Insulin Resistance
A metabolic condition where cells respond poorly to insulin, requiring higher hormone levels to maintain normal glucose. Insulin resistance is central to type 2 diabetes and metabolic syndrome. Weight loss from GLP-1 receptor agonists improves insulin sensitivity beyond their direct insulin-stimulating effects.
Technical Context
Insulin resistance pathophysiology: lipid accumulation in muscle and liver (ectopic fat deposition from positive energy balance) activates inflammatory pathways (NF-κB, JNK) and generates diacylglycerols and ceramides that interfere with insulin receptor substrate (IRS) phosphorylation, disrupting the PI3K/Akt signalling cascade required for GLUT4 translocation and glucose uptake. Measurement: the hyperinsulinaemic-euglycaemic clamp (gold standard — measuring glucose infusion rate required to maintain euglycaemia during insulin infusion) and HOMA-IR (homeostatic model assessment — calculated from fasting glucose × fasting insulin / 405, a practical clinical proxy). GLP-1 RAs improve insulin resistance through: direct weight loss (visceral fat reduction improves hepatic and muscle insulin sensitivity), reduced hepatic glucose output, improved beta cell function (reducing glucotoxicity), and possible direct anti-inflammatory effects in adipose tissue.