A B S T R A C T The effect of epinephrine on basal and insulin-stimulated glucose uptake in perfused hindlimbs offed rats was studied. Insulin increased glucose uptake in a dose-dependent manner from a basal value of 1.5+0.3 up to a maximum value of 5.3 ±0.9 ,umol/min per 100 g with 6 nM (1 mU/ml). Epinephrine at 10 nM and 0.1 ,uM also increased glucose uptake to 2.6±0.1 and 3.1±0.1 ,mol/min per 100 g, respectively. These same concentrations of epinephrine, however, suppressed the insulin-stimulated glucose uptake to 3.2±0.3 Amol/min per 100 g. Both the stimulatory and inhibitory effects of epinephrine on glucose uptake were completely reversed by propranolol, but were not significantly altered by phentolamine.Uptake of 3-O-methylglucose and 2-deoxyglucose into thigh muscles of the perfused hindlimbs was stimulated fivefold by insulin, but was unaffected by epinephrine. Epinephrine also did not inhibit the stimulation of uptake by insulin. Epinephrine decreased the phosphorylation of 2-deoxyglucose, however, and caused the intracellular accumulation of free glucose. These last two effects were more prominent in the presence of insulin. Whereas epinephrine caused large rises in glucose-6-P and fructose-6-P, insulin did not alter the concentration of these metabolites either in the absence or presence ofepinephrine.These data indicate that: (a) epinephrine has a stimulatory effect on glucose uptake by perfused rat hindlimbs that does not appear to be exerted on skeletal muscle; (b) epinephrine does not affect hexose transport in skeletal muscle; (c) epinephrine inhibits insulinstimulated glucose uptake in skeletal muscle by inhibiting glucose phosphorylation. It is hypothesized that the inhibition of glucose phosphorylation is due to the stimulation of glycogenolysis, which leads to the Dr. Chiasson's present address is

Intravenous or oral administration of concentrated glucose solution into fasted rats simultaneously injected with 14C-bicarbonate resulted in an inhibition of [14C]glucose release into the blood and in an accelerated [14C]glycogen formation associated with glycogen synthetase activation and phosphorylase inactivation in the liver. The specific activity of glycogen was much higher than that of blood glucose after the glucose load, indicating that glycogen originated from gluconeogenesis rather than blood glucose. These metabolic changes induced by the glucose load were not mediated by endogenous insulin because they were observed to the same extent in rats treated with anti-insulin serum. However, they were mostly, if not totally, abolished by adrenalectomy, which suppressed gluconeogenesis and glycogenesis. Glucose tolerance was markedly impaired not only by anti-insulin serum, which inhibits peripheral glucose utilization, but also by adrenalectomy, which affects hepatic metabolism. It is concluded that a glucose load diverts the final product of hepatic gluconeogenesis from blood glucose to liver glycogen; these metabolic changes in the liver are an important determinant of glucose tolerance.

Using the perfused rat hindlimb preparation, the role of insulin in the regulation of glycogen metabolism in voluntary skeletal muscle has been characterized. A maximally effective concentration of insulin (1 mU/ml) caused a threefold increase in glucose clearance by 5 min. However, the -glucose-6-P/+glucose-6-P activity ratio of glycogen synthase was not significantly increased before 20 min. Insulin concentrations as low as 0.1 mU/ml significantly modified the glycogen synthase activity ratio and the half-maximal activation constant (A0.5) for glucose-6-P at 30 min, but had no effect on tissue cAMP. These changes were not dependent on the presence of glucose and were not modified by fasting. These results indicate that high physiological concentrations of insulin activate glycogen synthase in voluntary skeletal muscle and that this effect is independent of changes in glucose uptake or tissue cyclic AMP.

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