Reducing plasma free fatty acids by acipimox improves glucose tolerance in high-fat fed mice

To study whether free fatty acids (FFAs) contribute to glucose intolerance in high-fat fed mice, the derivative of nicotinic acid, acipimox, which inhibits lipolysis, was administered intraperitoneally (50 mg kg(-1)) to C57BL/6J mice which had been on a high-fat diet for 3 months. Four hours after administration of acipimox, plasma FFA levels were reduced to 0.46 +/- 0.06 mmol L(-1) compared with 0.88 +/- 0.10 mmol L(-1) in controls (P < 0.001). At this point, the glucose elimination rate after an intravenous glucose load (1 g kg(-1)) was markedly improved. Thus, the elimination constant (KG) for the glucose disposal between 1 and 50 min after the glucose challenge was increased from 0.54 +/- 0.01% min-1 in controls to 0.66 +/- 0.01% min-1 by acipimox (P < 0.001). In contrast, the acute insulin response to glucose (1-5 min) was not significantly different between the groups, although the area under the insulin for the entire 50-min period after glucose administration was significantly reduced by acipimox from 32.1 +/- 2.9 to 23.9 +/- 1.2 nmol L(-1) x 50 min (P = 0.036). This, however, was mainly because of lower insulin levels at 20 and 50 min because of the lowered glucose levels. In contrast, administration of acipimox to mice fed a normal diet did not affect plasma levels of FFA or the glucose elimination or insulin levels after the glucose load. It is concluded that reducing FFA levels by acipimox in glucose intolerant high-fat fed mice improves glucose tolerance mainly by improving insulin sensitivity making the ambient islet function adequate, suggesting that increased FFA levels are of pathophysiological importance in this model of glucose intolerance.