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

摘要

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 p-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of p-cell GLP-1 receptor (GLP-1 R) 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, (i-cell-specific Glpir 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. Glpir knockdown in p-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 p-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 p-cell GLP-1 signaling in obesity.