β-cell Gɑs signaling is critical for physiological and pharmacological enhancement of insulin secretion

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Abstract

The incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors coordinate β-cell secretion that is proportional to nutrient intake. This effect permits consistent and restricted glucose excursions across a range of carbohydrate intake. The canonical signaling downstream of ligand-activated incretin receptors involves coupling to Gɑs protein and generation of intracellular cyclic adenosine monophosphate (cAMP). However, recent reports have highlighted the importance of additional signaling nodes engaged by incretin receptors, including other G-proteins and β-arrestin proteins. Here, the importance of Gɑs signaling was tested in mice with conditional, post-developmental β-cell deletion of Gnas (encoding Gɑs) under physiological and pharmacological conditions. Deletion of Gɑs/cAMP signaling induced immediate and profound hyperglycemia that responded minimally to incretin receptor agonists, a sulfonylurea, or bethanechol. While islet area and insulin content were not affected in Gnasβcell-/-, perifusion of isolated islets demonstrated impaired responses to glucose, incretins, acetylcholine and IBMX. In the absence of Gɑs, incretin-stimulated insulin secretion was impaired but not absent, with some contribution from Gɑq signaling. Collectively, these findings validate a central role for cAMP to mediate incretin signaling, but also demonstrate broad impairment of insulin secretion in the absence of Gɑs that causes both fasting hyperglycemia and glucose intolerance.

Authors

Megan E. Capozzi, David Bouslov, Ashot Sargsyan, Michelle Y. Chan, Sarah M. Gray, Katrina Viloria, Akshay Bareja, Jonathan D. Douros, Sophie L. Lewandowski, Jason C.L. Tong, Annie Hasib, Federica Cuozzo, Elizabeth C. Ross, Matthew W. Foster, Lee S. Weinstein, Mehboob A. Hussain, Matthew J. Merrins, Francis S. Willard, Mark O. Huising, Kyle W. Sloop, David J. Hodson, David A. D'Alessio, Jonathan E. Campbell