Diabetes Mellitus

Estimated prevalence of diabetes worldwide in 2025

Number of persons<5,0005,000 – 74,00075,000 – 349,000350,000 – 1,500,000>1,500,000No 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.

1. Progressive beta cell dysfunction: -Reduced Insulin secretion in response to

serum glucose 2. Insulin resistance: genetic -increases with age and weight. - glucotoxicity - lipotoxicity

Pathophysiology- Type 2 DM

3. Impaired insulin processing: proinsulin ratio increase to 40% in T2DM

from a nl ratio of 10-15%

Pathophyisiology-T2DM

Epidemiology: - bimodal: a. one peak at 4-6 years of age b. second in early puberty (10-14 years) M=F.

Pathophysiology -Type 1DM

 • 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

Genetic susceptibility -T1DM 

 • Viral infections  • Immunizations  • Diet: cow's milk at an early age  • Vitamin D deficiency  • Perinatal factors:maternal age, h/o pre-

eclampsia, and neonatal jaundice

Low birth weight decreases the risk of developing type 1 diabetes

Environmental factors-T1DM  

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

Type 1 versus type 2 diabetes 

3• Insulin resistance : acanthosis nigricans,HTN, dyslipidemia, and

PCOS4• FH: type 2 > type 15• Autoimmune Abs: T1DM: +:GAD, tyrosine phosphatase (IA2),

and/or insulin Abs T2DM: 30 % have + Abs

Insulin resistance and -cell dysfunction

Insulinresistanc

e

High insulin demand

glucoto

xicity

lipotoxicity

Increased lipolysis and release of free fatty acids

Elevated circulating FFA

Decreased glucose uptake into glucose output

Hyperglycemia

Type 2 diabetes

-Cell dysfunction

muscle and adipose tissue and raised hepatic

Beta-cell function progressively declines

Extrapolation of beta-cell function prior to diagnosis0

20

40

100

–4 6–10 –8 –6 –2 0 2 4

80

60

–12 8

Diabetes diagnosis

Years from diagnosis

Beta

-cell

funct

ion (

%,

HO

MA

)

HOMA: homeostasis model assessmentLebovitz. 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 %

The lifetime risk for a first-degree relative of a pt with T2DM is 5-10 x higher than age- & wt-matched

Genetic susceptibilty- T2DM

Increasing weight and less exercise

Obesity epidemic

Increasing T2DM in children and adolescents

ROLE OF DIET, OBESITY, AND INFLAMMATION

- 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

MAJOR RISK FACTORS ( Type2DM)

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)

Symptoms

Weight loss: muscle weakness Decreases sensation Loss of tendon reflexes Foot Inter-digital fungal infections Retinal changes by fundoscopy

Signs

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.

Criteria for the diagnosis of diabetes

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)

2. metformin (850 mg BID) + information on diet and exercise

3. Placebo plus information on diet and exercise

Diabetes Prevention-DPP trial

The intensive lifestyle and metformin

 interventions reduced the cumulative incidence of diabetes by 58 and 31 %, respectively compared to placebo.

DPP

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.

DPP

16 % reduction in DM risk for every kg lost

Improvements in insulin sensitivity and insulin secretion, correlated directly with decreased risk of diabetes

DPP

1. Lifestyle modifications: - Medical nutrition therapy - increased physical activity - wt reduction 2. Oral Drug Therapy/Noninsulin sc therapy 3. Insulin therapy

Management of Type2DM

Key challenges of type 2 diabetes: outcome

43% of patients do not

achieve glycaemic targets (HbA1c<7%)

Ford et al (NHANES). Diabetes Care 2008;31:102–4

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%

Current available Therapy

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.

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,

Drug therapy-2

3. Alpha- glucosidase inhibitors: Acarbose - inhibits GI glucose absorption - prominent GI S/E - modest HbA1c reductions 0.6%

Drug therapy-3

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 %

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

Drug therapy-3

b. GLP1 agonists: Exenetide: synthetic exendin4, from

saliva of Gila monster, 53% homology with natural GLP1.

- augments insulin release (glucose- dependent ).

- 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.

Drug therapy 4

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

PRAMLINTIDE : amylin analog -approved for both type 1 and insulin-

treated 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.

Drug therapy 5

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

Insulins

Most therapies result in weight gain over time

Glibenclamide (n=277)

Years from randomisation

Insulin (n=409)

Metformin (n=342)

Conventional treatment (n=411); diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/L

UKPDS: up to 8 kg in 12 years ADOPT: up to 4.8 kg in 5 years

Weig

ht

(kg)

Rosiglitazone Metformin Glibenclamide

Change in w

eig

ht

(kg)

0

1

5

0 3 6 9 12

8

7

6

4

3

2

Years

0 1 2 3 4 5

96

92

88

0

100

UKPDS 34. Lancet 1998:352:854–65. n=at baseline; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43

6.2% – upper limit of normal range

Media

n H

bA

1c

(%)

Conventional*GlibenclamideMetforminInsulin

UKPDS

6

7

8

9

Years from randomisation2 4 6 8 100

7.5

8.5

6.5

Recommended treatment

target <7.0%†

8

6

7.5

7

6.5

Time (years)0 2 3 4 51

ADOPT MetforminGlibenclamide

Rosiglitazone

Over time, glycaemic control deteriorates

*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

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