1. Diabetes mellitus complications & morphology

2. Complications of diabetes  In type 1 &2 diabetes  Variable onset, severity,organs of involvement  Macrovascular disease: Accelerated atherosclerosis-MI,CVA,gangrene of legs  Microvascular disease (microangiopathy)- retinopathy, nephropathy, neuropathy  Good control of blood glucose minimizes microangiopathy

3. Pathogenesis  Metabolic derangements, hyperglycemia  Disease modifying elements ? Genetic  3 probable pathways  Non enzymatic glycosylation:Formation of advanced glycosylation end products (AGE)  Activation of protein kinase C (PKC )  Intracellular hyperglycemia with disturbances in polyol pathways

4. Advanced Glycosylation End products(AGE )  Non enzymatic reaction between *intracellular glucose-derived precusors & *Amino group of intracellular & extracellular proteins Have chemical & biological detrimental effects on extracellular matrix components & target cells of diabetic complications eg endothelial cells

5. AGE effect on extracellular matrix components  On collagen & laminin  Cross linkage of polylpeptides –abn matrix-matrix or matrix cell linkages  Resistant to proteolytic digestion  Trap non-glycated plasma or interstitial proteins

6. AGE Effects on Circulating plasma proteins  Generation of cytokines growth factors & pro inflammatory molecules eg insulin like growth factor,TGF β, PDGF,VEGF.  ↑ endothelial permeability  ↑ procoagulant activity  ↑proliferation & synthesis of ECM by fibroblasts & smooth muscle cells

7. Activation of protein kinase C  Intracellular hyperglycemia causes de- novo synthesis of DAG from glycolytic intermediates & then activation of PKC (Normally by Ca) (Normally by Ca)  Production of VEGF—endothelial &smooth muscle proliferation  ↑ activity of endothelin 1 (vasoconstrictor)  ↓ activity of endothelial NO synthase (vasodilator )-- ↑ microvascular contractility

8. Intracellular hyperglycemia disturbances in polyol pathways  Hyperglycemia-------------sorbitol--fructose Aldose reductase-cofactor NADPH Aldose reductase-cofactor NADPH  NADPH also needed as cofactor by glutathione reductase to produce reduced glutathione (GSH)-antioxidant  ↑ susceptibility to oxidative stress  Sorbitol may be directly toxic to cells Excessive reactive oxygen species

9. Complications ofDM  Acute metabolic complications DKA, hyperosmolar non ketotic coma,hypoglycemia  Late systemic complications; Macrovascular,microangoipathy Macrovascular,microangoipathy

11. Macrovascular disease  Accelerated atherosclerosis of aorta & large and medium sized arteries  Myocardial infarction (women & men)  Gangrene of lower limbs  Hyaline arteriosclerosis associated with hypertension

15. Diabetic microangiopathy  Diffuse thickening of basement membranes (but it is leaky)  Concentric layers of type IV collagen

16. Diabetic nephropathy  Clinical syndromes  Asymptomatic proteinuria  Nephrotic syndrome  Progressive renal failure  Hypertension  End stage renal failure

17. Diabetic nephropathy (cont.)  Diabetic glomerulosclerosis: Diffuse glomerulosclerosis:inv all parts of glomerulus  Thickening of GBM &diffuse increase in mesangial matrix and mesangial cells  Capsular drop,  Fibrin cap  Nodular glomerulosclerosis (Kimmelstiel – Wilson lesion)-PAS +,nodule, contain mesangial cells, pathognomonic of DM

20. Diabetic nephropathy (cont)  Renal vessel atherosclerosis,  Hyaline arteriolosclerosis (afferent & efferent)  Chr Pyelonephritis,necrotizing papillitis  Tubular lesions Armanii Ebstein lesions

22.  Ocular: retinopathy (background non proliferative,proliferative ),cataract glaucoma  Neuropathy:sensorimotor / autonomic

24. DKA

25. Pregnancy  Infants of diabetic mothers  Large for date  Hyperplasia of β cells of islet of Langerhan ---hypoglycemia  5-10% risk of developmental abn of heart; neural tube defects.