Insulin resistance is the pathophysiological hallmark of type 2 diabetes (T2D), defined as a diminished biological response to physiological insulin concentrations in target tissues — primarily skeletal muscle, liver, and adipose tissue. Understanding the molecular mechanisms allows the NP to select targeted pharmacotherapy and counsel patients on disease modification. In skeletal muscle (responsible for ~80% of postprandial glucose disposal), insulin normally binds its receptor tyrosine kinase, activating the IRS-1/PI3K/Akt signaling cascade, which translocates GLUT4 glucose transporters from intracellular vesicles to the cell membrane. In insulin resistance, multiple defects impair this pathway: serine phosphorylation of IRS-1 (by inflammatory kinases JNK and IKK-β, free fatty acids via PKC-θ, and ceramides) blocks the normal tyrosine phosphorylation required for downstream signaling, reducing GLUT4 translocation by 50-70%. Skeletal muscle thus fails to uptake glucose adequately after meals, causing postprandial hyperglycemia — the earliest metabolic abnormality in T2D. In the liver, insulin normally suppresses gluconeogenesis (new glucose production from lactate, amino acids, and glycerol) and glycogenolysis (glycogen breakdown to glucose). In the insulin-resistant state, hepatic insulin signaling is selectively impaired: the glucose-regulatory pathway (suppression of gluconeogenesis)...