AbstractDespite intensive investigation, a clear understanding of the metabolic disturbances in diabetes mellitus and their temporal relationship to each other during disease development has still not emerged. With emphasis on non‐insulin‐dependent diabetes (NIDDM), three possibilities are explored here: (1) that the insulin resistance characteristic of obesity/NIDDM syndromes is the result rather than the cause of hyperinsulinemia, as is widely held, (2) that the linkage between hyperactivity of the pancreatic β‐cell and peripheral insulin resistance is vested in excessive delivery of lipid substrate from liver to the muscle bed, and (3) that conceivably hyperamylinemia works in concert with hyperinsulinemia in promoting overproduction of very‐low‐density lipoproteins by the liver, and thus in the etiology of muscle insulin resistance. © 1994 Wile