β Cell Gαs signaling is critical for physiological and pharmacological enhancement of insulin secretion
The incretin peptides glucose-dependent insulinotropic polypeptide and glucagon-like peptide-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 Gαs protein and generation of intracellular 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 Gαs signaling was tested in mice with conditional, postdevelopmental β cell deletion of Gnas (encoding Gαs) under physiological and pharmacological conditions. Deletion of Gαs/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 Gαs, incretin-stimulated insulin secretion was impaired but not absent, with some contribution from Gαq signaling. Collectively, these findings validate a central role for cAMP in mediating incretin signaling, but also demonstrate broad impairment of insulin secretion in the absence of Gαs that causes both fasting hyperglycemia and glucose intolerance.
Authors
- Ashot Sargsyan (ORCID: https://orcid.org/0000-0003-1662-7548)
- Jonathan D. Douros (ORCID: https://orcid.org/0000-0003-2299-6163)
- Lee S. Weinstein (ORCID: https://orcid.org/0000-0002-1899-5152)
- Akshay Bareja (ORCID: https://orcid.org/0000-0001-9033-4116)
- Megan E. Capozzi (ORCID: https://orcid.org/0000-0002-7587-0663)
- Mark O. Huising (ORCID: https://orcid.org/0000-0002-6594-2205)
- Annie Hasib (ORCID: https://orcid.org/0000-0002-5388-6461)
- Katrina Viloria (ORCID: https://orcid.org/0000-0003-3572-4669)
- Federica Cuozzo (ORCID: https://orcid.org/0000-0001-8399-1281)
- Matthew J. Merrins (ORCID: https://orcid.org/0000-0003-1599-9227)
- Michelle Chan (ORCID: https://orcid.org/0000-0001-6037-7051)
- David J. Hodson (ORCID: https://orcid.org/0000-0002-8641-8568)
- Liz Ross
- Matthew W. Foster (ORCID: https://orcid.org/0000-0003-0212-2346)
- Kyle W. Sloop (ORCID: https://orcid.org/0000-0001-6748-9929)
- Sarah M. Gray (ORCID: https://orcid.org/0000-0003-2370-7968)
- Francis S. Willard (ORCID: https://orcid.org/0000-0002-4260-2451)
- Sophie L. Lewandowski (ORCID: https://orcid.org/0000-0002-2838-7054)
- David Bouslov
- Jinjin Tong (ORCID: https://orcid.org/0009-0002-4195-273X)
- Jonathan E. Campbell (ORCID: https://orcid.org/0000-0003-4358-6331)
- Mehboob A. Hussain
Institutions
- University of Wisconsin–Madison (US)
- Eli Lilly (United States) (US)
- Duke University (US)
- University of Washington (US)
- University of California, Irvine (US)
- Indiana Biosciences Research Institute (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Abterra Biosciences (United States) (US)
- Oxford Centre for Diabetes, Endocrinology and Metabolism (GB)
- University of Birmingham (GB)
- University of California, Davis (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1172/jci183741
- Citations
- 5
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 10.03
Funders
- Eli Lilly and Company
- Diabetes UK
- Novo Nordisk
- National Institutes of Health