Based on studies of both man and rat, it is proposed that at least three distinct syndromes of hypertriglyceridemia occur as the result of abnormalities of carbohydrate metabolism. We believe that these syndromes are the predictable results of the changes in plasma insulin and/or free fatty acid (FFA) concentration that occur in patients with impaired glucose tolerance (IGT), non-insulin-dependent diabetes mellitus (NIDDM), and insulin-dependent diabetes mellitus (IDDM). In patients with IGT the basic defect is postulated to be loss of normal insulin sensitivity, leading to compensatory hyperinsulinism, increased very low density lipoprotein (VLDL)-triglyceride (TG) secretion, and hypertriglyceridemia. In contrast, patients with NIDDM have ambient insulin concentrations that are "normal" in absolute terms, and in these subjects we believe that the elevated circulating FFA concentrations increase hepatic VLDL-TG secretion, which, in turn, is responsible for the hypertriglyceridemia. However, elevated FFA levels do not stimulate hepatic VLDL-TG secretion in insulin-deficient patients with IDDM, presumably because the livers of such individuals are not capable of responding to the increased FFA flux. In these subjects, the development of hypertriglyceridemia, when it does occur, is secondary to the existence of a profound defect in the removal of VLDL-TG from plasma. These generalizations are consistent with results in both man and rat, and provide models that account for the development of hypertriglyceridemia in the three major clinical categories of abnormal carbohydrate metabolism.