L41 - Pathophysiology of diabetes Flashcards
Summarize all the major pathways for glucose to induce damage? (4)
1) Glycation pathway:
i) Reactive carbonyl species (Amadori products)
ii) Advanced Glycation Endproducts (AGE)
2) Polyol pathway: DAG synthesis and PKC activation:
i) increase oxidative stress
ii) osmotic pressure change
iii) Vascular occlusion
3) Hexoasmine pathway: transcription:
i) Increase plasminogen activator inhibitor (PAI)
ii) Increase TGF-B for inflammation
4) PARP activation from DNA damage >> activate all above pathways via GAPDH
Describe non-enzymatic glycation?
Glucose react and added to macromoelcules e.g. protein, lipid, nucleic acid without enzyme
Occurs intra and intracellularly
Describe the formation of Reactive carbonyl compounds from glycation reactions?
NH2-group on protiens + glucose >> Schiff base adducts >> Amadori products >> Reactive carbonyl compounds
List the 3 types of reactive carbonyl products formed by glycation?
- Auto-oxidation reaction: make GLYOXAL
- Glycolysis: intermediate Glyceraldehyde 3-phosphate not broken down fast enough > METHYLGLYOXAL
- Reaction with protein via Amadori pathway > 3-deoxyglucosone
Describe the formation of AGE from Amadori products?
Amadori products undergo lots of rxns (e.g. Re-arrangements; Elimination; Condensation; oxidation)
Form extremely reactive carbonyl compounds >> crosslinking and aggregate into AGE
Describe how AGE is normally eliminated in body?
Normal AGE production kept at minimum: reactive carbonyl species inactivated by reductases
>> AGE degraded by cells, excreted by kidneys
Outline cellular damages caused by hyperglycaemia-caused AGE production?
1a) Impair binding of LDL to LDL-R: abolish LDL-receptor recognition
1b) Impair degradation of LDL by fibroblast
2) Inhibit lateral association of Type 4 collagen: disrupt Heparin sulphate, proteoglycan binding to Basement membrane
3) Alter packing of Type 1 collagen and laminin = abolish cell-matrix interaction
4) Dampen Nitric Oxide action
Outline the cellular effects of AGE on Macrophage/ monocyte/ endothelial cells?
Macrophage/ monocyte:
- Proliferation + secrete inflammatory cytokines
Endothelial cells:
- Decrease thrombomodulin (anti-coagulant)
- Increase Tissue Factor production
>>> increase coagulation
Describe how the Polyol pathway affect glycolysis and PPP pathway under hyperglycaemia?
Hyperglycaemia:
Increase G 6-P made >> feedback inhibition on Glycolysis and PPP
Glucose forced to accumulate into Polyol pathway >> cause depletion of NADPH (anti-oxidation) and NAD (less for glycolysis)
Describe how the Polyol pathway causes PKC activation?
Increase conversion of Glyceraldehyde 3-Phosphate to Dihydroxyacetone phosphate (instead of pyruvate)
Dihydroxyacetone phosphate >>> Glycerol-3 phosphate >>> diacylglycerol synthesis >> PKC activation
Summarize the intracellular effects of the polyol pathway?
1) Competes with glycolytic pathway for NAD
2) Accumulation of glycerol 3-phosphate >> more PKC activation >> vascular damages
3) Use NAPDH = oxidative damage (GSH)
4) Accumulation of sorbitol >> change osmotic pressure in lens >> cataracts
List the damages caused by PKC activation on vascular function.
- Vascular occlusion (due to procoagulant activity)
- capillary occlusion (due to extracellular matrix synthesis)
- Vascular permeability
- Blood flow abnormality
- Inhibits NO formation by ↓expression of eNOS = vasoconstrict
Outline the pathways for polyol pathway to cause oxidative damage?
Depletion of NADPH
>> Less reduction of GSSH into GSH
>> Less intracellular oxidative compound inactivation
Describe the hexosamine pathway to increase pro-inflammatory gene transcription?
1) Increase conversion of glucose to glucosamine 6-phosphate
2) More UDP- N-acetylglucosamine formed >> More O-linked glycosylation of nuclear transcription factors
3) Activation of glycosylated transcription factors e.g. Plasminogen activation inhibitor (> less fibrinolysis) and TGF-B
Summarize the intracellular and vascular damages caused by hyperglycemia via different pathways?
What is the link between increased normal glycose metabolism and all the pathways for hyperglycemia damage?
Hyperglycaemia: overloads normal mitochondiral respiration and electron transport chain
>> Increase superoxide production***
>> Nuclear DNA damage cause increase DNA repair signal Polyadenine ribose polymerase (PARP)***
>> Polyribosylation cause Inactivation of Glyceraldehyde 3phosphate dehydrogenase (GAPDH)***
>> lead to AGE, hexosamine, Polyol pathways…etc
*** = bridge
Explain why not all cells are equally affected by damaging effects of hyperglycemia?
Only cells that cannot control influx and transport of glucose in hyperglycemia are most affected
e.g. endothelial cells in blood vessels
Describe the polyribosylation reaction of GADPH?
