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

Abstract

SUMMARYBariatric 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.

Bariatric surgery normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice

“…In the HFD model, mild weight loss was observed at week ten post-operatively, yet glucose clearance rate increased significantly, as we have previously reported (16). These findings validate the metabolic phenotype of the VSG mouse model as reported in multiple studies (47,50). Of note, insulin sensitivity curves between lean and HFD mice were almost identical ( As an initial assessment of the glucocorticoid regulation following VSG, we measured circulating corticosterone in the early morning and late afternoon in all mice.…”

“…The two most widely used types of bariatric surgery are currently VSG and Roux-n-Y-Gastric-Bypass (46). Despite the similar metabolic outcomes between the two procedures, VSG is reported to have lower mortality in mice (47,48), but also allows for gradual weight regain, which is why it was chosen for this study (11,49). Both lean and HFD-induced hyperglycemic models were deployed in order to compare glucocorticoid responses to bariatric surgery in models of health and disease.…”

Impact of bariatric surgery on type 2 diabetes: contribution of inflammation and gut microbiome?

“…Rather than increase observed previously, a decrease in pancreatic β-cell mass was shown due to the reduction in pancreatic steatosis and decreased pancreatic insulin content, a phenomenon suggested to be linked to pancreas adaptation following weight loss. Similarly to heterogeneous findings in humans, animal model studies report either enhanced 101,102 or decreased 95,103,104…”

Sleeve gastrectomy rapidly enhances islet function independently of body weight

“…Transcripts for GLP-1 receptor (Glp1r), GIP receptor (Gipr), and glucagon receptor (Gcgr) -G-protein coupled receptors known to stimulate cAMP -are not modified in the islet (Supplemental Table 1), indicating that sensitivity to acute incretin stimuli may not be enhanced at the receptor expression level after VSG. However, the role of α-to β cell communication (i.e., α cell proglucagon products potentiating insulin release) remains unknown (52,53). Ultimately, these data demonstrate a unique remodeling of the islet transcriptomic profile by VSG, which may functionally potentiate Ca 2+ signaling and, subsequently, GSIS.…”