HEPATIC GLUCOSE-PRODUCTION IS REGULATED BOTH BY DIRECT HEPATIC AND EXTRAHEPATIC EFFECTS OF INSULIN IN HUMANS

The present study examines the effect of the route of insulin delivery on glucose turnover in humans. By using a new noninvasive in vivo met hod, the acute effect of insulin secreted by we pancreas can be compar ed with that of insulin delivered by a peripheral vein, Three euglycem ic-hyperinsulinemic studies were performed in lean healthy men, in the first study (n = 10), constant portal hyperinsulinemia was produced u sing a programmed intravenous tolbutamide infusion algorithm, and the insulin secretion rate was mathematically derived by deconvolution fro m peripheral plasma C-peptide levels. In the second study (n = 10), ex ogenous insulin was infused by peripheral vein at the same rate as tha t determined in the first study, in the third study (n = 7), the perip heral insulin levels in the first study were matched by infusing exoge nous insulin into a peripheral vein at half that rate, Peripheral insu lin levels were higher (P < 0.001) with the full-rate peripheral insul in infusion (266.3 +/- 28.1 pmol/l) than with the portal delivery of i nsulin (171.1 +/- 30.4 pmol/l) or the half-rate peripheral insulin inf usion (158.6 +/- 7.4 pmol/l) (portal versus half-rate peripheral insul in infusion, NS). Calculated hepatic insulin levels were higher (P < 0 .001) in the portal insulin study (443.1 +/- 52.6 pmol/l) than in tile fill-rate peripheral insulin study (303.6 +/- 30.9 pmol/l) or in the half-rate peripheral insulin study (204.5 +/- 9.8 pmol/l), Hepatic glu cose production (HGP) was suppressed to a greater extent with the full -rate peripheral insulin infusion (69.3 +/- 7.8%, P < 0.001 vs, portal or half-rate peripheral insulin) than portal (50.3 +/- 9.8%) or half- rate peripheral insulin infusion (36.8 +/- 3.8%). In the portal insuli n study, however, suppression was greater than in the half-rate periph eral insulin study (P < 0.01), in spite of equal peripheral insulin le vels. The assumption that tolbutamide, when used in this fashion, has no independent effect on glucose turnover, glucagon, or gluconeogenic precursor and energy substrates for gluconeogenesis was validated in f ive C-peptide-negative patients with IDDM. We conclude that in nondiab etic humans, 1) peripheral effects of insulin are important in suppres sing HGP, as evidenced by the greater suppression of HGP with equivale nt rate peripheral versus portal insulin delivery, and 2) because HGP was suppressed to a greater extent with portal versus peripheral insul in delivery at half the rate when peripheral insulin levels were match ed, insulin-induced suppression of HGP is also partly mediated by a di rect hepatic effect.