3. Diabetes mellitus Flashcards
Definition of diabetes mellitus
Group of metabolic disorders sharing in common disordered carbohydrate, fat & protein metabolism, characterized in it fully- expressed clinical form by fasting hyperglycemia & glycosuria
Types of diabetes mellitus
- Primary (idiopathic) diabetes mellitus
- Type I diabetes mellitus
- Type II diabetes mellitus - Secondary diabetes mellitus
- Chronic pancreatitis & post-pancreatectomy
- Hormonal tumours (e.g. pheochromocytoma, pituitary tumours)
- Drugs (exogenous corticosteroids)
- Hemochromatosis
- Genetic disorders
- Gestational diabetes mellitus
Genetic involvement in type 1 DM
- 50% concordance in twins
2. HLA-D linked
Characteristic cause of type 1 DM
Absolute insulin deficiency
Pathogenesis of type 1 DM
- Autoimmunity
- Genetic factors
- Viral infection (molecular mimicry)
- Beta cell damage
- Producing self-reactive T lymphocytes & autoantibodies - Severe insulin deficiency results from beta cell destruction
Clinical features of type 1 DM
- Polyuria & glycosuria
- Polydipsia
- Polyphagia
- Weight loss
- Diabetic ketoacidosis
Histological features of type 1 DM
- Marked reduction in number & size of islets
2. Insulitis (leukocytic infiltration of islets)
Genetic involvement in type 2 DM
- 90-100% concordance in twins
2. No HLA association
Characteristic cause of type 2 DM
Insulin resistance with relative insulin deficiency
Pathogenesis of type 2 DM
- 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) - Exhaustion of beta cells
- Due to increasing peripheral insulin resistance
- Confounded by primary genetic beta cell defect predisposing to beta cell decompensation
Clinical features of type 2 DM
May have polyuria, polydipsia, weight loss
- Hyperosmolar non-ketotic coma (typically in physically incapacitated elderly unable to rehydrate adequately)
Histological features of type 2 DM
- Moderate reduction in number & size of islets
2. Amyloid replacement of islets
Pathogenesis of complications of diabetes
- 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 - 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
Complications of diabetes
- Macrovascular disease
- Due to accelerated atherosclerosis
- Affects various systemic arteries:
i. Cerebral: stroke
ii. Coronary: acute myocardial infarction
iii. Limbs: peripheral vascular disease - 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)
- 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
