Diabetes mellitusDiabetes mellituscomplications & complications &

morphologymorphology

Complications of diabetesComplications of diabetes

In type 1 &2 diabetesIn type 1 &2 diabetes Variable onset, severity ,organs of Variable onset, severity ,organs of

involvement involvement Macrovascular disease: Accelerated Macrovascular disease: Accelerated

atherosclerosis-MI,CVA,gangrene of legsatherosclerosis-MI,CVA,gangrene of legs Microvascular disease (microangiopathy)-Microvascular disease (microangiopathy)-

retinopathy, nephropathy, neuropathyretinopathy, nephropathy, neuropathy Good control of blood glucose minimizes Good control of blood glucose minimizes

microangiopathymicroangiopathy

PathogenesisPathogenesis

Metabolic derangements, hyperglycemiaMetabolic derangements, hyperglycemia Disease modifying elements ? GeneticDisease modifying elements ? Genetic 3 probable pathways3 probable pathways Non enzymatic glycosylation:Formation of Non enzymatic glycosylation:Formation of

advanced glycosylation end products advanced glycosylation end products (AGE)(AGE)

Activation of protein kinase C (PKC )Activation of protein kinase C (PKC ) Intracellular hyperglycemia with Intracellular hyperglycemia with

disturbances in polyol pathwaysdisturbances in polyol pathways

Advanced Glycosylation End Advanced Glycosylation End products(AGE )products(AGE )

Non enzymatic reaction betweenNon enzymatic reaction between

*intracellular glucose-derived precusors &*intracellular glucose-derived precusors &

*Amino group of intracellular & *Amino group of intracellular & extracellular proteinsextracellular proteins

Have chemical & biological detrimental Have chemical & biological detrimental effects on extracellular matrix components effects on extracellular matrix components & target cells of diabetic complications eg & target cells of diabetic complications eg endothelial cellsendothelial cells

AGE effect on extracellular matrix AGE effect on extracellular matrix componentscomponents

On collagen & lamininOn collagen & laminin Cross linkage of polylpeptides –abn Cross linkage of polylpeptides –abn

matrix-matrix or matrix cell linkagesmatrix-matrix or matrix cell linkages Resistant to proteolytic digestionResistant to proteolytic digestion Trap non-glycated plasma or interstitial Trap non-glycated plasma or interstitial

proteinsproteins

AGE Effects on Circulating plasma AGE Effects on Circulating plasma proteins proteins

Generation of cytokines growth factors & Generation of cytokines growth factors & pro inflammatory molecules eg insulin like pro inflammatory molecules eg insulin like growth factor,TGF growth factor,TGF ββ, PDGF,VEGF., PDGF,VEGF.

↑ ↑ endothelial permeabilityendothelial permeability ↑ ↑ procoagulant activityprocoagulant activity ↑↑proliferation & synthesis of ECM by proliferation & synthesis of ECM by

fibroblasts & smooth muscle cellsfibroblasts & smooth muscle cells

Activation of protein kinase C Activation of protein kinase C

Intracellular hyperglycemia causes de-Intracellular hyperglycemia causes de-novo synthesis of DAG from glycolytic novo synthesis of DAG from glycolytic intermediates & then activation of PKCintermediates & then activation of PKC

(Normally by Ca)(Normally by Ca) Production of VEGF—endothelial &smooth Production of VEGF—endothelial &smooth

muscle proliferationmuscle proliferation ↑ ↑ activity of endothelin 1 (vasoconstrictor)activity of endothelin 1 (vasoconstrictor) ↓ ↓ activity of endothelial NO synthase activity of endothelial NO synthase

(vasodilator )-- ↑ microvascular contractility(vasodilator )-- ↑ microvascular contractility

Intracellular hyperglycemia Intracellular hyperglycemia disturbances in polyol pathwaysdisturbances in polyol pathways

Hyperglycemia-------------sorbitol--fructoseHyperglycemia-------------sorbitol--fructose• Aldose reductase-cofactor NADPHAldose reductase-cofactor NADPH

NADPH also needed as cofactor by NADPH also needed as cofactor by glutathione reductase to produce reduced glutathione reductase to produce reduced glutathione (GSH)-antioxidantglutathione (GSH)-antioxidant

↑ ↑ susceptibility to oxidative stresssusceptibility to oxidative stress Sorbitol may be directly toxic to cellsSorbitol may be directly toxic to cells

Excessive reactive oxygen speciesExcessive reactive oxygen species

Complications ofComplications of DMDM

Acute metabolic complicationsAcute metabolic complications

DKA, hyperosmolar non ketotic DKA, hyperosmolar non ketotic coma,hypoglycemiacoma,hypoglycemia

Late systemic complications;Late systemic complications;

Macrovascular ,microangoipathyMacrovascular ,microangoipathy

Macrovascular diseaseMacrovascular disease

Accelerated atherosclerosis of aorta & Accelerated atherosclerosis of aorta & large and medium sized arterieslarge and medium sized arteries

Myocardial infarction (women & men)Myocardial infarction (women & men) Gangrene of lower limbs Gangrene of lower limbs Hyaline arteriosclerosis associated with Hyaline arteriosclerosis associated with

hypertension hypertension

Diabetic microangiopathyDiabetic microangiopathy

Diffuse thickening of basement Diffuse thickening of basement membranes (but it is leaky)membranes (but it is leaky)

Concentric layers of type IV collagen Concentric layers of type IV collagen

Diabetic nephropathyDiabetic nephropathy

Clinical syndromesClinical syndromes Asymptomatic proteinuriaAsymptomatic proteinuria Nephrotic syndromeNephrotic syndrome Progressive renal failureProgressive renal failure HypertensionHypertension End stage renal failureEnd stage renal failure

Diabetic nephropathy (cont.)Diabetic nephropathy (cont.) Diabetic glomerulosclerosis:Diabetic glomerulosclerosis:

Diffuse glomerulosclerosis:inv all parts of Diffuse glomerulosclerosis:inv all parts of glomerulusglomerulus

Thickening of GBM &diffuse increase in Thickening of GBM &diffuse increase in mesangial matrix and mesangial cellsmesangial matrix and mesangial cells

Capsular drop,Capsular drop, Fibrin capFibrin cap Nodular glomerulosclerosis (Kimmelstiel –Nodular glomerulosclerosis (Kimmelstiel –

Wilson lesion)-PAS +,nodule, contain Wilson lesion)-PAS +,nodule, contain mesangial cells, pathognomonic of DMmesangial cells, pathognomonic of DM

Diabetic nephropathy (cont)Diabetic nephropathy (cont)

Renal vessel atherosclerosis,Renal vessel atherosclerosis, Hyaline arteriolosclerosis (afferent & Hyaline arteriolosclerosis (afferent &

efferent)efferent)

Chr Pyelonephritis,necrotizing papillitisChr Pyelonephritis,necrotizing papillitis

Tubular lesions Armanii Ebstein lesionsTubular lesions Armanii Ebstein lesions

Ocular: retinopathy (background non Ocular: retinopathy (background non proliferative ,proliferative ),cataract proliferative ,proliferative ),cataract glaucomaglaucoma

Neuropathy:sensorimotor / autonomicNeuropathy:sensorimotor / autonomic

DKADKA

Pregnancy Pregnancy

Infants of diabetic mothersInfants of diabetic mothers Large for dateLarge for date Hyperplasia of Hyperplasia of ββ cells of cells of islet of Langerhan islet of Langerhan

---hypoglycemia---hypoglycemia 5-10% risk of developmental abn of heart; 5-10% risk of developmental abn of heart;

neural tube defects. neural tube defects.