Mechanisms of Epinephrine-induced Glucose Intolerance in Normal Humans

Abstract

A B S T R A C T 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 [3-3H]glucose with hepatic vein catheterization. Normal humans received a 90-min infusion of either glucose alone (6.5 mg/kg-' per min-') or epinephrine plus glucose at two dose levels: (a) in amounts that simulated the hyperglycemia seen with glucose alone (3.0 mg/kg-' per min-'); 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-' per min-') 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-' 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 postabsorptive 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.

Elevation of plasma epinephrine concentrations inhibits proteolysis and leucine oxidation in man via beta-adrenergic mechanisms.

“…During epinephrine infusion, net forearm leucine release increased threefold, suggesting that the 22% fall of total body leucine flux during epinephrine was the result of a considerably greater fall of leucine appearance from nonmuscle tissues such as splanchnic organs. These respond to epinephrine with no appreciable increase in local blood flow (33).…”

Adrenergic blockade alters glucose kinetics during exercise in insulin-dependent diabetics.

“…In the insulindependent diabetics, the priming dose of 3-[3Hlglucose was increased in proportion to the increase in fasting glucose concentration, and the continuous infusion was administered for 180 min before exercise (Protocol I) or propranolol or phentolamine (Protocols II and III) to allow adequate time for equilibration with the glucose pool. Previous studies by Sacca et al (19) have shown that tritiated glucose infusion in the fasted state does not result in significant labeling of liver glycogen. In all studies, the 3-[3H]glucose infusion was continued throughout the exercise and recovery periods.…”

The interaction between the adenylate cyclase system and insulin-stimulated glucose transport. Evidence for the importance of both cyclic-AMP-dependent and -independent mechanisms

“…Peripheral insulin resistance is rapidly induced in vivo by catecholamine infusion (Deibert & DeFronzo, 1980;Sacca et al, 1982;Lager et al, 1986). Detailed studies have shown that catecholamines decrease the response to a maximally effective concentration of insulin and produce a marked rightward shift of the dose-response curve for insulin effects on peripheral glucose uptake (Lager et al, 1986).…”