Clinical meaning
Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder characterized by insulin resistance and relative insulin deficiency, resulting in chronic hyperglycemia. The pathophysiology involves DeFronzo's 'ominous octet' — eight pathological mechanisms: (1) Decreased insulin secretion from pancreatic β-cells: glucotoxicity and lipotoxicity cause progressive β-cell apoptosis via oxidative stress, ER stress, and amyloid deposition (IAPP — islet amyloid polypeptide); by the time of diagnosis, 50% of β-cell function is already lost, and β-cell decline continues at 4–5% per year regardless of treatment. (2) Increased hepatic glucose production: insulin resistance in hepatocytes fails to suppress gluconeogenesis and glycogenolysis, particularly overnight — this drives fasting hyperglycemia and is the target of metformin. (3) Decreased peripheral glucose uptake: insulin resistance in skeletal muscle impairs GLUT4 translocation to the cell membrane, reducing glucose uptake by 40–50% — skeletal muscle accounts for 80% of postprandial glucose disposal. (4) Increased lipolysis from adipocytes: insulin resistance fails to suppress hormone-sensitive lipase, releasing excess free fatty acids (FFAs) that cause lipotoxicity in β-cells, liver, and muscle (Randle cycle — FFAs compete with glucose for oxidation). (5) Impaired incretin...