Insulin resistance pathophysiology in type 2 diabetes
Core concept
- Insulin resistance = reduced tissue response to a given insulin concentration -- post-receptor signalling defect, not primarily a receptor-number or insulin-deficiency problem (early disease)
- Key mechanism: ectopic lipid accumulation (intramyocellular and intrahepatic fat, driven by visceral obesity) -> diacylglycerol/ceramide accumulation -> impaired insulin receptor substrate (IRS-1) signalling -> reduced GLUT4 translocation in muscle/fat, reduced suppression of hepatic gluconeogenesis
- Compensatory hyperinsulinaemia initially maintains euglycaemia; beta-cell failure over time (glucotoxicity, lipotoxicity, amyloid deposition) -> progression to overt hyperglycaemia
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