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 effect: GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide), released by intestinal L-cells and K-cells respectively, are responsible for 50–70% of postprandial insulin secretion in healthy individuals. In T2DM, GIP action is impaired and GLP-1 secretion is reduced — however, pharmacologic GLP-1 concentrations restore the incretin effect, which is the basis for GLP-1 receptor agonist therapy. (6) Increased glucagon secretion from pancreatic α-cells: paradoxical hyperglucagonemia in T2DM (loss of paracrine inhibition from failing β-cells) drives hepatic glucose output. (7) Increased renal glucose reabsorption: SGLT2 transporters in the proximal tubule reabsorb ~90% of filtered glucose; in T2DM, SGLT2 is upregulated, increasing the renal threshold for glucosuria and maintaining hyperglycemia — SGLT2 inhibitors block this transporter, causing therapeutic glucosuria. (8) CNS insulin resistance/neurotransmitter dysfunction: hypothalamic insulin signaling regulates appetite and hepatic glucose production; dysfunction contributes to obesity and metabolic syndrome.