Adrenergic Mechanisms for the Effects of Epinephrine on Glucose Production and Clearance in Man

Abstract

A B S T R A C T The present studies were undertaken to assess the adrenergic mechanisms by which epinephrine stimulates glucose production and suppresses glucose clearance in man: epinephrine (50 ng/kg per min) was infused for 180 min alone and during either alpha (phentolamine) or beta (propranolol)-adrenergic blockade in normal subjects under conditions in which plasma insulin, glucagon, and glucose were maintained at comparable levels by infusion of somatostatin (100 ,ug/h), insulin (0.2 mU/kg per min), and variable amounts of glucose. In additional experiments, to control for the effects of the hyperglycemia caused by epinephrine, variable amounts of glucose without epinephrine were infused along with somatostatin and insulin to produce hyperglycemia comparable with that observed during infusion of epinephrine. This glucose infusion suppressed glucose production from basal rates of 1.8+0.1 to 0.0±0.1 mg/kg per min (P < 0.01), but did not alter glucose clearance. During infusion of epinephrine, glucose production increased transiently from a basal rate of 1.8+0.1 to a maximum of 3.0±0.2 mg/kg per min (P < 0.01) at min 30, and returned to near basal rates at min 180 (1.9±0.1 mg/kg per min). Glucose clearance decreased from a basal rate of 2.0±0.1 to 1.5±0.2 ml/kg per min at the end of the epinephrine infusion (P < 0.01). Infusion of phentolamine did not alter these effects ofepinephrine on glucose production and clearance. In contrast, infusion of propranolol completely prevented the suppression ofglucose clearance by epinephrine, and inhibited the stimulation of glucose production by epinephrine by 80±6% (P < 0.001). These results indicate that, under conditions Dr. Rizza is a recipient of a Clinical Investigator Award

Differentiation of hemodynamic, humoral and metabolic responses to beta 1- and beta 2-adrenergic stimulation in man using atenolol and propranolol.

“…This is consistent with the dominant role of sympathetic neuronal activation in mediating exerciseinduced increases in renin release. release, a contention borne out by the recent studies of Felig et al 23 Second, Rizza et al 24 showed that the clearance of epinephrine after infusion appears to depend on a 13 mechanism and, thus, epinephrine levels could be increased by competition for a receptor. Our results are compatible with those of other investigations, but until now, no distinction was made between the type of 13-adrenoceptor antagonist used.…”

“…Further investigations of the metabolic effects of these drugs when given chronically are indicated. 24 hours showed that nifedipine significantly reduced systolic and diastolic blood pressure throughout the day and the night. The variability of blood pressure was not altered by nifedipine therapy.…”

Evaluation of insulin resistance during inhibition of endogenous insulin and glucagon secretion by somatostatin in non-obese subjects with impaired glucose tolerance

“…Bernstein et al [2] have pointed out, however, that adrenaline and propranolol could interfere with the ability of insulin to stimulate glucose disposal and/or inhibit hepatic glucose production. Adrenaline increases glucose production, decreases glucose clearance [23], and impairs tissue sensitivity to insulin in man [5]. Propranolol had no effect on insulin mediated glucose metabolism [5].…”

Increased insulin sensitivity in the high sodium one-kidney, one figure-8 hypertensive rat.

“…23 " 29 In fact, acute catecholamine administration determines impaired insulin action 24 -26 through the inhibition of net glycogen synthesis 28 - 29 and through the stimulation of hepatic glucose production. 24 " 26 However, it is also established that reduced sensitivity to ^-receptor stimulation follows the chronic administration of ^-agonists. 34 - 36 Particularly, Scheidegger et al 61 showed a 30% increase in insulin-stimulated glucose uptake after chronic /3-receptor stimulation in healthy volunteers.…”

“…23 - 29 Particularly, suppression of insulin secretion by catecholamines is mediated through a-adrenergic receptors, 25 whereas in human subjects, the direct effects of catecholamines on periph-eral and hepatic glucose metabolism appear to be mediated largely through /3-adrenergic receptors. 26 Acute /3-adrenergic stimulation results in impaired insulin action, mainly through the decrease in net glycogen deposition (stimulation of glycogen phosphorylase and inhibition of glycogen synthase) and the increase in hepatic glucose output. 23 - 29 However, the effect of the chronic elevation of the plasma catecholamine concentration on insulin action is still controversial.…”