The inhibitory heterotrimeric G protein, Gz, regulates alpha‐cell active glucagon‐like peptide 1 (GLP‐1) levels

Abstract

Biologically‐active glucagon‐like peptide 1 (GLP‐1) is a product of the proglucagon gene and amplifies glucose stimulated insulin secretion and promotes beta‐cell survival via stimulation of cAMP production. Neighboring alpha cells produce and secrete active GLP‐1 to influence beta‐cell function. Although alpha‐cell GLP‐1 production and secretion is poorly understood, cyclic AMP (cAMP) signaling promotes GLP‐1 released from gut L‐cells. Furthermore, cAMP signaling, through activation of cyclic AMP‐responsive transcription factors, may influence expression of the prohormone convertase enzymes specific for GLP‐1. Therefore, it is possible cAMP positively regulates both GLP‐1 production and secretion. Cyclic AMP levels are augmented by stimulatory heterotrimeric G proteins (Gs) and blocked by inhibitory heterotrimeric G proteins (Gi). A unique Gi family member, Gz, is expressed in both alpha and beta cells. Mice lacking the catalytic alpha subunit of Gz (Gαz), are protected from hyperglycemia in several diabetes model systems due to increased beta‐cell function and beta‐cell replication. At least part of this phenotype is beta‐cell autonomous. We hypothesized part of the protective phenotype may be due to loss of Gαz in the alpha‐cell and increased GLP‐1 production and/or secretion. To determine alpha‐cell levels of active GLP‐1, we used immunofluorescence to co‐localize active GLP‐1 to glucagon positive alpha cells in pancreas sections from wild‐type and Gαz‐null mice in different models of diabetes mellitus. Pancreas sections lacking Gαz displayed a dramatic increase in the percentage of cells that are both active GLP‐1 positive and glucagon positive compared to wild‐type counterparts. To determine if beta‐cell Gαz regulates alpha‐cell active GLP‐1 levels, we imaged pancreas sections from beta‐cell specific Gz‐null mice. Because published evidence has shown that alpha‐cell active GLP‐1 levels are elevated in pre‐diabetic and diabetic conditions, we determined if beta cell Gαz expression altered this compensatory increase in active GLP‐1 production. Whether increased active GLP‐1 levels correlated with increased active GLP‐1 secretion over time was determined by high‐sensitivity ELISA of islet incubation medium. Future experiments will focus whether the Gaz‐null mutation affects the production and/or secretion of active GLP‐1 in response to the glucolipotoxic conditions of severe insulin resistance and type 2 diabetes. Our results identify Gαz as a potential new therapeutic target to promote beta‐cell function and replication and underscore the role of intra‐islet cell‐cell communication in beta‐cell biology.Support or Funding InformationVA Merit Review Award: I01 BX003700‐01A1, VA BLR&DR01: R01 DK102598, NIH/NIDDK Type 2 Diabetes/Fatty Acid Diet projects (started by 2016) American Diabetes Association Innovative Basic Science Award: 1‐14‐BS‐115 Type 1 Diabetes projects or projects using Gaz‐floxed miceJDRF J&J Industry Partnership Award: 17‐2011‐608This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.