Epinephrine (50 ng . kg-1 . min-1) was infused for 120 min in seven normal volunteers alone (combined alpha- and beta-adrenergic stimulation), with propranolol (alpha-adrenergic stimulation), and with propranolol plus phentolamine (alpha-adrenergic blockade superimposed on alpha-adrenergic stimulation). During alpha-adrenergic stimulation, plasma glucose and glucose production increased 32 and 42% less, respectively, than during infusion of epinephrine alone, whereas glucose clearance was suppressed comparably. Plasma insulin decreased during alpha-adrenergic stimulation but increased during infusion of epinephrine alone. Plasma epinephrine was threefold greater during infusion of epinephrine plus propranolol than during infusion of epinephrine alone. When alpha-adrenergic blockade was superimposed on alpha-adrenergic stimulation, the increases in plasma glucose and glucose production as well as the decreases in plasma insulin and glucose clearance observed during alpha-adrenergic stimulation were virtually abolished, whereas plasma epinephrine levels were unaltered. These results indicate that in man epinephrine can cause hyperglycemia via both alpha- and beta-adrenergic stimulation of glucose production and suppression of glucose clearance, either directly or indirectly. alpha-Adrenergic effects on glucose production and clearance may be mediated by inhibition of insulin secretion.

Glucose clearance (glucose utilization divided by plasma glucose) is commonly used to assess glucose utilization under conditions in which plasma glucose concentrations vary. The validity of this practice requires that glucose clearance itself be independent of plasma glucose concentration. The present studies were, therefore, undertaken to determine the relationship between glucose clearance and plasma glucose concentration in man. Using the glucose clamp technique, rates of glucose utilization (measured isotopically with 3-3H-glucose) and glucose clearance were determined in 5 normal volunteers at steady-state plasma glucose concentrations of approximately 60, 95, 130, and 165 mg/dl, while plasma insulin concentrations were maintained constant (approximately 18 microU/ml) by infusion of insulin and somatostatin. Despite virtually identical 0.4 mg X kg-1 X min-1 increments in glucose utilization for each 35-mg/dl increment in plasma glucose, glucose clearance decreased as a function of plasma glucose concentration (r = -0.85, P less than 0.001). These results indicate that glucose clearance is not independent of changes in plasma glucose concentration and, thus, use of glucose clearance to evaluate glucose utilization of differing plasma glucose concentration is not valid. Whether this conclusion also applies to similar use of clearance for other substrates remains to be determined.

A B S T R A C T Infusion of glucagon causes only a transient increase in glucose production in normial and diabetic man. To assess the effect ofintermittent endogenous hyperglucagonemia that might more closely reflect physiologic conditions, arginine (10 g over 30 min) was infused four times to 8 normal subjects and 13 insulin-dependent diabetic subjects (4 of whom were infused concomitantly with somatostatin to examine effects ofarginine during prevention ofhyperglucagonemia). Each arginine infusion was separated by 60 min. Diabetic subjects were infused throughout the experiments with insulin at rates (0.07-0.48 mU/kg per min) that had normalized base-line plasma glucose and rates of glucose appearance (Ra) and disappearance (Rd). Basal plasma glucagon and arginine-induced hyperglucagonemia were similar in both groups; basal serum insulin in the diabetics (16+1 ,U/ml, P < 0.05) exceeded those ofthe normal subjects (10+ 1 ,U/ml,P < 0.05) but did not increase with arginine. Serum insulin in normal subjects increased 15-20,U/ml with each arginine infusion. In both groups each arginine inifusion increased plasma glucose and Ra. Increments ofRa in the diabetics exceeded those of normal subjects, (P < 0.02); Rd was similar in both groups. In normal subjects, plasma glucose returned to basal levels after each arginine infusion, whereas in the diabetics hyperglycemia persisted reaching 151 + 15 mg/dl after the last arginine infusion. When glucagon responses were prevented by somatostatin, arginine infusions did not alter plasma glucose or Ra.

A B S T R A C T The present studies were undertaken to assess the mechanism by which insulin increases glucose uptake in man. Because glucose uptake in most mammalian tissues occurs predominantly by a facilitated transport system that follows Michaelis-Menten kinetics, glucose uptake was measured isotopically in normal volunteers over the physiologic range of plasma glucose and insulin concentrations and was subjected to Lineweaver-Burk and Eadie-Hofstee analysis. With both methods, increases in plasma insulin from 18 .tU/ ml to 80 and 150 tU/ml were found to increase the maximum velocity (Vmax) for gluicose uptake nearly three-and fivefold, respectively, (P <0.025 and P < 0.001) without significantly altering the Michaelis constant (K.). Because an increase in the affinity or molecular activity of transport sites or provision of additional transport sites that differed from those present basally should have altered the Ki, whereas a mere increase in the number of transport sites would have only increased the Vmax, our results indicate that in man, insulin may increase glucose uptake merely by providing additional transport sites.