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Modulation of Arginine-Induced Glucagon Release by Epinephrine and Glucose Levels in Man^*

James C. Beard, Clarice Weinberg, Michael A. Pfeifer, James D. Best, Jeffrey B. Halter and Daniel Porte, Jr.

Departments of Medicine and Biostatistics, University of Washington School of Medicine, and the Geriatric Research, Education, and Clinical Center of the Veterans Administration Medical Center, Seattle, Washington 98108

Address requests for reprints to: James C. Beard, M.D. (151), Veterans Administration Medical Center, 4435 Beacon Avenue South, Seattle, Washington 98108.

To assess how physiological epinephrine (EPI) elevations and EPI-induced hyperglycemia interact in the regulation of glucagon secretion, we measured acute glucagon responses (AGR) to arginine at controlled glucose levels during EPI infusions in man. With glucose levels matched at 166 ± 5 mg/dl using glucose clamp techniques, the AGR (mean change at 2–5 min) to a 5-g iv arginine injection was greater in each subject during the infusion of 15 ng/kg·min EPI (low EPI) than during the control glucose infusion and was still greater during the infusion of 80 ng/kg·min EPI (high EPI; 69 ± 15, 76 ± 13, and 142 ± 22 pg/ml, respectively; n = 8; P < 0.003). With glucose levels matched at 256 ± 5 mg/dl, a similar dose-related enhancement of AGR by EPI was seen (control, 53 ± 12 pg/ml; low EPI, 63 ± 5 pg/ml; high EPI, 130 ± 20 pg/ml; P < 0.008). During control infusions, raising the glucose level from 102 ± 2 to 166 ± 5 to 256 ± 5 mg/dl suppressed AGR from 77 ± 17 to 69 ± 15 to 53 ± 12 pg/ml (P < 0.002). During low EPI, the same glycemic increments lowered GR from 108 ± 19 to 76 ± 13 to 63 ± 5 pg/ ml (P < 0.02). This suppression of AGR by hyperglycemia was sufficient to obscure stimulation by EPI: at a glucose level of 102 ± 2 mg/dl during control infusions, AGR was 77 ± 17 pg/ml, compared to only 76 ± 13 pg/ml during low EPI with the glucose level higher (166 ± 5 mg/dl). Multiple linear regression analysis showed a highly significant dependence of AGR on both EPI and glucose levels, accounting for 80% of the within-subject variation in AGR (P < 0.0001).

These data show that 1) EPI is a dose-dependent amplifier of arginine-induced glucagon secretion in man, and 2) hyperglycemia suppresses arginine-induced glucagon secretion, potentially masking the stimulation caused by EPI. The findings suggest that the feedback effect of hyperglycemia on glucagon secretion may help regulate the level of hyperglycemia resulting from adrenergic stimulation. (J Clin Endocrinol Metab 56:1271, 1983)

^* Presented in part at the Annual Meeting of the American Diabetes Association, June 14,1981 [Diabetes [Suppl 1] 29:42,1981 (Abstract)]. This work was supported by the NIH (Grants AM-12829, AM-17047, AG-01926, and AM-00738) and by the V.A.

Fellow of the Juvenile Diabetes Foundation.

Present address: University of Louisville School of Medicine, Louisville, Kentucky 40208.

Received October 13, 1982.