Glucagon and insulin are commonly believed to have counteracting effects on blood glucose levels. However, recent studies have demonstrated that glucagon has a physiologic role to activate β cells and enhance insulin secretion. To date, the actions of glucagon have been studied mostly in fasting or hypoglycemic states, yet it is clear that mixed-nutrient meals elicit secretion of both glucagon and insulin, suggesting that glucagon also contributes to glucose regulation in the postprandial state. We hypothesized that the elevated glycemia seen in the fed state would allow glucagon to stimulate insulin secretion and reduce blood glucose. In fact, exogenous glucagon given under fed conditions did robustly stimulate insulin secretion and lower glycemia. Exogenous glucagon given to fed Gcgr:Glp1rβcell–/– mice failed to stimulate insulin secretion or reduce glycemia, demonstrating the importance of an insulinotropic glucagon effect. The action of endogenous glucagon to reduce glycemia in the fed state was tested with administration of alanine, a potent glucagon secretagogue. Alanine raised blood glucose in fasted WT mice or fed Gcgr:Glp1rβcell–/– mice, conditions where glucagon is unable to stimulate β cell activity. However, alanine given to fed WT mice produced a decrease in glycemia, along with elevated insulin and glucagon levels. Overall, our data support a model in which glucagon serves as an insulinotropic hormone in the fed state and complements rather than opposes insulin action to maintain euglycemia.
Megan E. Capozzi, Jacob B. Wait, Jepchumba Koech, Andrew N. Gordon, Reilly W. Coch, Berit Svendsen, Brian Finan, David A. D’Alessio, Jonathan E. Campbell
Title and authors | Publication | Year |
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The Limited Role of Glucagon for Ketogenesis During Fasting or in Response to SGLT2 Inhibition
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Diabetes | 2020 |
The kinetics of glucagon action on the liver during insulin-induced hypoglycemia
C Pedersen, G Kraft, DS Edgerton, M Scott, B Farmer, M Smith, DC Laneve, PE Williams, LM Moore, AD Cherrington |
American journal of physiology. Endocrinology and metabolism | 2020 |
Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation
BA McLean, CK Wong, JE Campbell, DJ Hodson, S Trapp, DJ Drucker |
Endocrine reviews | 2020 |
Pharmacological antagonism of the incretin system protects against diet-induced obesity
B Svendsen, ME Capozzi, J Nui, SA Hannou, B Finan, J Naylor, P Ravn, DA D'Alessio, JE Campbell |
Molecular Metabolism | 2020 |
Dipeptidyl Peptidase-4 at the Interface Between Inflammation and Metabolism
NA Trzaskalski, E Fadzeyeva, EE Mulvihill |
Clinical Medicine Insights. Endocrinology and Diabetes | 2020 |
Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms
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Molecular Metabolism | 2020 |
Updating the Role of α-Cell Preproglucagon Products on GLP-1 Receptor–Mediated Insulin Secretion
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Diabetes | 2020 |
Repositioning the Alpha Cell in Postprandial Metabolism
K El, ME Capozzi, JE Campbell |
Endocrinology | 2020 |
Paracrine regulation of insulin secretion
MO Huising |
Diabetologia | 2020 |
Type 2 diabetes: one disease, many pathways
J Ha, A Sherman |
American journal of physiology. Endocrinology and metabolism | 2020 |
In vivo studies of glucagon secretion by human islets transplanted in mice
K Tellez, Y Hang, X Gu, CA Chang, RW Stein, SK Kim |
Nature metabolism | 2020 |
The role of GIP in α-cells and glucagon secretion
K El, JE Campbell |
Peptides | 2020 |
Selective stimulation of colonic L cells improves metabolic outcomes in mice
JE Lewis, EL Miedzybrodzka, RE Foreman, OR Woodward, RG Kay, DA Goldspink, FM Gribble, F Reimann |
Diabetologia | 2020 |
Alpha cell regulation of beta cell function
T Moede, IB Leibiger, PO Berggren |
Diabetologia | 2020 |
Islet cell dysfunction in patients with chronic pancreatitis
A Roy, J Sahoo, S Kamalanathan, D Naik, P Mohan, B Pottakkat |
World journal of diabetes | 2020 |