Transient hepatic response to glucagon in man: Role of insulin and hyperglycemia

We infused glucagon into normal humans with preventing changes in plasma glucose and insulin. Insulin (0.45 mU.min^-1.kg^-1) was infused for 90 min, while euglycemia was maintained by a variable glucose infusion. Subsequently, glucagon (6 ng.min^-1.kg^-1) was added, and changes in plasma glycose were avoided by appropriately reducing the glucose infusion. With insulin alone, glucose production (GP) fell to zero. When hyperglucagonemia (530 ± 32 pg.ml) was superimposed, GP rose promptly and then slowly declined. However, between 180 and 240 min, GP remained elevated (1.72 ± 0.30 mg.min^-1.kg^-1) as compard to an insulin control study (0.03 ± 0.20, P < 0.025). When hyperglycemia (+25 mg/100 ml) was induced between 180 and 240 min, glucagon-stimulated GP was completely suppressed. To determine whether this effect was mediated by hyperglycemia per se or glucose-induced hyperinsulinemia, between 180 and 240 min we increased either a) the insulin infusion (by 0.25 mU.min^-1.kg^-1) while maintaining euglycemia or b) plasma glucose (+25 mg/100 ml) while blocking insulin release with somatostatin. When the insulin was increased, GP declined by 68 ± 13% (P < 0.02). When plasma glucose alone was raised, GP fell from 1.44 ± 0.09 to 0.07 ± 0.16 mg.min^-1.kg^-1 (< 0.002). In conclusion, the hepatic response to sustained hyperglucagonemia is more persistent if changes in plasma glucose are prevented, and its transient nature is in part explained by a feedback adjustment to glucagon-induced hyperglycemia and hyperinsulinemia.