH insulin has been with us a long time
How should we address the limitations
of old technology?
Limitations of NPH: a relatively short action
profile with a peak

GIR, glucose infusion rate; GIR curves adapted from references; NPH, neutral protamine Hagedorn
Human insulins do not closely match the
endogenous insulin response

Adapted from: Polonsky et al. J Clin Invest 1988;81:442–8

Insulin analogues address the limitations of
human insulin

Adapted from: Polonsky et al. J Clin Invest 1988;81:442–8

 Defining glucose variability
• Hypoglycaemic events
• Postprandial glucose excursions
• Minor fluctuations in blood glucose levels

Monnier and Colette. Diabetes Care 2008;31(Suppl.2):S150–4

The basal/bolus insulin concept
 Basal insulin
• Suppresses glucose production between meals
and overnight
• 40% to 50% of daily needs

 Bolus insulin (mealtime)

• Limits hyperglycaemia after meals
• Immediate rise and sharp peak at 1 hour
• 10% to 20% of total daily insulin requirement
at each meal
 Nonglycemic effects of oral therapy
Cardiovascular risk Sulfonil Rapid- Metform Thiazolidindi -
factor urea acting in ones glucosida
insulin se
secretago inhibitors
gues

Insulin resistance 0 0   0

Hyperinsulinemia 0 0   
LDL chol levels 0 0   or 0 0
LDL particle pattern 0 0 ? Large buoyant 0
HDL chol levels 0 0 0  0
Triglycerides 0 0   0
LP (a) 0 0   0
PAI-1 0 0   0
Endothelial function 0 0   0
Body weight     0
Visceral adiposity  ?  0 or  0

Modified fromHE Lebovitz, Endocrinol clin North Am, 2001, 30: 909-933
 Potential down-sides of pharmacological
treatment modalities in patients with T2DM
Potential problem Avoid or reconsider
Unwanted weight gain Sulphonylureas, glinides,
glitazones, insulin

Gastrointestinal symptoms Biguanides, alpha-glucosidase

inhibitors

Sulphonylureas, glinides, insulin

Hypoglycemia

Biguanides, sulphonylureas
Impaired kidney function

Glinides, glitazones, biguanides,

Impaired liver function
alpha-glucosidase

Biguanides, glitazones
Impaired cardio-pulmonary
function

ESC, EASD Guidelines, 2007

 Suggested policy for the selection of glucose-
lowering therapy according to the glucometabolic
situation

Post-prandial alpha-glucosidase inhibitors, short-

hyperglycemia acting SU, glinides, short-acting regular
insulin or insulin analogs

Fasting hyperglycemia Biguanides, long-acting SU, glitazones,

long-acting insulin or insulin analogs

Insulin resistance Biguanides, glitazones, alpha-

glucosidase inhibitors

Insulin deficiency SU, glinides, insulin

ESC, EASD Guidelines, 2007

 Revisit T2DM treatment strategies:
the evolving HbA1c position

Persistent HbA1c >7%

ACTION

Realistic target:
lowest HbA1c possible without
unacceptable hypoglycaemia

Healthy individual HbA1c 4–6%

Achieving and maintaining HbA1c at target may require

incremental and combination therapies
Treat-to-target concept

Adapted from Rosenstock J, Riddle MC. Chapter 9: Insulin therapy in type 2 diabetes. In: Cefalu
WT, Gerich JE, LeRoith D (eds). The CADRE Handbook of Diabetes Management. New York:
Medical Information Press; 2004:145―68.
 Summary of antidiabetic interventions as
monotherapy
Interventions Expected Advantages Disadvantages
decrease
in A1c
(%)
Step 1: initial
 Lifestyle to decrease weight 1-2 Low cost, many Fails for most in first year
and increase activity benefits GI side effects, rare lactic
 Metformin 1.5 Weight neutral, acidosis
inexpensive
Step 2: additional therapy Injections, monitoring,
 Insulin 1.5-2.5 No dose limit, hypoglycemia, weight gain
inexpensive,
improved lipid profile
 Sulphonylureas 1.5 Inexpensive Weight gain, hypoglycemia
 TZDs 0.5-1.4 Improved lipid Fluid retention, weight
profile gain, expensive
 Other drugs
 -glucosidase inhibitors 0.5-0.8 Weight neutral Frequent GI side effects,
expensive
 Exenatide 0.5-1.0 Weight loss Injections, frequent GI side
effects, expensive, little
experience
 Glinides 1-1.5 Short duration 3x/ day dosing, expensive
 Pramlintide 0.5-1.0 Weight loss Injections, frequent GI side
effects, expensive, little
experience

A consensus statement from ADA and EASD. Diabetologia, 2006, 49: 1711-21
 Management of hyperglycemia in type 2 diabetes
How do I establish and sustain glycemic control?

Lifestyle change: an

Q A
option?
Is metformin still the
first line drug?
&
Which drugs after
metformin?
Sulphonylureas, TZDs
or insulin?
And then? Three oral agents,
insulin as add-on or insulin alone?
What is the evidence for the
proposed algorithm?
Will new drugs be able to halt
the decline of beta-cell function?

RJ Heine et al. BMJ, 9 december 2006, 333: 1200-1204

 Contraindications can damage your health—is
metformin a case in point?
 Standard contraindications to the use of metformin should be relaxed,
and that the benefits of reducing the number of patients excluded from
using it would by far outweigh the potential risks
 propose removal of the following contraindications from the list:
1. old age
2. chronic renal insufficiency (as long as GFR>40 ml/min)
3. chronic heart failure (NYHA stages I and II)
4. discontinuation of metformin therapy 2 days before surgery
and i.v. contrast medium administration
 A clear re-definition of metformin contraindications will enable more
physicians to prescribe within the guidelines
 The main effect of revising these contraindications and precautions will
be to bring the official guidelines into harmony with day-to-day clinical
practice
A Holstein, M. Stumwoll. Doiabetologia, 2005, 48:2454-59
 Insulin

Oral agents
SIOFOR 1000

Chacra RA et al. Diabetes, Obesity, Metab, 2005, 7: 148-160

 Management of
Type 2 Diabetes

Glycemic control Treat associated Screen for/manage

Diet / Lifestyle conditions complications of
Exercise Dyslipidemia diabetes
Medication Hypertension Retinopathy
Obesity Cardiovascular
Coronary heart disease
disease Nephropathy
Neuropathy
Other complications
 Dyslipidemia in Diabetes

Triglycerides LDL Triglycerides

¯ HDL ¯ HDL
LDL

Medical nutritional therapy, increased physical activity

Improve glycemic HMG CoA Improve glycemic

control reductase inhibitor control
HMG CoA
 GLP-1
SNC
Stomac
Cord Neuroprotecţie
Apetitul
Cardioprotecţie

Funcţia cardiacă
Evacuarea
Intestinul conţinutului gastric

GLP-1
Ficat
Pancreas
Producţia de
glucoză

Sensibilitate
Muşchi la insulină Secreţia de insulină

Ţesut Secreţia de glucagon

Sinteza de insulină
adipos
Proliferarea beta-celulară
Preluarea şi stocarea Apoptoza celulelor beta
glucozei

Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157 Reprodus cu permisiune Elsevier© 2007.
Efects ofGLP-1 in healthy
subjects

Eliberare de
insulină

Insulină
53
Exenatid is not inactivated by
DPP-4

Eliberare de
insulină

Insulină
54
 Acute compication
 Diabetic ketoacidosis DKA
 Hyperosmolar hyperglycemic state
HHS
 Lactic acidosis LA
 Hypoglycemia
 DKA-pathogenesis
 Insulin deficency
 Increased counterregulatory
hormones
 dehydratation
 Causes of DKA
 Acute apendicites
 Myocardial infarction
 Shock,sepsis
 Urinary tract infections
 Pneumonia
 Oral or dental infections
 Infection in imunocompromised
individuals
 Laboratory test
 Glucose
 Electrolytes
 Complete bloood count
 Arterial blood gas
 Ketones
 Electrocardiogram
 Osmolality
 other:phosphor, chest ray, CT scan
 Management
 Fluid
1. ½-1h 1 liter
2. 2nd h 1 liter
3. 3rd h 500ml-1 liter
4. 4th h 500 ml-1 liter
Total 1-5h 3.5-5 liters
Normal saline
 Management
 Serum K meq/l
1. <3.5 – 40 meq/l

2. 3.5 -4.4 – 20meq/l

3. 4.5-5.5 – 10meq/l

4. >5.5 – stop infusion

Do not administrate if is anuric

 Management
 Bicarbonat theraphy related with PH
– 100ml NaHCO3 over 45 min
 Insulin theraphy – 0.1u/bw in bolus,

than 0.1u/bw/h
 Decrease insulin when glycemia is

less than 250mg/dl

 Glucose 10% at low rate

Check regulary!!
 Complications of DKA
 Cerebral edema
 Pulmonary edema
 Cardiac arrest
 Hypoglycemia
Hyperosmolar hyperglycemic state
HHS
 Insulin is present
 Appear in old patients with type2

Osmolarity=2(Na)(mEq/l)
+glucose(mg/dl)/18+BUN(mg/dl)
 N=290+/-5mOsm/Kg
 Lactic acidosis
 Blood lactate level>7mMol
 There are two catthegories
1. Type A, associate with hypoxia and
hypoperfusion
2. Type B, associate with many
disease, diabetes,liver disease,
renal failure,malignicy, alchool
 Hypoglycemia
 Most freq complication
 Great emergency
 Represent 4% of death
 Can be mild, moderate and severe
(hypoglycemic coma)
 Hypoglycemia-signs
 Neurogenic
1. Tremor
2. Palpitations
3. Pallor
4. Anxiety
5. hypertension
 Hypoglycemia-signs
 Neuroglycopenic
1. Cognitive impairment
2. Fatigue
3. Visual changes
4. Hungry
5. Parestesia
6. Innapropiate behavoir
7. Neurological deficit
8. Loss of consciousnes
 Hypoglycemia treatment
 Mild and moderate-carbohydrate
intake
 Severe-glucagon inj, hypertone
glucose and transport to hospital

Never giving something to drink

 Microvascular complications
 Rethinopathy
 Nephropathy
 Arteriopathy
 neuropathy
 Rethinopathy

Nonproloferative
 Dot or blot hemorrahages

 Microaneurysm

 Cotton wool spots

 Hard exudates

 Venous caliber abnormalites

 Rethinopathy

Proloferative
 Vascular proliferations

 Fibrous tissue proliferation

 Preretinal and vitrous hemorrages

Macular edema
 Maccular hard exudat

 Retinal modifications

 Seight loss
 Rethinopathy-treatment
1.Agresive care is needed to prevent
evolution to the next stage for
 Hyperglycemia

 Hypertension

 Dyslipidemya

 Proteinuria

 Anemia

2. Treatment - photocoagulation
 Nephropathy

 Risk
 Increasing durations of diabetes
 Poor control
 Family history of nephropathy
 Hypertension
 smoking
 Nephropathy

 The earliest sign is microalbuminuria

 GFR using MDRD formula rooutnily
 80%of patients with rethinopathy will
develop nephropathy in next 10
years
 Hypertension in patients with microal
contribute to the progression of
nephropathy
 Nephropathy

 Microalb is a marker for cardiovascular

morbidity
 Treating hyperlipidemia will slow down
the progression of renal disease
 Presence of micro and macroalb
indicates needs for aggressive
treatment of BG and BP
 Reduce creatinine clearance is a
manifestation of late diab nephropathy
 Nephropathy
diagnosis
 Microalbuminuria – 24h urine
 Albumin to creatinin ratio in spot urine
 Serum creatinine
 Estimated GRF
 Creatinine clearance
Mesurements of albumin excretion
category 24h Timed Spot
colection collection colection
micrg/min
normal <30 <20 <30

microalb 30-299 20-199 30-299

Clinical >300 >200 >300

microalb
 Serum creatinine and GRF
 A marker of renal function
 Every doubling of serum creatinine
indicates a loss of 50%of renal
function
 GRF a formula available at
www.kidney.org
 Factors that cause transient
elevation of microalb
 Urinary infection
 Short term hyperglycemia
 Acute febrile illness
 Heart failure
 Marker hypertension
 Strenuous exercise
 Pregnancy
 Treatment
 Tight glucose control
 Hypertension control
 Use of ACEinhibitors and angiotensin
receptor blockers
 Low protein diet
 Neuropathy
Symmetrical Neuropathy
 Distal symmetrical sensorimotor

 Autonomic

 Acute painful

 Hyperglygemic

 Symetrical prroximal lower limb

extremity
 Neuropathy
Focal and multifocal
 Cranial

 Diabetic amyotrophy

 Thoraco-abdominal

 Focal limb
 Neuropathy-clinical features
 Numbness and paresthesia
 Sensory deficit simetrical
 Glove and stocking pattern of
sensory deficit
 Affected of distal portion of thoracic
intercostal nerves
 Superficial burning, deep,aching
pain,dysesthesia during night
 Autonomic Neuropathy
 Cardiovascular system: tachycardia,
orthostatic hypotension, “dead in
bad”sindrom
 Urogenital system: bladder dysfuction,
urinary retension, erectil dysfunction
 Gastrointestinal system: gastroparesis
diabeticorum, diarrhea, abdominal
discomfort
 Sudomotor system: anhidrosis or
hyperhidrosis
 Neuropathy - evaluation
 Clinical examination:pin prick, tuning
fork, reflexes
 Cardiac vagal examination
 Measuring blood pressure in ortho
and clinostatism
 Electromyogram
 Periodical foot examination
 Neuropathy-treatment
 Hyperglycemia
 Dopamine agonist, metoclopramide
 Macrolide compound, erithromycyn, as
they havemotilin agonist properties
 Antysecretory, H2antagonist and
proton-pump inhibitors
 Duloxetin (norepinehrine and
serotoninreuptake
inhibit),anticonvulsivants