Transcript Diabetes mellitus complications & clinical features

Diabetes mellitus
complications &
morphology
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
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
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
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
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
Activation of protein kinase C
Intracellular hyperglycemia causes denovo synthesis of DAG from glycolytic
intermediates & then activation of PKC
(Normally by Ca)
 Production of VEGF—endothelial &smooth
muscle proliferation
 ↑ activity of endothelin 1 (vasoconstrictor)
 ↓ activity of endothelial NO synthase
(vasodilator )-- ↑ microvascular contractility

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
Complications of DM
 Acute
metabolic complications
DKA, hyperosmolar non ketotic
coma,hypoglycemia
 Late systemic complications;
Macrovascular ,microangoipathy
Macrovascular disease
 Accelerated
atherosclerosis of aorta &
large and medium sized arteries
 Myocardial infarction (women & men)
 Gangrene of lower limbs
 Hyaline arteriosclerosis associated with
hypertension
Diabetic microangiopathy
 Diffuse
thickening of basement
membranes (but it is leaky)
 Concentric layers of type IV collagen
Diabetic nephropathy
 Clinical
syndromes
 Asymptomatic proteinuria
 Nephrotic syndrome
 Progressive renal failure
 Hypertension
 End stage renal failure
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
Diabetic nephropathy (cont)
 Renal
vessel atherosclerosis,
 Hyaline arteriolosclerosis (afferent &
efferent)
 Chr
Pyelonephritis,necrotizing papillitis
 Tubular
lesions Armanii Ebstein lesions
 Ocular:
retinopathy (background non
proliferative ,proliferative ),cataract
glaucoma
 Neuropathy:sensorimotor / autonomic
DKA
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.