Diabetes

Question 1

WHO diagnostic criteria for DM

Answer 1

1. Fasting plasma glucose:
 >= 126 mg/dl
2. Random blood glucose: 
 >= 200 mg/dl
3. 2 hr plasma glucose:
 >= 200 mg/dl by OGTT
4. HbA1c >= 6.5%

Diagnosis is made by performing these tests on separate occasions and days

Question 2

Pre-diabetes / Impaired Glucose tolerance

WHO diagnostic criteria

Answer 2

1. Fasting blood glucose:
 100-125 mg/dl
2. Random plasma glucose:
 140-199 mg/dl
3. HbA1c 5.7-6.4%

Diagnosis is made by performing these tests on separate occasions and days

Question 3

Transient hyperglycemia

Answer 3

Acute states like infections, burns, trauma

Due to catecholamine release

Question 4

HbA1c levels

Answer 4

Glucose + β globin
< 5.6 % normal
5.7 - 6.4 % prediabetic
>= 6.5 % diabetic
In a diabetic, maintain the HbA1c < 7%

Question 5

Type 1 DM

basics

Answer 5

5-10 % of patients
Young adults
Due to autoimmune β cell destruction
2 factors: genetics, environmental

Question 6

Factors affecting DM type 1

Answer 6

Genetics factors:
• HLA on short arm of chr 6p
 HLA DR3, DR4, DQ8
• Polymorphism in CTLA4, PTPN22
Environmental:
 Virus - Coxsackie, mumps

Question 7

Pathogenesis of type 1 DM

Answer 7

1. Autoantigens on β cells and circulate in blood stream and lymphatics
2. Processing and presentation of autoantigen by antigen presenting cells
3. Activation of TH1 & TH2
   • IFN-γ ➡️ macrophage activation with IL-1 and TNF-α release
   • IL-2 ➡️ activation of autoantigen specific cytotoxic T (CD8) cells
   • IL-4 ➡️ activation of B cells to produce islet cell autoantibodies and antiGAD65 antibodies
4. Destruction of β cells with 🔽 insulin secretion

Question 8

Factors affecting type 2 DM

Answer 8

No autoimmune etiology
Genetic:
• No HLA association
• polymorphism in TCFTL2 green
Environmental factors:
 Central/abdominal obesity

Question 9

Cardinal features of pathogenesis of type 2 DM

Answer 9

1. 🔽 response of peripheral tissues

2. β cell dysfunction

Question 10

Insulin resistance

mechanisms

Answer 10

1. Failure to inhibit hepatic gluconeogenesis
2. Failure of glucose uptake ➡️ glycogen synthesis in skeletal muscle
3. Fat cells ➡️ failure to inhibit lipoprotein lipase ➡️ 🔼 circulation of free fatty acid

Question 11

Why does obesity increase risk of insulin resistance

Answer 11

1. Free fat acid production
2. 🔼 in preglycemic adipokines like resistin & retinol binding protein
3. Inflammation:
   🔼 cytokines ➡️ 🔽 insulin sensitivity

Question 12

How does free fatty acid 🔼 insulin resistance

& why is central obesity more harmful

Answer 12

1. Central adipose tissue (more lipolytic than peripheral) ➡️
2. Excess FFA ➡️ non-esterified FFA (NEFFA)
3. Accumulation of toxic metabolites like DAG
4. Attenuate signaling through insulin receptor pathway

Question 13

Adipokines

Answer 13

1. Pre-glycemic:
 Resistin
 Retinol binding protein
2. Anti-glycemic:
 Leptin
 Adiponectin

Question 14

Development of overt DM

Answer 14

1. Insulin resistance ➡️ impaired glucose tolerance
2. Initially β cell function 🔼 to compensate for insulin resistance
3. Slowly β cells exhaust their capacity
4. DM

Question 15

DM complications

Answer 15

1. Acute:
 DKA
2. Chronic:
 Macrovascular: MI, PVD
 Microvascular:
  Retinopathy, neuropathy, nephropathy

Question 16

Pathogenesis of DM complications

Answer 16

1. Formation of advanced glycation end products AGEs
2. AGEs + RAGE receptors on inflammatory cell (macrophages)
3. Activation of protein kinase-C

Question 17

Formation of advanced glycation end products AGEs

Answer 17

In DM
By non-enzymatic reaction between intracellular glucose intermediates like glyoxal + amino group of both intra & extra cellular proteins ➡️ AGEs

Question 18

AGEs + RAGE receptors on inflammatory cell (macrophages)

effects

Answer 18

1. Release of cytokines like TGF-β, VEGF
2. Generation of reactive oxygen species
3. 🔼 procoagulant activity
4. Enhanced proliferation of smooth muscle & 🔼 synthesis of extracellular matrix material