FATTY-ACIDS MEDIATE THE ACUTE EXTRAHEPATIC EFFECTS OF INSULIN ON HEPATIC GLUCOSE-PRODUCTION IN HUMANS

We have shown previously in humans that insulin partly suppresses hepa tic glucose production (HGP) by an extrahepatic (indirect) mechanism. In the present study, we investigated the role of free fatty acids (FF As) in mediating the extrahepatic effects of insulin in humans and det ermined the extent to which insulin can regulate HGP by a non-FFA-medi ated effect. Sixteen healthy men received an intravenous tolbutamide i nfusion for 3 h, and pancreatic insulin secretion was calculated by de convolution of peripheral C-peptide levels. On a subsequent occasion, equimolar exogenous insulin was infused by peripheral vein. In both st udies, glucose was clamped at euglycemia. We have previously validated this method and shown no independent insulin-like activity of tolbuta mide. During the clamp, 9 of the 16 subjects received a low dose of he parin and Intralipid to prevent the insulin-induced suppression of FFA s, chile 7 subjects received a high dose of heparin and Intralipid to raise FFAs similar to 2.5-fold. In both the high- and low-dose groups, peripheral insulin was higher and calculated portal insulin lower wit h peripheral versus portal insulin delivery. In the low-dose group, HG P decreased by 68.3 +/- 2.1% with portal insulin delivery and 64.7 +/- 3.7% with peripheral insulin delivery (NS). In the high-dose group, R GP decreased by 58.0 +/- 4.5% with portal insulin and 48.3 +/- 5.0% wi th peripheral insulin (P < 0.05). Four individuals who participated in the high-dose group underwent an additional peripheral insulin study in which the same dose of exogenous insulin was infused as in the high -dose group but in the absence of heparin and Intralipid. During this latter study, FFA levels declined by similar to 90% during hyperinsuli nemia, and HGP was suppressed by 71.8 +/- 5.6%, which was a much great er suppression (P < 0.01) than when FFA levels were raised in these su bjects during the equivalent rate insulin infusion. In summary, the pr eviously observed greater suppression of HGP with equimolar peripheral versus portal insulin is eliminated or reversed, depending on plasma FFA levels, if FFAs are prevented from decreasing, suggesting an impor tant role of FFAs in mediating the extrahepatic effects of insulin on HGP. However, the effect of FFA clamping is relatively small with a si gnificant degree of suppression of HGP (by similar to 50%), which rema ins even when FFAs are elevated above basal levels, suggesting that in the physiological range FFAs only partially influence the suppression of HGP in humans. This suggests that other mechanisms, most likely he patic, dominate the acute insulin-induced suppression of glucose produ ction.