Mechanisms of Epinephrine-induced Glucose Intolerance in Normal Humans

Abstract

To evaluate the role of the splanchnic bed in epinephrine-induced glucose intolerance, we selectively assessed the components of net splanchnic glucose balance, i.e., splanchnic glucose uptake and hepatic glucose production, and peripheral glucose uptake by combining infusion of [3-(3)H]glucose with hepatic vein catheterization. Normal humans received a 90-min infusion of either glucose alone (6.5 mg/kg(-1) per min(-1)) or epinephrine plus glucose at two dose levels: (a) in amounts that simulated the hyperglycemia seen with glucose alone (3.0 mg/kg(-1) per min(-1)); and (b) in amounts identical to the control study. During infusion of glucose alone, blood glucose rose twofold, insulin levels and net posthepatic insulin release increased three- to fourfold, and net splanchnic glucose output switched from a net output (1.65+/-0.12 mg/kg(-1) per min(-1)) to a net uptake (1.56+/-0.18). This was due to a 90-95% fall (P < 0.001) in hepatic glucose production and a 100% rise (P < 0.001) in splanchnic glucose uptake (from 0.86+/-0.14 to 1.71+/-0.12 mg/kg(-1) per min(-1)), which in the basal state amounted to 30-35% of total glucose uptake. Peripheral glucose uptake rose by 170-185% (P < 0.001). When epinephrine was combined with the lower glucose dose, blood glucose, insulin release, and hepatic blood flow were no different from values observed with glucose alone. However, hepatic glucose production fell only 40-45% (P < 0.05 vs. glucose alone) and, most importantly, the rise in splanchnic glucose uptake was totally blocked. As a result, splanchnic glucose clearance fell by 50% (P < 0.05), and net splanchnic glucose uptake did not occur. The rise in peripheral glucose uptake was also reduced by 50-60% (P < 0.001). When epinephrine was added to the same dose of glucose used in the control study, blood glucose rose twofold higher (P < 0.001). The initial rise in splanchnic glucose uptake was totally prevented; however, beyond 30 min, splanchnic glucose uptake increased, reaching levels seen in the control study when severe hyperglycemia occurred. Splanchnic glucose clearance, nevertheless, remained suppressed throughout the entire study (40%-50%, P < 0.01). It is concluded that (a) the splanchnic bed accounts for one-third of total body glucose uptake in the basal state in normal humans; (b) epinephrine markedly inhibits the rise in splanchnic glucose uptake induced by infusion of glucose; and (c) this effect does not require a fall in insulin and is modulated by the level of hyperglycemia. Our data indicate that the splanchnic bed is an important site of glucose uptake in post-absorptive humans and that epinephrine impairs glucose tolerance by suppressing glucose uptake by both splanchnic and peripheral tissues, as well as by its well known stimulatory effect on endogenous glucose production.