Enhanced Glucose Control Following Vertical Sleeve Gastrectomy Does Not Require a β-Cell Glucagon-Like Peptide 1 Receptor

Abstract

Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in great part because of the ∼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct β-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of β-cell GLP-1 receptor (GLP-1R) for improving glucose control after VSG, a mouse model of this procedure was developed and combined with a genetically modified mouse line allowing an inducible, β-cell-specific Glp1r knockdown (Glp1r^β-cell-ko). Mice with VSG lost ∼20% of body weight over 30 days compared with sham-operated controls and had a ∼60% improvement in glucose tolerance. Isolated islets from VSG mice had significantly greater insulin responses to glucose than controls. Glp1r knockdown in β-cells caused glucose intolerance in diet-induced obese mice compared with obese controls, but VSG improved glycemic profiles to similar levels during oral and intraperitoneal glucose challenges in Glp1r^β-cell-ko and Glp1r^WT mice. Therefore, even though the β-cell GLP-1R seems to be important for maintaining glucose tolerance in obese mice, in these experiments it is dispensable for the improvement in glucose tolerance after VSG. Moreover, the metabolic physiology activated by VSG can overcome the deficits in glucose regulation caused by lack of β-cell GLP-1 signaling in obesity.

Figure 1

Validation of mouse model for VSG. Body weight (A) along with glucose curve (B), integrated glucose AUC (C), and circulating insulin concentration at time points 0 and 20 min (D) during an IPGTT for animals subjected to sham surgery (red), VSG (blue), or pair-feeding regimen (black). Data are presented as mean ± SEM. *P < 0.05 compared with pair-fed controls or as indicated. #P < 0.05 compared with sham-operated group.

Figure 2

Effect of VSG on ex vivo insulin secretion. GSIS from isolated islets in ex vivo static culture represented as absolute insulin concentration in ng/mL (A) and as the ratio of insulin secretion from 15 mmol/L to 3 mmol/L glucose (B). Total islet insulin content is also presented (C). Animals in these experiments were subjected to either sham surgery (red), VSG (blue), or pair-feeding regimen (black). Data are presented as mean ± SEM. *P < 0.05 compared with pair-fed controls or as indicated. #P < 0.05 between Sham-AL and VSG groups.

Figure 3

Response to mixed nutrient gavage following VSG. Glucose curve (A) and integrated glucose AUC (B) following a mixed nutrient gavage (12 cal/g body weight Ensure Plus). Circulating insulin (C) and GLP-1 (D) concentration at time points 0 and 10 min are also shown. Animals were subjected to either a sham operation and pair-feeding regimen (black) or VSG (blue). Data are presented as mean ± SEM. *P < 0.05 compared with pair-fed controls.

Figure 4

Glucose curve (A) and AUC (B) for mice that are either Glp1r^WT (closed squares) or Glp1r^β-cell-ko (open squares) after 12 weeks on HFD. C: Body weights. Arrow denotes time of glucose tolerance testing. D–F: Glucose curves during an OGTT for Glp1r^WT (D) or Glp1r^β-cell-ko (E) mice given either sham (solid black line) or VSG (dashed blue line) operation, and glucose AUCs (F) for these OGTTs. G–I: Glucose curves during an IPGTT for Glp1r^WT (G) or Glp1r^β-cell-ko (H) mice given either sham (solid black line) or VSG (dashed blue line) operation, and glucose AUCs (I) for these IPGTTs. Data are presented as mean ± SEM. KO, knockout; WT, wild type. *P < 0.05 compared with sham-operated controls or as indicated.