GLUCAGON ENHANCES THE DIRECT SUPPRESSIVE EFFECT OF INSULIN ON HEPATICGLUCOSE-PRODUCTION IN HUMANS

The present study examines the role of glucagon in modulating the hepa tic and extrahepatic effects of insulin on hepatic glucose production (HGP). We infused glucagon at a constant rate (0.65 ng . kg(-1). min(- 1)) during equimolar portal and peripheral insulin delivery in seven h ealthy males by our previously published tolbutamide infusion method. In contrast to our previous study, in which glucagon fell by similar t o 30% during hyperinsulinemia and suppression of HGP was significantly greater with equimolar peripheral than with portal insulin delivery, HGP was actually suppressed to a lesser extent with peripheral insulin delivery (69 +/- 10%) than when insulin was delivered portally (76 +/ - 5%, P < 0.05). To further examine whether glucagon was enhancing the effect of portal insulin, in four additional individuals HGP was supp ressed to a greater extent during a tolbutamide infusion when glucagon was administered continuously throughout the basal and hyperinsulinem ic periods than when glucagon was infused during the basal period only ; HGP suppressed by 63 +/- 3 vs. 52 +/- 3%, respectively, P = 0.02). T olbutamide had no effect on HGP when infused into three C-peptide-nega tive individuals with type I diabetes during a low-dose insulin and gl ucagon infusion. These data suggest that glucagon levels are an import ant determinant of the balance between insulin's direct and indirect e ffects on HGP, with glucagon likely potentiating the direct hepatic ef fect of insulin.