Lecture 28 - Pathology Of Diabetes

Pathology Of Diabetes Mellitus

Diabetes Mellitus • • • •

Disorder of metabolism (Carb, Prot & Fat) Due to Absolute/relative deficiency of insulin. Characterized by hyperglycemia Clinically: • • •

Polyuria Polydypsia, Polyphagia.

Introduction • Diabetes mellitus (sweet urine) • 3% of world population, 100 million people • Incidence is increasing alarmingly (40% in the past decade, more in future. 259 m by 2025. • Most Common non-communicable disease • High Morbidity & mortality. • DM shortens life span by 15 years. • Leading cause of blindness and Kidney disease.

THE ENDOCRINE PANCREAS • • •

Approximately 1 million Islets of Langerhans Most located in the body and tail Contain cells that manufacture and secrete different hormones: • • • • •

beta cells alpha cells delta cells PP cells D1 cells

•

enterochromaffin cells rare

70% 20% 5‑10% 1‑2% rare

insulin glucagons somatostatin pancreatic polypeptide vasoactive intestinal peptide (VIP) serotonin

Blood Glucose & Hormones Hormone • Insulin • Glucortocoids • Glucagon • Growth Hormone • Epinephrine

Action ∀ ↓ Glucose ∀ ↑ Glucose ∀ ↑ Glucose ∀ ↑ Glucose ∀ ↑ Glucose

Normal Pancreatic Islet: ß cells (Insulin)

α cells (Glucagon)

Cellular Glucose Uptake

Insulin Requiring

Non-Insulin Requiring

• • • •

• • • •

Striated Muscle Cardiac Muscle Fibroblasts FAT

Blood Vessels Nerves Kidney Eye Lens

Pathology in Diabetes: • Low glucose inside cell – Decreased cell metabolism (muscle, liver)

• High glucose outside cell – Glycosylation damage (Blood Vessels) – Osmotic damage

Pathogenesis of Type I Diabetes Mellitus Type I DM results from an absolute deficiency in insulin secondary to a reduced beta‑cell mass. Three basic components: 1. Genetic susceptibility (e.g. HLA‑DR3, ‑DR4) 2. Autoimmune reaction to islet beta cells 3. Initiating environmental insult (e.g. virus, chemical, etc.).

Pathogenesis of Type II Diabetes Mellitus 1. 2. 3. 4.

Genetic factors more important than in type I DM Age-related Obesity-related No evidence of an autoimmune mechanism

Evidence points to two biochemical defects 8. relative decrease in insulin 9. insulin resistance.

Pathogenesis of Type II Diabetes Mellitus THEORIES 1. Relative or absolute insulin deficiency Age-related loss of beta cell ability to manufacture and secrete insulin, or to respond to hyperglycemic stimuli. •

Peripheral insulin resistance Obesity causes insulin resistance of its own

Cellular defects in insulin resistance: • Decreased numbers of insulin receptors on peripheral cells • Defects in receptor‑associated tyrosine kinase • Post‑receptor defects in the cytoplasmic glucose transport unit proteins.

Type-I DM • • • • • • • • • •

Less common Children < 25 Years Insulin- Dependent Duration: Weeks Acute Metabolic complications Autoantibody: Yes Family History: No Insulin levels: very low Islets: Insulitis 50% in twins

Type-II DM • • • • • • • • • •

More common Adult >25 Years Insulin Independent * Months to years Chronic Vascular complications. No Yes Normal or high * Normal / Exhaustion 60-80% in twins

Insulitis In Type I DM

Insulinitis

Islets in Type II DM Loss of ß cells, replaced by Amyloid deposits (hyalinization)

Islets in Type II Diabetes: Loss of ß cells, replaced by Amyloid deposits (hyalinization)

Complications Of DM: •

Short term Complications: (metabolic) 1. 2. 3. 4.

•

Hypoglycemia Diabetic Ketoacidosis Non Ketotic hyperosmolar diabetic coma Lactic acidosis

Long term Complications:(Angiopathy) – Microngiopathy: Retinopathy, Nephropathy Neurophathy, Dermatopathy

– Macroangiopathy Atherosclerosis

Microangiopathy Pathogenesis: Chronic Hyperglycemia Glycosylation of basement membrane proteins  Leaky blood vessels. Thick and Leaky blood vessels Narrow lumen Ischemic Organ Damage...

Diabetic Microangiopathy Normal

   

Glucose Glycosylation BM damage leak ‘AGE’ deposition

Diabetic

Neuropathy • Sensory  Motor (myelin) • Peripheral Neuropathy – Bilateral, symmetric – Progressive, irreversible – Paraesthesia, pain, muscle atrophy

• Visceral neuropathy – Cranial nerve – diplopia, Bell palsy – GIT- constipation, diarrhea – CVS – orthostatic hypotension

Neuropathic ulcers

Features: •Painless •At pressure points •Good foot pulses •May not be associated with gangrene

:

DIABETIC NEPHROPATHY • Kidney is the most severely damaged organ in DM • DM is the most common cause of end‑stage renal disease • Nephropathy is more common in type I DM • Nephropathy develops in kidneys transplanted in diabetics

Diabetic Nephropathy • Arteriolosclerosis • Diffuse or nodular diabetic glomerulosclerosis (Kimmelstiel Wilson Syndrome)

• Renal papillary necrosis • Pyelonephritis • End stage kidney

Nephropathy • Nodular Glomerulosclerosis. • Deposition of ‘AGE’ (Advanced Glycosylation End-products) as nodules • Nephrotic syndrome • End stage renal failure

Nodular Glomerulosclerosis (Kimmelstiel Wilson Syndrome)

Renal papillary necrosis

DIABETIC RETINOPATHY • Fourth leading cause of legal blindness • Leading cause of new cases of blindness in adults • Other causes of blindness in diabetic patients include: – Glaucoma – cataracts – optic neuropathy

• Approximately 60% of diabetics develop retinopathy • Vision‑threatening retinopathy is commoner in type I DM • Duration of diabetes is important in the severity of disease

Normal Retina

Retinopathy • Non-proliferative – – – – –

Microaneurysms, Dot blot hemorrhages Hard and soft exudates Cotton wool – infarcts Macular edema.

• Proliferative. – – – –

Neovascularization Large hemorrhages Retinal detachment Fibrosis

Dot blot – Hemorrhages

Cotton wool spots

Pre-retinal Hemorrhage

Fibrous plaques

Cataract

Macroangiopathy Atherosclerosis DM is a major risk factor for the development of Atherosclerosis • Hyperlipidemia ∀ ↓ HDL • Non-Enzymatic Glycosylation ∀ ↑ Platelet Adhesiveness ∀ ↑ Thromboxane A2 • Endothelial damage  Atherosclerosis

Risk Factors for Atherosclerosis: Non modifiable • Age • Male Sex, • Genetic - Hyperchol. • Family history

Potentially Modifiable • Hyperlipidemia – HDL/LDL ratio. • Hypertension. • Smoking. • Diabetes.

Atherosclerosis:

Infections in Diabetes: Causes: • Decreased metabolism • Decreased function of lymphocytes & neutrophils • Glycosylation of immune mediators. Ab • Impaired inflammation. • Ischemia & infarctions • Diabetes  State of immunosuppression

SKIN LESIONS IN DIABETES MELLITUS Occurs in 30% of diabetic patients Lesions: D) Necrobiosis Lipoidica Diabeticorum E) Diabetic dermopathy ("skin spots") F) Granuloma Annulare G) Injection site lipodystrophy