Glucagon chronically impairs hepatic and muscle glucose disposal

Defects in insulin secretion and/ or action contribute to the hyperglycemia of stressed and diabetic patients, and we hypothesize that failure to suppress glucagon also plays a role. We examined the chronic impact of glucagon on glucose uptake in chronically catheterized conscious depancreatized dogs placed on 5 days of nutritional support ( NS). For 3 days of NS, a variable intraportal infusion of insulin was given to maintain isoglycemia ( similar to 120 mg/ dl). On day 3 of NS, animals received a constant low infusion of insulin ( 0.4 mU . kg(-1) . min(-1)) and either no glucagon ( CONT), basal glucagon ( 0.7 ng . kg(-1) . min(-1); BasG), or elevated glucagon ( 2.4 ng . kg(-1) . min(-1); HiG) for the remaining 2 days. Glucose in NS was varied to maintain isoglycemia. An additional group ( HiG + I) received elevated insulin ( 1 mU . kg(-1) . min(-1)) to maintain glucose requirements in the presence of elevated glucagon. On day 5 of NS, hepatic substrate balance was assessed. Insulin and glucagon levels were 10 +/- 2, 9 +/- 1, 7 +/- 1, and 24 +/- 4 mu U/ ml, and 24 +/- 5, 39 +/- 3, 80 +/- 11, and 79 +/- 5 pg/ ml, CONT, BasG, HiG, and HiG + I, respectively. Glucagon infusion decreased the glucose requirements ( 9.3 +/- 0.1, 4.6 +/- 1.2, 0.9 +/- 0.4, and 11.3 +/- 1.0 mg . kg(-1) . min(-1)). Glucose uptake by both hepatic ( 5.1 +/- 0.4, 1.7 +/- 0.9, - 1.0 +/- 0.4, and 1.2 +/- 0.4 mg . kg(-1) . min(-1)) and nonhepatic ( 4.2 +/- 0.3, 2.9 +/- 0.7, 1.9 +/- 0.3, and 10.2 +/- 1.0 mg . kg(-1) . min(-1)) tissues decreased. Additional insulin augmented nonhepatic glucose uptake and only partially improved hepatic glucose uptake. Thus, glucagon impaired glucose uptake by hepatic and nonhepatic tissues. Compensatory hyperinsulinemia restored nonhepatic glucose uptake and partially corrected hepatic metabolism. Thus, persistent inappropriate secretion of glucagon likely contributes to the insulin resistance and glucose intolerance observed in obese and diabetic individuals.