Overnight lowering of free fatty acids with acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects

Obesity is commonly associated with elevated plasma free fatty acid (FFA) l evels, as well as with insulin resistance and hyperinsulinemia, two importa nt cardiovascular risk factors. What causes insulin resistance and hyperins ulinemia in obesity remains uncertain. Here, we have tested the hypothesis that FFAs are the link between obesity and insulin resistance/hyperinsuline mia and that;, therefore, lowering of chronically elevated plasma FFA level s would improve insulin resistance/hyperinsulinemia and glucose tolerance i n obese nondiabetic and diabetic subjects. Acipimox (250 mg), a long-acting antilipolytic drug, or placebo was given overnight (at 7:00 P.M., 1:00 A.M ., 7:00 A.M.) to 9 lean control subjects, 13 obese nondiabetic subjects, 10 obese subjects with impaired glucose tolerance, and 11 patients with type 2 diabetes. Euglycemic-hyperinsulinemic clamps and oral glucose tolerance t ests (75 g) were performed on separate mornings after overnight Acipimox or placebo treatment. In the three obese study groups, Acipimox lowered fasti ng levels of plasma FFAs (by 60-70%) and plasma insulin (by similar to 50%) . Insulin-stimulated glucose uptake during euglycemic-hyperinsulinemic clam ping was more than twofold higher after Acipimox than after placebo. Areas under the glucose and insulin curves during oral glucose tolerance testing were both similar to 30% lower after Acipimox administration than after pla cebo. We conclude that lowering of elevated plasma FFA levels can reduce in sulin resistance/hyperinsulinemia and improve oral glucose tolerance in lea n and obese nondiabetic subjects and in obese patients with type 2 diabetes .