Page 577 - Concise Pathology for Exam Preparation ( PDFDrive )

562 SECTION II Diseases of Organ Systems

glycated basement membrane resulting in basement membrane thickening characteristic
of diabetic microangiopathy)
• Shows resistance to proteolytic digestion (AGE crosslinked proteins are resistant to
protein digestion; thus, decreasing protein removal and enhancing protein deposition)
Biologic properties of AGE–RAGE complex
• Leads to generation of reactive oxygen species and NF-kB activation
• Induces monocyte emigration
• Induces cytokine and growth factor secretion
• Increases vascular permeability and procoagulant activity
• Increases ECM production and cellular proliferation
2. Activation of protein kinase C (Flowchart 20.18)

Intracellular hyperglycaemia

Increased de novo synthesis of diacylglycerol (second messenger)
(important signal transduction pathway in many cellular systems)

Activation of protein kinase C (PKC) by calcium ions and second messenger
FLOWCHART 20.18. Activation of protein kinase C.

Downstream effects of PKC
• Stimulates production of VEGF (induces neovascularization characterizing diabetic
retinopathy)
• Increases activity of vasoconstrictor endothelin-1
• Decreases activity of vasodilator nitric oxide synthase (NOS)
• Increases production of profibrogenic molecule TGF-b leading to increased deposition
of extracellular matrix and basement membrane material
• Increases production of procoagulant molecule of plasminogen activator inhibitor
(PAI-1) leading to decreased fibrinolysis and vascular occlusive episodes
• Enhances formation of proinflammatory cytokines by vascular endothelium
3. Polyol pathway (Flowchart 20.19)

↑ Glucose
• NADPH (cofactor)
• Aldose reductase
Sorbitol
Dehydrogenase
Fructose
FLOWCHART 20.19. Polyol pathway.

• Both sorbitol and fructose are osmotically active and draw water into tissues, leading to
permanent damage.
• Complications with osmotic damage include destruction of Schwann cells (causing
peripheral neuropathy and cataracts) and damage to pericytes, weakening the vessel
wall (causing microaneurysms in diabetic retinopathy).
• NADPH is used as a cofactor by enzyme glutathione reductase for regenerating reduced
glutathione (GSH). GSH is an antioxidant and reduction in GSH level increases cellular
susceptibility to oxidative stress (NADPH is used as cofactor in polyol pathway).
Morphology of Diabetes and its Late Complications
Pancreas:
• Reduction in number and size of islets (more in Type I than in Type II diabetes)
• Insulitis (leukocytic infiltration of the islets)
• Amyloid replacement of islets in long-standing Type II diabetes

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