PAL3 Pathology of Endocrine Pancreas

• Diabetes Mellitus

  An abnormal metabolic state characterized by glucose intolerance due to inadequate insulin action

  
• Diabetes Mellitus

  • Disorder of metabolism (Carb, Prot & Fat)
  • Due to Absolute/relative deficiency of insulin
  • Deficiency in insulin (anabolic steroid) – leads to increased catabolism

  
• Diabetes Mellitus is the most Common non communicable disease
• Diabetes Mellitus is the leading cause of blindness and Kidney disease

  
• Diabetes Mellitus

  Characterized by hyperglycemia
• Diabetes Mellitus

  Clinically: Polyuria, Polydypsia, Polyphagia
• Cell types in the islets of Langerhans

  • ß cells
  • α cells
  • δ cells
  • pp Cells
• ß cells

  Produce insulin, promote glucose entry into cells, glycogen synthesis, lipogenesis & protein synthesis

  
• α cells

  Produce glucagon, promote breakdown of glycogen and gluconeogenesis
• δ cells

  Produce stomatostatin, inhibit insulin & glucagon secretion

  
• pp Cells

  Produce pancreatic polypeptide, function unknown
• Cellular Glucose Uptake

  • Insulin Requiring: Striated Muscle, Cardiac Muscle, Fibroblasts, FAT
  • Non-Insulin Requiring: Blood Vessels, Nerves, Kidney, Eye Lens

  
• Metabolic actions of insulin

  In striated muscle, adipose tissue, and liver

  
• Low glucose inside cell, decreased cell metabolism (muscle, liver)
• High glucose outside, Glycosylation damage, Polyol products – osmotic damage
• Classification of Diabetes Mellitus

  • Primary DM (without other diseases): Type 1 (IDDM), Type 2 (NIDDM), Gestational DM
  • Secondary DM (with other underlying diseases): Pancreatitis/Tumours/Haemochromatosis, Infections, Endocrinopathy, Drugs

  
• Type 1 DM

  Insulin-Dependent, Less common (10%), Onset in Children (<25 Years), Autoantibody: Yes, Family History: No, Insulin levels: very low (absolute insulin deficiency) due to autoimmune pancreatic beta cells destruction

  
• Type 2 DM

  Insulin-Independent, More common (80%), Onset in Adults (>25 Years), Autoantibody: No, Family History: Yes, Insulin levels: Normal or high (relative insulin deficiency) due to peripheral resistance to insulin action and inadequate compensatory response of insulin secretion by the pancreatic beta cells

  
• Pathogenesis of Type 1 DM

  1. Genetic (HLA-DR3/4)

  2. Environment (Viral infection?)

  3. Autoimmune Insulitis

  4. Antibodies to beta cells/insulin

  5. Beta cell destruction

  6. Insulin deficiency

  
• Pathogenesis of Type 2 DM

  1. Obesity/Lifestyle?

  2. Beta cell exhaustion

  3. Insulin resistance

  4. Abnormal insulin secretion

  5. Relative insulin deficiency

  
• Type 1 DM: Insulitis (Autoimmune)
• Type 2 DM: Loss of beta islet cells, replaced by Amyloid deposits (hyalinization)
• Short term (Acute) Complications of Diabetes Mellitus

  • Non-Ketotic hyperosmolar diabetic coma
  • Diabetic Ketoacidotic coma
  • Lactic acidosis
  • Hypoglycemia

  
• Long term (Chronic) Complications of Diabetes Mellitus

  • Microvascular: Retinopathy, Nephropathy, Neuropathy, Dermatopathy
  • Macrovascular: Atherosclerosis
  • Hyaline arteriolosclerosis

  
• HbA1C is used for the assessment of long term Diabetes Mellitus

  
• Long term vascular complications in Diabetes Mellitus

  • Large blood vessels: Atheroma leading to myocardial infarction, CVDs, ischemic limb, gangrene
  • Small blood vessels: Endothelial cells and basal lamina damage leading to retinopathy, nephropathy
  • Peripheral nerve: Neuropathy
  • Neutrophils: Prone to infection
  • Pregnancy: Pre-eclamptic toxaemia, large babies, neonatal hypoglycemia
  • Skin: Infections, gangrene
• Pathogenesis of Diabetic Microangiopathy

  1. Chronic hyperglycemia - Glucotoxicity - Glycosylation & damage of basement membrane proteins

  2. Thick & leaky blood vessels – narrowed lumen – ischemic organ damage

  3. 'AGE' deposition <Advanced Glycation End products>

  4. AGE – RAGE binding <receptor on macrophages and T cells: Release of pro-inflammatory cytokines and growth factors by these cells

  5. Generation of reactive oxygen species in endothelial cells

  6. Increased procoagulant activity

  7. Enhanced vascular smooth muscle cells proliferation and extracellular matrix synthesis

  
• Diabetic Neuropathy

  Sensory and Motor (focal demyelination)<|>Peripheral Neuropathy: Bilateral, symmetric, progressive, irreversible, paraesthesia, pain, muscle atrophy<|>Visceral neuropathy: Cranial nerve – diplopia, Bell palsy, GIT- constipation, diarrhoea, CVS – orthostatic hypotension
• Pathogenesis of Diabetic Neuropathy

  1. Capillary damage

  2. Nerve damage

  3. Physical Injury

  4. Infection
• Diabetic Neuropathic ulcer

  Painless, surrounded by callus, at pressure points +/- gangrene<|>Etiology: peripheral sensory neuropathy, Trauma & deformity, Factors: Ischemia, callus formation, and edema
• Diabetic Nephropathy (Gross): Necrotizing renal papillitis, Pyelonephritis, End stage kidney
• Diabetic Nephropathy (Microangiopathy)

  Deposition of 'AGE' Advanced Glycosylation End-products as nodules<|>Renal arteriolosclerosis & atherosclerosis<|>Diffuse Nodular Glomerulosclerosis (Kimmelstiel-Wilson Disease)<|>Nephrotic syndrome<|>Necrotizing renal papillitis<|>Pyelonephritis<|>End stage kidney – Renal Failure
• Stages of Diabetic Retinopathy

  • Non Proliferative: Microaneurysms, Dot blot hemorrhages, Hard and soft exudates, Cotton wool – infarcts, Macular edema
  • Proliferative: Neovascularization, Large hemorrhages, Retinal detachment, Fibrous plaques, Sudden visual defect
• Diabetic Amyotrophy is painful muscle wasting
• Acanthosis Nigricans is a skin condition associated with Diabetes
• Infections are more common in Diabetes due to decreased metabolism, low immunity, glycosylation of immune mediators, capillary thickening, and ischemia

  
• Pathogenesis of Diabetic Macroangiopathy: Atherosclerosis

  1. Dyslipidemia

  2. Decreased HDL

  3. Non-Enzymatic Glycosylation

  4. Increased platelet adhesiveness

  5. Increased Thromboxane A2

  6. Decreased Prostacyclin

  7. Endothelial damage

  
• Complications of Diabetic Macroangiopathy

  • Myocardial infarction
  • Cerebrovascular accident
  • Peripheral vascular disease and gangrene of leg
  • Renal insufficiency
• Laboratory Diagnosis of Diabetes Mellitus

  • Urine Glucose: Dipstick screening
  • Blood Tests: Random glucose, Fasting glucose, 2hrs after 75g glucose, HbA1c, Fructosamine

  
• Pancreatic Neuroendocrine Tumors

  Insulinoma: Hyperinsulinism<|>Gastrinoma: Hypergastrinemia and Zollinger-Ellison syndrome<|>MEN