β Cell GLP-1R Signaling Alters α Cell Proglucagon Processing after Vertical Sleeve Gastrectomy in Mice

• Published in: Cell reports (Cambridge) 2018-04, Vol.23 (4), p.967-973
• Main Authors: Garibay, Darline, Lou, Jon, Lee, Seon A., Zaborska, Karolina E., Weissman, Margot H., Sloma, Erica, Donahue, Leanne, Miller, Andrew D., White, Andrew C., Michael, M. Dodson, Sloop, Kyle W., Cummings, Bethany P.
• Format: Article
• Language: English
• Subjects: Animals; Bariatric Surgery; Gastrectomy; GLP-1; Glucagon-Like Peptide-1 Receptor - genetics; Glucagon-Like Peptide-1 Receptor - metabolism; Glucagon-Secreting Cells - metabolism; Glucagon-Secreting Cells - pathology; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Mice; Mice, Knockout; Paracrine Communication; Proglucagon - genetics; Proglucagon - metabolism; prohormone convertase 1/3; Proprotein Convertases - genetics; Proprotein Convertases - metabolism; Signal Transduction; vertical sleeve gastrectomy; β cell
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.03.120

Bariatric surgery, such as vertical sleeve gastrectomy (VSG), causes high rates of type 2 diabetes remission and remarkable increases in postprandial glucagon-like peptide-1 (GLP-1) secretion. GLP-1 plays a critical role in islet function by potentiating glucose-stimulated insulin secretion; however, the mechanisms remain incompletely defined. Therefore, we applied a murine VSG model to an inducible β cell-specific GLP-1 receptor (GLP-1R) knockout mouse model to investigate the role of the β cell GLP-1R in islet function. Our data show that loss of β cell GLP-1R signaling decreases α cell GLP-1 expression after VSG. Furthermore, we find a β cell GLP-1R-dependent increase in α cell expression of the prohormone convertase required for the production of GLP-1 after VSG. Together, the findings herein reveal two concepts. First, our data support a paracrine role for α cell-derived GLP-1 in the metabolic benefits observed after VSG. Second, we have identified a role for the β cell GLP-1R as a regulator of α cell proglucagon processing. [Display omitted] •VSG increases α cell GLP-1 expression in a β cell GLP-1R-dependent manner•VSG increases α cell PC1/3 expression in a β cell GLP-1R-dependent manner•β cell GLP-1R signaling increases α cell PC1/3 expression and GLP-1 production The mechanisms by which GLP-1 enhances insulin secretion remain incompletely defined. Garibay et al. show that β cell GLP-1R signaling regulates α cell PC1/3 expression and GLP-1 production, pointing to an intra-islet paracrine positive feedback loop by which GLP-1-potentiated insulin secretion is amplified.