3. Diabetes mellitus

Question 1

Definition of diabetes mellitus

Answer 1

Group of metabolic disorders sharing in common disordered carbohydrate, fat & protein metabolism, characterized in it fully- expressed clinical form by fasting hyperglycemia & glycosuria

Question 2

Types of diabetes mellitus

Answer 2

1. Primary (idiopathic) diabetes mellitus
   - Type I diabetes mellitus
   - Type II diabetes mellitus
2. Secondary diabetes mellitus
   - Chronic pancreatitis & post-pancreatectomy
   - Hormonal tumours (e.g. pheochromocytoma, pituitary tumours)
   - Drugs (exogenous corticosteroids)
   - Hemochromatosis
   - Genetic disorders
   - Gestational diabetes mellitus

Question 3

Genetic involvement in type 1 DM

Answer 3

1. 50% concordance in twins

2. HLA-D linked

Question 4

Characteristic cause of type 1 DM

Answer 4

Absolute insulin deficiency

Question 5

Pathogenesis of type 1 DM

Answer 5

1. Autoimmunity
   - Genetic factors
   - Viral infection (molecular mimicry)
   - Beta cell damage
   - Producing self-reactive T lymphocytes & autoantibodies
2. Severe insulin deficiency results from beta cell destruction

Question 6

Clinical features of type 1 DM

Answer 6

1. Polyuria & glycosuria
2. Polydipsia
3. Polyphagia
4. Weight loss
5. Diabetic ketoacidosis

Question 7

Histological features of type 1 DM

Answer 7

1. Marked reduction in number & size of islets

2. Insulitis (leukocytic infiltration of islets)

Question 8

Genetic involvement in type 2 DM

Answer 8

1. 90-100% concordance in twins

2. No HLA association

Question 9

Characteristic cause of type 2 DM

Answer 9

Insulin resistance with relative insulin deficiency

Question 10

Pathogenesis of type 2 DM

Answer 10

1. Obesity-induced peripheral insulin resistance
   - Increased levels of plasma free fatty acids attenuates insulin signaling to increase gluconeogenesis
   - Decreased adipokines (anti- hyperglycemic hormones elaborated by adipocytes which increase peripheral insulin sensitivity)
2. Exhaustion of beta cells
   - Due to increasing peripheral insulin resistance
   - Confounded by primary genetic beta cell defect predisposing to beta cell decompensation

Question 11

Clinical features of type 2 DM

Answer 11

May have polyuria, polydipsia, weight loss

- Hyperosmolar non-ketotic coma (typically in physically incapacitated elderly unable to rehydrate adequately)

Question 12

Histological features of type 2 DM

Answer 12

1. Moderate reduction in number & size of islets

2. Amyloid replacement of islets

Question 13

Pathogenesis of complications of diabetes

Answer 13

1. Non-enzymatic glycosylation
   - Glucose chemically attaches to the amino group of proteins without the aid of enzymes, forming irreversible advanced glycosylation end-products
   - AGEs can directly cross-link with collagen & albumin, contributing to the thickening of basement membranes
   - Also, AGE-modified matrix components enhance trapping of LDLs which accelerates atherogenesis
   - Lastly, AGEs can bind to AGE receptors found on certain cell types (macrophages, endothelial cells, mesangial cells) which induces:
   i. Release of cytokines & growth factors
   ii. Increased endothelial permeability
   iii. Proliferation & synthesis of extracellular matrix
2. Intracellular hyperglycemia
   - Affects tissues not dependant on insulin for glucose transport (nerves, lens, kidneys, blood vessels)
   - Hyperglycemia causes increased intracellular glucose levels in such tissues
   - Increased intracellular glucose causes disturbance of the polyol pathway by providing increased substrate (glucose) for sequential conversion to sorbitol (by aldose reductase), then to fructose
   - Accumulation of fructose increases intracellular osmolarity, causing osmotic cell injury
   - Also, conversion process utilizes NADPH, which, when depleted by increased conversion, results in decreased glutathione regeneration, increasing cellular susceptibility to oxidative damage

Question 14

Complications of diabetes

Answer 14

1. Macrovascular disease
   - Due to accelerated atherosclerosis
   - Affects various systemic arteries:
   i. Cerebral: stroke
   ii. Coronary: acute myocardial infarction
   iii. Limbs: peripheral vascular disease
2. Microvascular disease
   - Retinopathy
   i. Neovascularization due to hypoxia-induced VEGF production in retina (causing blindness)
   ii. Also, increased risk of cataract and glaucoma

• Nephropathy
  i. Glomerular lesions (basement membrane thickening + diffuse mesangial sclerosis + nodular glomerulosclerosis aka Kimmelstiel-Wilson lesions)
  ii. Renal vascular lesions (atherosclerosis)
  iii. Pyelonephritis
• Neuropathy
  i. Peripheral neuropathy (lower extremities first, more sensory than motor deficits)
  ii. Autonomic neuropathy (disturbances in bowel & bladder movements, may have impotence)
  iii. Mononeuropathy (manifests as sudden wrist drop, foot drop or cranial nerve palsies)

3. Increased susceptibility to infections
   - Due to vascular compromise & ↓ leukocyte function
   - Common infections seen in diabetic patients:
   i. Skin infections
   ii. Tuberculosis
   iii. Pneumonia
   iv. Pyelonephritis