American Diabetes Association
DB23-0201 nlucagon-supplemental.pdf (713.24 kB)

High doses of exogenous glucagon stimulate insulin secretion and reduce insulin clearance in healthy humans

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posted on 2023-11-28, 17:24 authored by Sarah M. Gray, Elisha Goonatilleke, Michelle A. Emrick, Jessica O. Becker, Andrew N. Hoofnagle, Darko Stefanovski, Wentao He, Guofang Zhang, Jenny Tong, Jonathan Campbell, David A. D’Alessio

Abstract (186 words)

Glucagon is generally defined as a counter-regulatory hormone with a primary role to raise blood glucose concentrations by increasing endogenous glucose production (EGP) in response to hypoglycemia. However, glucagon has long been known to stimulate insulin release, and recent preclinical findings support a paracrine action of glucagon directly on islet b-cells that augments secretion. In mice, the insulinotropic effect of glucagon is glucose dependent and not present during basal euglycemia. To test the hypothesis that the relative effects of glucagon on hepatic and islet function were also varied with blood glucose, a group of healthy subjects received glucagon (100 ng/kg) during fasting glycemia or experimental hyperglycemia (~150 mg/dl) on two separate days. During fasting euglycemia, administration of glucagon caused blood glucose to rise due to increased EGP, with a delayed increase of insulin secretion. When given during experimental hyperglycemia, glucagon caused a rapid, 3-fold increase in insulin secretion, as well as a more gradual increase in EGP. Under both conditions, insulin clearance was decreased in response to glucagon infusion. The insulinotropic action of glucagon, which is proportional to elevated levels of blood glucose, suggests distinct physiologic roles in the fasting and prandial states.

Article Highlights

· This study was directed at the question of whether glucagon has divergent actions on insulin secretion at fasting compared to elevated blood glucose concentrations.

· Glucagon rapidly increased insulin secretion and reduced insulin clearance when given during experimental hyperglycemia at concentrations of blood glucose approximating the post-prandial state.

· When given during fasting euglycemia, glucagon increased endogenous glucose production and raised blood glucose, with a delayed rise of insulin secretion.

These data are compatible with distinct roles for glucagon on blood glucose regulation- as an incretin analogue after meals, and as a counter-regulatory hormone at eu- and hypo-glycemia.


U.S. Department of Health and Human Services > National Institutes of Health > National Institute of Diabetes and Digestive and Kidney Diseases F32DK12142 R01DK101991 U01DK121289


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