Number of persons
<5,000
5,000 – 74,000
75,000 – 349,000
350,000 – 1,500,000
>1,500,000
No data available
A projected 300 million people with diabetes
worldwide by 2025
WHO. The World Health Report 1998; 91;
King H, et al. Diabetes Care 1998; 21:1414–1431.
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1. Progressive beta cell dysfunction:
-Reduced Insulin secretion in response to
serum glucose
2. Insulin resistance: genetic
-increases with age and weight.
- glucotoxicity
- lipotoxicity
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3. Impaired insulin processing:
proinsulin ratio increase to 40% in T2DM
from a nl ratio of 10-15%
Epidemiology:
- bimodal:
a. one peak at 4-6 years of age
b. second in early puberty (10-14 years)
 M=F.
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No family history: 0.4 %
affected mother: 2 - 4 %
affected father: 5 to 8 %
both parents affected: 30 %
Non-twin sibling of affected patient: 5 %
Dizygotic twin: 8 %
Monozygotic twin: 50 % lifetime risk
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• Viral infections
• Immunizations
• Diet: cow's milk at an early age
• Vitamin D deficiency
• Perinatal factors:maternal age, h/o preeclampsia, and neonatal jaundice
Low birth weight decreases the risk of
developing type 1 diabetes
1 • Body habitus :
T2DM: overweight
T1DM: not overweight and often have a
recent history of weight loss.
2 • Age :
T2DM :after the onset of puberty.
T1DM bimodal: 4 -6 yrs, and10 -14 yrs
3• Insulin resistance :
acanthosis nigricans,HTN, dyslipidemia, and
PCOS
4• FH: type 2 > type 1
5• Autoimmune Abs:
T1DM: +:GAD, tyrosine phosphatase (IA2),
and/or insulin Abs
T2DM: 30 % have + Abs
Increased
lipolysis and
release of free
fatty acids
Insulin
resistance
Elevated
circulating FFA
High insulin demand
Decreased glucose
uptake into glucose
output
-Cell
dysfunction
Hyperglycemia
muscle and adipose tissue and raised he
Type 2 diabetes
Beta-cell function (%,
HOMA)
100
80
Diabetes
diagnosis
60
40
20
Extrapolation of beta-cell function prior to
0
diagnosis
–12 –10 –8 –6 –4 –2 0
2 4
6
8
Years from diagnosis
HOMA: homeostasis model assessment
Lebovitz. Diabetes Reviews 1999;7:139–53 (data are from the UKPDS population: UKPDS 16.
Diabetes 1995;44:1249–58)
- T2DM is 2-6x (blacks> whites)
 39% have at least one parent with the disease
 monozygotic twin: 90 %
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The lifetime risk for a first-degree relative of
a pt with T2DM is 5-10 x higher than age- &
wt-matched
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Increasing weight and less exercise
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Obesity epidemic
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Increasing T2DM in children and adolescents
- FH of DM
- Overweight (BMI > 25 kg/m2)
-physical inactivity
-Race/ethnicity (African-Americans, Hispanic-Americans)
- h/o IFG or IGT
-History of GDM or delivery of a baby weighing >9 lbs
-Signs of insulin resistance or conditions associated with
insulin resistance :
*Hypertension ( 140/90 mmHg in adults)
*HDL cholesterol 35 mg/dl (0.90 mmol/l) and/or a
triglyceride level 250 mg/dl (2.82 mmol/l)
*Polycystic ovary syndrome
*acanthosis nigricans
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Polyuria, increased frequency of urination,
nocturia.
Increased thirst, and dry mouth
Weight loss
Blurred vision
Numbness in fingers and toes
Fatigue
Impotence (in some men)
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Weight loss: muscle weakness
Decreases sensation
Loss of tendon reflexes
Foot Inter-digital fungal infections
Retinal changes by fundoscopy
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1. A1C ≥6.5 %. *
2. FPG ≥126 mg/dL . Fasting is defined as no
caloric intake for at least 8 h.*
3. Two-hour plasma glucose ≥200 mg/dL during
an OGTT. 75 g anhydrous glucose dissolved in
water.*
4. In a patient with classic symptoms of
hyperglycemia or hyperglycemic crisis, a random
plasma glucose ≥200 mg/dL .
* In the absence of unequivocal hyperglycemia,
criteria 1-3 should be confirmed by repeat
testing.
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3234 obese (average BMI 34 kg/m2)
age 25-85 yrs at high risk for DM (Obese+
IFG/IGT) were randomized to:
1. Intensive lifestyle changes: 7 % wt loss (
low-fat diet and exercise for 150 min/ wk)
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2. metformin (850 mg BID) + information
on diet and exercise
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3. Placebo plus information on diet and
exercise
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The intensive lifestyle and
metformin interventions reduced the
cumulative incidence of diabetes by 58 and
31 %, respectively compared to placebo.
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The diet and exercise group lost an average
of 6.8 kg (7%) of wt / 1st yr.
At 3 years, fewer patients in this group
developed diabetes (14 versus 22 and 29 %
in the metformin and placebo groups)
Lifestyle intervention was effective in men
and women in all age groups and in all
ethnic groups.
 16
% reduction in DM risk for
every kg lost
 Improvements in insulin
sensitivity and insulin secretion,
correlated directly with decreased
risk of diabetes
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1. Lifestyle modifications:
- Medical nutrition therapy
- increased physical activity
- wt reduction
2. Oral Drug Therapy/Noninsulin sc therapy
3. Insulin therapy
43% of patients
do not
achieve glycaemic targets
(HbA1c<7%)
Ford et al (NHANES). Diabetes Care 2008;31:102–4
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1. Biguanides: Metformin
-decrease hepatic glucose output
-increases glucose utilization in peripheral
tissues (such as muscle and liver)
-antilipolytic effect
-increases intestinal glucose utilization
Efficacy : HbA1c reduction by 1-1.5%
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Side Effects: GI upset initially, Lactic acidosis (
9 cases per 100,000 person-years of
exposure)e )
C/I : renal impairment S.Cr > 1.5 mg/dl
males, and S.Cr > 1.4 Females, liver failure,
advanced heart failure, sepsis, hypotension.
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2. Sufonylureas and Meglitinides:
Glibenclamide, Repagnilide
- Mechanism: activate SU receptor,
stimulate insulin secretion
- Efficacy : HbA1c reduction 1-2 % ( SU),
<1% Glinides
- S/E: Hypoglycemia, wt gain
- C/I: pregnancy,
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3. Alpha- glucosidase inhibitors: Acarbose
- inhibits GI glucose absorption
- prominent GI S/E
- modest HbA1c reductions 0.6%
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4. Thiazolidinediones:
Pioglitazones,Rosiglitazones
- PPAR Gamma agonists
-insulin sensitizer on adipose tissue, liver,
skeletal muscles.
-S/E: fluid retention-edema,CHF,
Hepatotoxicity, bone fractures, macular
edema
-Efficacy: HbA1c reduction 1-1.5 %
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5. Incretin based therapy:
a. DPP4 Inhibitors:
- inhibit Dipeptidylpeptidase 4 enzyme
which inactivates native GLP-1
- given orally
- Efficacy:HbA1c reduction 0.6 -0.8 %, up
to 1% if higher baseline HbA1c (>9%)
-S/E: ? Pancreatitis, hepatotoxicity, Skin
reactions
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b. GLP1 agonists:
Exenetide: synthetic exendin4, from saliva
of Gila monster, 53% homology with natural
GLP1.
- augments insulin release (glucosedependent ).
- slows gastric emptying,
-suppresses inappropriately elevated
glucagon levels, and leads to weight loss
- HbA1c reduction 1.1%
-S/E : GI (nausea), acute pancreatitis,acute
renal failure.
Liraglutide :GLP-1 analog, binds to serum
albumin resulting in slower degradation,
 -Once daily injection
 - HbA1c reduction of 1.5%
 -significant weight reduction
 - S/E: GI, pancreatitis, ? Thyroid C-cell
hyperplasia/malignancy in animal studies.
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6. Amylin analogues:AMYLIN is a 37-amino
acid peptide that is stored in pancreatic beta
cells and is co-secreted with insulin . Amylin
is deficient in type 1 diabetes and relatively
deficient in insulin-requiring type 2 diabetes
-slowed gastric emptying,
-regulation of postprandial glucagon
- reduction of food intake
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PRAMLINTIDE : amylin analog
-approved for both type 1 and insulintreated type 2 diabetes.
-effects are glucose-dependent and are
overridden as serum glucose levels fall. It
does not cause hypoglycemia
-HbA1c reduction < 1%
S/E : nausea, increase hypoglycemia risk if
insulin dose not reduced.
1. Ultra-short acting : Aspart-Lispro-Glulisine
 2. Short acting: Regular
 3. Intermediate acting : NPH
 4. intermediate—long : Insulin Detimir
 5. Long acting : Insulin Glargine
UKPDS: up to 8 kg in 12 years
ADOPT: up to 4.8 kg in 5 years
100
8
Insulin (n=409)
6
96
5
Weight (kg)
Change in weight (kg)
7
Glibenclamide (n=277)
4
3
2
92
88
1
Metformin (n=342)
0
0
3
6
9
Years from randomisation
Conventional treatment (n=411);
diet initially then sulphonylureas, insulin
and/or metformin if FPG >15 mmol/L
12
0
0
1
2
3
4
Years
Rosiglitazone
Metformin
Glibenclamide
UKPDS 34. Lancet 1998:352:854–65. n=at baseline; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43
5
UKPDS
9
Conventional*
Glibenclamide
Metformin
Insulin
Rosiglitazone
Metformin
Glibenclamide
ADOPT
8
Median HbA1c (%)
8.5
7.5
8
7.5
7
7
Recommended
treatment
target <7.0%†
6.5
6
6.5
6.2% – upper limit of normal range
0
2
4
6
Years from randomisation
8
10
6
0
1
*Diet initially then sulphonylureas, insulin and/or
metformin if FPG>15 mmol/L; †ADA clinical practice
recommendations. UKPDS 34, n=1704
UKPDS 34. Lancet 1998:352:854–65; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43
2
3
Time (years)
4
5