Elevations in plasma triglyceride (TG) and free fatty acid (FFA) concentrations are generally thought to play a role in the pathogenesis of insulin-resistant diabetes. The objective of this study was to investigate the relationship between hypertriglyceridemia and glucose-stimulated insulin responsiveness in non-diabetic patients. Forty subjects were divided into three BMI-matched groups as follows: one group consisted of 8 patients with a lipoprotein lipase (LPL) deficiency, another consisted of 12 patients with hypertriglyceridemia and a third consisted of 20 subjects with normal TG levels. In response to a 75 g oral glucose tolerance test, plasma insulin levels in the LPL-deficient subjects were higher (106+/-11 microU/ml) than those in the hypertriglyceridemic (69+/-16 microU/ml) and normolipidemic (29+/-3 microU/ml) subjects, at 30 min. On the other hand, their plasma glucose levels (127+/-6 mg/dl) were less than those seen in the normolipidemic group (165+/-9 mg/dl) after 90 min. Thus, LPL-deficient subjects with hypertriglyceridemia displayed an enhanced glucose-stimulated insulin response as well as lower blood glucose levels, the latter of which is not generally seen in those with hypertriglyceridemia and normolipidemia.