Insulin secretion has been evaluated after oral glucose loading and other stimuli (tolbutamide, glucagon, arginine and i.v. glucose) in a group of 3 patients with familial hyperchylomicronemia (Fredrickson’s Type I), 33 patients with primary hypercholesterolemia (Fredrickson’s Type II) and 89 patients with endogenous hypertriglyceridemia. In familial hyperchylomicronemia glucose tolerance and insulin secretion were normal. In patients with familial hypercholesterolemia the increased insulin secretion is conditioned by overweight. In hypertriglyceridemic patients no significant correlation has been observed after glucose loading between basal insulin and plasma triglycerides and between insulin response (insulin area) and plasma triglyceride levels. Mean insulin response to oral glucose was significantly increased in hypertriglyceridemic patients with normal glucose tolerance and still more in hypertriglyceridemic patients with chemical diabetes. A significant positive correlation has been found between overweight and insulin response after oral glucose in the hypertriglyceridemic patients with normal glucose tolerance. The insulin response after the other stimuli was not significantly different from that of the controls. In conclusion, in primary familial hypercholesterolemia, insulin secretion was increased after oral glucose, with normal glucose tolerance; overweight only partially explained the increased insulin response. In endogenous hypertriglyceridemia, plasma triglycerides were not related to the degree of insulin response after oral glucose. Overweight is related to insulin response only when glucose tolerance is still normal, but with the appearance of a diabetic state, insulin secretion seems to be conditioned by the reduced glucose tolerance. Increased insulin secretion seems to be the first alteration of glucose homeostasis, even in the presence of normal glucose tolerance.