ERS41 Pathophysiology Of Diabetes Flashcards
Type 1 / 2 DM complications
Type 1 / 2 DM
—> Hyperglycaemia
—> Extracellular + Intracellular effects
—> Vascular diseases (Retinopathy, Nephropathy, Atherosclerosis)
3 pathways of pathophysiology of Hyperglycaemia
- Non-enzymatic glycation
—> Reactive Carbonyl Species (RCS)
—> Advanced Glycation Endproducts (AGE) - Polyol pathway
—> DAG synthesis (PKC activation) + Sorbitol + Consumption of NADPH - Hexosamine pathway
Non-enzymatic glycation
Glycation: Reaction between Glucose (and its metabolites) with macromolecules (***Proteins, Lipids, Nucleic acids)
- addition of Glucose on Macromolecules —> products do damages
- no need enzyme
- elevated by Hyperglycaemia
- can occur within / outside cell
- involves multiple reactions, producing multiple products
Reaction between Glucose / Proteins
Reversible phase (Short duration): NH2 groups (from side chains, mostly by Lysine residues) in proteins —> ***Schiff base adducts (Reversible but difficult, hours) (simple addition of glucose onto NH2 group)
Irreversible phase (Long duration):
—> **Amadori products (Irreversible, days) (highly chemically undefined)
—> Rearrangement, Elimination, Condensation, Oxidation etc.
—> **Reactive carbonyl products (Irreversible, weeks) (Extremely reactive intermediates, responsible for damages)
—> Structural and functional modifications of proteins
—> Crosslinking of proteins via covalent bond
—> ***Advanced Glycation Endproducts (AGE)
—> Functions nullified
N.B.: Above reaction can also occur in Normoglycaemia, but Rate of Production «_space;Degradation
Glucose within cells (in which glucose uptake is independent of insulin)
Side reactions within cells to produce Reactive carbonyl products (RCS)
- Amadori pathway (reaction with proteins)
—> ***3-Deoxyglucosone - Auto-oxidation of Glucose
—> ***Glyoxal - Glycolysis (Alternative Breakdown of glyceraldehyde-3-phosphate if not cleared from cell quickly via subsequent glycolysis / glycolysis blocked)
—> ***Methylglyoxal
3-Deoxyglucosone, Glyoxal, Methylglyoxal
—> ALL are RCS
—> react with proteins within / outside cell
Outside cells:
Only Amadori pathway —> 3-Deoxyglucosone
Metabolism of Advanced Glycation Endproducts (AGE)
Under normal situation (Normoglycaemia):
1. RCS can be rendered inactive by **Reductases
—> Methylglyoxal + Glyoxal catabolised by **Glyoxalase system
2. AGE can be ***degraded by cells
3. Degradation products excreted by kidney
Hyperglycaemia condition:
- Production of AGE»_space; Rate of Degradation
Reaction of RCS / Direct glycation on Modification of ***Protein function
Example: Lipoprotein
—> Both lipids + protein components are modified by RCS
LDL (lipoproteins with high cholesterol content, come from VLDL)
1. Impairs binding and degradation of LDL by Fibroblast
2. Abolishes recognition by LDL-R
—> **LDL remain in circulation
3. Generation of **Anti-glycated LDL-Ab
4. ***Foam cell formation (modified LDL taken up) —> Atherogenic
HDL
1. ***Compromised reverse-transport of cholesterol (Glycation / Modification by RCS on HDL)
Reaction of RCS / Direct glycation on Modification of ***Extracellular matrix
- Inhibits lateral association of ***Type 4 collagen molecules
- Alters packing of ***Type 1 collagen and laminin
- Disrupts binding of **Heparan sulphate / other **Proteoglycan molecules to basement membrane
—> ***dysfunction of Basement membrane (e.g. Kidney, Blood vessels)
—> e.g. filtration property of kidney, affect response of blood vessel to NO - Abolish ***cell-matrix interaction
—> cell receiving wrong signal from ECM
—> cell cannot function properly - ***Dampens action of NO
—> dysregulation of vascular tone
AGE and AGE-R: Stimulation of cellular activities
AGE-R / Scavenger receptors / RAGE:
AGE bind to RAGE on cell surface
—> Intracellular signals
—> ***Change in cell activities
Cells with RAGE:
- Macrophages
- Monocytes
- Mesangial cells
- Endothelial cells
Macrophage / Monocytes: - Secrete IL-1, IGF-1, TNF-α - Proliferation - Cytokine secretion —> ***Overall ↑ Pro-inflammatory reactions
Endothelial cells:
- ↓ Thrombomodulin (anticoagulant) production
- ↑ Tissue factor (extrinsic pathway) production
—> ***Overall ↑ Pro-coagulant activity (↑ clotting tendency)
簡單而言: AGE —> ↑ Pro-inflammatory + ↑ Pro-coagulant activity
Polyol pathway activation: Consequence of Hyperglycaemia
Hyperglycaemia
—> Influx of Glucose into cell
—> Glucose 6-phosphate (by Hexokinase: inhibited by high G6P formation)
—> Inhibition of conversion from Glucose to G6P
—> Accumulation of Glucose
—> Channel into Polyol pathway
—> Glucose —> Sorbitol (deplete NADPH —> NADP) (NADPH: reducing agent, important for suppressing ROS)
—> Sorbitol —> Fructose (deplete NAD —> NADH) (**NAD required for Glycolysis —> **suppression of Glycolysis)
(G6P —> Glycolysis / Pentose phosphate pathway)
Effect of Polyol pathway on Glycolysis
- NAD depleted by Sorbitol pathway
—> Glycolysis suppressed
—> **Glyceraldehyde 3-phosphate accumulate (cannot undergo Glycolysis to form Pyruvate)
—> **Methylglyoxal formation (RCS) - Enhance conversion of Glyceraldehyde 3-phosphate to **Dihydroxyacetone phosphate
—> conversion to **Glycerol 3-phosphate (enhanced due to ↑ NADH supply by Polyol pathway)
—> Glycerol 3-phosphate accumulate
—> react with Fatty acids from Lipolysis
—> **DAG formation
—> **PKC activation
簡單而言: Polyol pathway: Methylglyoxal formation (RCS) + PKC activation
***Summary: Consequences of Polyol pathway activity
- Competes with Glycolysis for NAD
—> NAD depletion
—> suppression of Glycolysis
—> Glycerol 3-phosphate accumulation + Methylglyoxal (RCS) formation from Glyceraldehyde 3-phosphate accumulation
—> **PKC activation + **AGE formation + further weakens cell ability to utilise glucose - Consumes NADPH (from Pentose phosphate pathway)
—> **slows down re-generation of Glutathione (GSH: intracellular Antioxidant)
—> cell more prone to **oxidative damage -
**Sorbitol accumulation
—> changes **Intracellular osmotic pressure in Lens cells
—> change in **crystalline structure of lens proteins (also by AGE formation)
—> **Cataract
***Consequence of PKC activation
- Vascular occlusion (∵ Pro-coagulant activity)
- Capillary occlusion (∵ ECM synthesis)
- Changes in vascular permeability
- Blood flow abnormality
- Inhibits NO formation (∵ ↓ expression of NO synthase) —> Vasoconstriction
(Pentose phosphate pathway producing NADPH)
(NADPH:
—> **Oxidised GSH (GSSG) —> **Reduced GSH
—> Reduced GSH helps converts intracellular ROS —> inactivated oxidative compounds)
Hexosamine pathway
Modify activities of transcription factors
Glucose (intracellular)
—> Fructose 6P
—> Glucosamine 6P (amino group added to F6P, from Glutamine —> Glutamate, by GFAT)
—> **UDP-GlcNAc (UDP-N-Acetyl-Glucosamine)
—> Nuclear transcription factors —(O-linked glycosylation)—> GlcNAc-linked Nuclear transcription factors
—> Activation of gene transcription (e.g. TGFβ, PAI (Inhibitors of Plasminogen activator))
—> **TGFβ: Inflammatory reaction + ***PAI: Inhibition of fibrinolysis
