Introduction and Objective: The relative contribution of circulating glucose and insulin concentrations to glucagon secretion in healthy individuals is unknown. We therefore assessed glucagon secretion using 13C9,15N1-glucagon tracer at varying insulin and glucose concentrations in healthy individuals. Methods: After overnight fast, twelve healthy individuals underwent three separate clamp visits (hypo-, eu-, hyper-glycemia) in random order at two insulin infusion rates. Five (3F; mean±SE: age=27.6±4.1 y; BMI=24.1±1.8 kg/m²) received insulin infusion at 0.25 and 0.75 mU/kg/min for 90 min each; the remaining (3F; age=27.6±1.8 y; BMI=26.4±1.0 kg/m²) at 0.5 and 1 mU/kg/min over the same intervals. Simultaneously, 13C9,15N1-glucagon tracer was infused. Arterialized venous blood was collected for plasma glucose, insulin, glucagon and glucagon tracer measurements. Systemic rate of glucagon appearance (Ra) was calculated as recently described. Results: At hyperglycemia, glucagon Ra was suppressed and did not differ from 0 at any insulin concentration. At euglycemia, a negative trend in glucagon Ra was observed with rising insulin levels. During hypoglycemia, glucagon Ra was significantly higher than eu- and hyper-glycemia (p0.001), with no apparent effects of increasing insulin concentrations. Conclusion: Glucagon secretion appears to be primarily regulated by circulating glucose and not by insulin concentrations in healthy adults. Disclosure E. Zagallo: None. M. Schiavon: Research Support; Current; Sanofi. F. Ruchi: None. C. Dalla Man: Other - Webinar provider; Ended; Sanofi. Other - Joint research project; Current; Sanofi-Aventis Deutschland GmbH. R. Basu: None. A. Basu: Research Support; Current; Dexcom, Inc. Funding National Institutes of Health (DK085516), National Institutes of Health (DK029953)
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