Loss of β‐cell Gα z protects against high‐fat diet induced glucose intolerance by preserving incretin responsiveness and enhancing insulin secretion

• Published in: The FASEB journal 2020-04, Vol.34 (S1), p.1-1
• Main Authors: Carbajal, Kathryn, Schaid, Michael, Green, Cara, Laundre, Erin, Harrington, Jeffrey, Kelly, Grant, Reuter, Austin, Fenske, Rachel, Wehner, Molly, Lamming, Dudley, Kimple, Michelle
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.2020.34.s1.04098

Abstract only Cyclic‐adenosine monophosphate (cAMP) is an important secondary messenger in the insulin‐secreting pancreatic β‐cells. Intracellular production of cAMP is augmented by stimulatory heterotrimeric G proteins (Gs) and blocked by inhibitory heterotrimeric G proteins (Gi). Pancreatic expression of the unique Gi family member, Gα z , is restricted to the islet, which contains β‐cells and other endocrine cell types, including glucagon/GLP‐1‐secreting alpha cells and somatostatin‐secreting delta cells. We have previously shown that full body Gα z ‐null mice are protected from hyperglycemia in several diabetes model systems. Here, we use a high fat diet (HFD) model of obesity and insulin resistance to explore the impact of loss of beta‐cell Gα z on the type 2 diabetes (T2D) phenotype of male C57BL/6J mice. We hypothesized that loss of beta‐cell Gα z in the context of HFD feeding would enhance insulin secretion, protecting mice from HFD‐induced glucose intolerance. To generate beta‐cell specific Gα z ‐null and control mice, we bred Gα z flox/flox mice with rat insulin promoter RIP‐Cre herr mice. At 12 weeks of age, transgenic Gα z ‐null mice were fed a diet containing 45 kcal% fat or a 10 kcal% fat control diet for 26 weeks. At study end, mice were metabolically phenotyped and sacrificed for whole pancreas and islet phenotyping. Beta‐cell‐specific Gα z loss protected mice from HFD induced glucose intolerance due to a selective effect on islet insulin secretion, particularly in concert with a stable agonist of the Gs‐coupled GLP‐1 receptor. This protective effect was independent of changes in Gα z ‐coupled EP3 receptor signaling, as neither EP3 expression nor production of its endogenous ligand, PGE2, were enhanced in islets from HFD‐fed mice. This protective effect was also beta‐cell autonomous, as both full‐body and beta‐cell‐specific Gα z ‐null mice had enhanced GLP‐1‐positive alpha‐cells, albeit with no changes in active GLP‐1 secretion. Finally, gene microarray results confirm that Gα z loss and HFD feeding synergize to differentially regulate islet gene expression, specifically up‐regulating secretion‐centric genes, many of which are related to cAMP signaling. This study presents a novel inhibitory mechanism of receptor‐independent G‐protein signaling that may hold promise for developing beta‐cell targeted diabetes therapeutics.