Diabetes mellitus complications

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Diabetes mellituscomplications morphology
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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)-retinopath
  y, nephropathy, neuropathy
• Good control of blood glucose minimizes
  microangiopathy

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Pathogenesis

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

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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

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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

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AGE Effects on Circulating plasma proteins

• Generation of cytokines growth factors pro
  inflammatory molecules eg insulin like growth
  factor,TGF ß, PDGF,VEGF.
• ? endothelial permeability
• ? procoagulant activity
• ?proliferation synthesis of ECM by fibroblasts
  smooth muscle cells

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Activation of protein kinase C

• Intracellular hyperglycemia causes de-novo
  synthesis of DAG from glycolytic intermediates
  then activation of PKC
• (Normally by Ca)
• Production of VEGFendothelial smooth muscle
  proliferation
• ? activity of endothelin 1 (vasoconstrictor)
• ? activity of endothelial NO synthase
  (vasodilator )-- ? microvascular contractility

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Intracellular hyperglycemia disturbances in
polyol pathways

• Hyperglycemia-------------sorbitol--fructose
• 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

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Complications of DM

• Acute metabolic complications
• DKA, hyperosmolar non ketotic coma,hypoglycemia
• Late systemic complications
• Macrovascular ,microangoipathy

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Macrovascular disease

• Accelerated atherosclerosis of aorta large and
  medium sized arteries
• Myocardial infarction (women men)
• Gangrene of lower limbs
• Hyaline arteriosclerosis associated with
  hypertension

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Diabetic microangiopathy

• Diffuse thickening of basement membranes (but it
  is leaky)
• Concentric layers of type IV collagen

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Diabetic nephropathy

• Clinical syndromes
• Asymptomatic proteinuria
• Nephrotic syndrome
• Progressive renal failure
• Hypertension
• End stage renal failure

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Diabetic nephropathy (cont.)

• Diabetic glomerulosclerosisDiffuse
  glomerulosclerosisinv 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

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Diabetic nephropathy (cont)

• Renal vessel atherosclerosis,
• Hyaline arteriolosclerosis (afferent efferent)
• Chr Pyelonephritis,necrotizing papillitis
• Tubular lesions Armanii Ebstein lesions

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• Ocular retinopathy (background non proliferative
  ,proliferative ),cataract glaucoma
• Neuropathysensorimotor / autonomic

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DKA
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Pregnancy

• Infants of diabetic mothers
• Large for date
• Hyperplasia of ß cells of islet of Langerhan
  ---hypoglycemia
• 5-10 risk of developmental abn of heart neural
  tube defects.

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