ROLE OF FREE FATTY-ACIDS AND GLUCAGON IN THE PERIPHERAL EFFECT OF INSULIN ON GLUCOSE-PRODUCTION IN HUMANS

We have shown previously that the greater suppression of endogenous gl ucose production (GP) with equimolar peripheral vs, portal insulin can not be detected or is minimally reversed when the insulin-induced supp ression of either free fatty acids (FFA) or glucagon alone is prevente d. The present experiments were designed to minimize the insulin suppr ession of both glucagon and FFA in an attempt to further examine the m echanism of insulin's peripheral effect on CTP. In nine healthy men, w e investigated the effect of limiting the insulin suppression of both FFA and glucagon by infusing heparin (250 U/h), Intralipid 10% (25 ml/ h), and glucagon (0.65 ng.kg(-1).min(-1)) during 1) portal(n = 9), 2) equimolar peripheral (n = 9), and 3) half-dose peripheral insulin deli very (n = 4) by use of our previously published tolbutamide infusion m ethod, with calculation and matching of insulin secretion rate. GP dec reased by 57.2 +/- 2.6% with portal, 39.0 +/- 4.1%? with equimolar per ipheral, and 31.5 +/- 2.7% with half-dose peripheral insulin delivery (P < 0.001 for portal vs. peripheral and P < 0.001 for portal vs. half -dose peripheral). In contrast, in six control subjects in whom glucag on and FFA were not replaced, GP decreased by 62.6 +/- 2.4% with porta l (n = 6), 75.7 +/- 3.0% with peripheral (n = 6), and 56.3 +/- 3.0% wi th half-dose peripheral (n = 4) insulin delivery (P < 0.01 for portal vs. peripheral and P = not significant for portal vs. half-dose periph eral). In summary, the greater suppression of GP with equimolar periph eral vs. portal insulin is eliminated and markedly reversed if the acu te insulin-induced suppression of both plasma FFA and glucagon is mini mized. This suggests that the insulin-induced suppression of glucagon and FFA has additive or cooperative effects in mediating the acute ext rahepatic effect of insulin on GP.