Insulin Resistance: Molecular Mechanisms and Metabolic

Insulin resistance is a state of diminished cellular responsiveness to insulin signaling, requiring compensatory hyperinsulinemia to maintain glucose homeostasis. At the molecular level, insulin binds its tyrosine kinase receptor, triggering IRS-1/IRS-2 phosphorylation and downstream PI3K/Akt signaling that promotes GLUT-4 translocation to the cell membrane for glucose uptake. In insulin resistance, serine phosphorylation of IRS-1 (instead of tyrosine) by inflammatory kinases (JNK, IKKβ, PKCθ) disrupts this signaling cascade. Excess free fatty acids from visceral adiposity activate inflammatory pathways (via TLR4), increase intracellular diacylglycerol and ceramide, and promote ectopic fat deposition in liver (NAFLD/NASH) and muscle. Adipose tissue dysfunction releases pro-inflammatory adipokines (TNF-alpha, IL-6, resistin) while reducing anti-inflammatory adiponectin. Chronic hyperinsulinemia promotes sodium retention (hypertension), hepatic lipogenesis (dyslipidemia), endothelial dysfunction, and eventually beta-cell exhaustion (progression to type 2 diabetes). Metabolic syndrome (NCEP ATP III criteria: any 3 of 5 — waist circumference >102 cm male/>88 cm female, triglycerides ≥150, HDL <40 male/<50 female, BP ≥130/85, fasting glucose ≥100) identifies patients at highest cardiovascular risk from insulin resistance.