Diabetes mellitus complications & clinical features
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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.