Insulin can modulate glucagon-stimulated hepatic glucose production and is considered to be the major factor acting in vivo to exert a counterregulatory action to glucagon. The insulindependent diabetic, therefore, might be especially vulnerable to enhanced hepatic glucose production promoted by glucagon. To investigate this hypothesis, low-dose glucagon infusions were administered to normal and diabetic men to compare the effects of glucagon on net splanchnic glucose production (NSGP). Four normal and three insulin-dependent, ketosis-prone, hyperglycemic diabetic men (insulin withheld for 24 hours) underwent brachialartery-hepatic-vein catheterization. Each received a 90-minute glucagon infusion at 5 ng./kg./min. Glucagon levels rose four-tofivefold in both groups, plateauing at 300–600 pg./ml. In the normals, NSGP rose from 92 ± 12 to 211 ± 31 mg./min. at 15 minutes and returned to basal levels by 45 minutes. Insulin measured in the hepatic vein rose from 19 ± 6 to 33 ± 11 /μU./ml., while plasma glucose rose 17 mg./dl. In the insulin-dependent diabetics, NSGP rose from 78 ± 24 to a peak of 221 ± 33 mg./min. at 30 minutes and then fell sharply to 113 ± 15 mg./min. at 60 minutes despite continuing hyperglucagonemia. Plasma glucose in the diabetics rose 21 mg./dl.

These data suggest a mechanism that acts to rapidly diminish glucagon-induced hepatic glucose production in diabetic man but does not appear to be mediated by increased insulin secretion.

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