DIABETES : APPROACH TO LONG CASE AND DISCUSSION : MD FINAL EXAMINATIONS PRACTICAL CASE AND VIVA

DIABETES : APPROACH TO LONG CASE AND DISCUSSION : MD FINAL EXAMINATIONS PRACTICAL CASE AND VIVA Definition / general Chronic disorder of carbohydrate, fat and protein metabolism due to defective or deficient insulin secretory response Etiology Destruction of islets due to drugs , hemochromatosis ("bronze diabetes" due to hemosiderin deposition in pancreas), hereditary ceruloplasmin , infections (congenital rubella, CMV, coxsackievirus, enteroviruses , pancreatitis, surgery, tumors, endocrinopathies (pituitary, adrenal, pregnancy) or idiopathic Type 1 Chronic disease of carbohydrate, fat and protein metabolism due to reduction in beta cell mass causing severe, absolute lack of insulin 10% of all cases Without insulin, patients develop diabetic ketoacidosis (DKA), coma and death Etiology Presumed autoimmune cause for islet cell destruction but precise etiology unclear (Wikipedia: Diabetes Mellitus Type 1 Usually Northern European descent 70% concordance in identical twins, HLA-D linked Genetic predisposition may affect immune responsiveness to a beta cell autoantigen or method of presentation to T cells Viruses and IDDM: Viruses may damage beta cells, exposing antigens which trigger an autoimmune response May be due to molecular mimicry (immune response develops against shared amino acid sequences): GAD and Coxsackie B4 virus share a six amino acid sequence Retrovirus may serve as a superantigen Autoimmune aspects: Islet cell autoantibodies present in 70%; also CD8+ T cell infiltrate in islets Antigens are glutamic acid decarboxylase (GAD), islet autoantigen 2, insulin associated antibody, gangliosides GAD antibodies precede clinical symptoms, present in most newly diagnosed patients and 80% of first degree relatives GAD antibody also causes stiff man syndrome, whose patients often have a history of IDDM Many IDDM patients also have antithyroid peroxidase, antiparietal cell and antiadrenocortical antibodies Some NIDDM patients have autoantibodies but no other features of IDDM Usually chronic (years) Clinical disease when 90% of islet cells are destroyed Clinical features Onset at age 20 years, normal weight (unlike most NIDDM) Characterized by PPP (polyuria, polydipsia, polyphagia) and ketoacidosis (DKA) Polyphagia combined with weight loss is specific for IDDM; type 2 patients rarely have either Severe fasting hypoglycemia is due to cessation of glycogen storage in fat and muscle Glycosemia causes glycosuria with depletion of water and electrolytes Also: low / absent plasma insulin, high plasma glucagon, unstable glucose tolerance (very sensitive to changes in insulin, diet, exercise, infection, stress), presence of free fatty acids (due to breakdown of adipose stores), which produces ketone bodies (acetoacetic acid and beta hydroxybutyric acid) May get hyperosmotic nonketotic coma - dehydration due to hyperglycemic diuresis with failure to drink enough fluids to compensate, often in an elderly person with diabetes and stroke / infection "Dead in bed syndrome": sudden death in young people with type 1 diabetes Type 2 (NIDDM) Also called adult onset, non insulin dependent diabetes mellitus / NIDDM, type 2 80 - 90% of cases of diabetes (Wikipedia: Diabetes Mellitus Type 2 Usually 30 years old, obese (80% of cases, abdominal obesity more important than subcutaneous obesity), normal or increased blood insulin, rare diabetic ketoacidosis, no anti-islet antibodies Pathophysiology Early: Normal insulin secretion and plasma levels but loss of pulsatile, oscillating pattern of secretion Also loss of rapid first phase of insulin secretion triggered by glucose NO insulinitis is present Later: Mild / moderate insulin deficiency, may be due to beta cell damage Beta cells may be "exhausted" due to chronic hyperglycemia and persistent beta cell stimulation Amylin: 37 amino acid peptide, normally produced by beta cells, packaged and cosecreted with insulin In NIDDM patients, tends to accumulate outside beta cells and resembles amyloid Microscopic (histologic) description Type 1: inconsistent reduction in number and size of islets, uneven insulinitis (T lymphocytes) Type 1: early insulinitis with marked islet atrophy and fibrosis and severe beta cell depletion (Islets 2011;3:131) Type 2: subtle reduction in islet cell mass, amyloid replacement of islets due to amylin fibrils (also seen in aging nondiabetics); associated with marked fatty replacement Type 2: amyloid in the islets of Langerhans is the uniform pathologic feature Gestational diabetes: lower total insulin+ area due to smaller islets Infants of diabetic mothers: islet cell hypertrophy / hyperplasia