RESUMEN
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 â¼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct ß-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of ß-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, ß-cell-specific Glp1r knockdown (Glp1rß-cell-ko). Mice with VSG lost â¼20% of body weight over 30 days compared with sham-operated controls and had a â¼60% improvement in glucose tolerance. Isolated islets from VSG mice had significantly greater insulin responses to glucose than controls. Glp1r knockdown in ß-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 Glp1rß-cell-ko and Glp1rWT mice. Therefore, even though the ß-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 ß-cell GLP-1 signaling in obesity.
Asunto(s)
Modelos Animales de Enfermedad , Gastroplastia , Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Intolerancia a la Glucosa/prevención & control , Células Secretoras de Insulina/metabolismo , Obesidad/cirugía , Animales , Dieta Alta en Grasa/efectos adversos , Péptido 1 Similar al Glucagón/sangre , Receptor del Péptido 1 Similar al Glucagón/genética , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Intolerancia a la Glucosa/etiología , Hipoglucemiantes/farmacología , Insulina/sangre , Insulina/metabolismo , Insulina/farmacología , Resistencia a la Insulina , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Obesidad/sangre , Obesidad/metabolismo , Obesidad/fisiopatología , Especificidad de Órganos , Transducción de Señal/efectos de los fármacos , Técnicas de Cultivo de Tejidos , Pérdida de PesoRESUMEN
Glucagon-like peptide-1 (GLP-1), an insulinotropic gut peptide released after eating, is essential for normal glucose tolerance (GT). To determine whether this effect is mediated directly by GLP-1 receptors (GLP1R) on islet ß cells, we developed mice with ß cell-specific knockdown of Glp1r. ß cell Glp1r knockdown mice had impaired GT after intraperitoneal (i.p.) glucose and did not secrete insulin in response to i.p. or intravenous GLP-1. However, they had normal GT after oral glucose, a response that was impaired by a GLP1R antagonist. ß cell Glp1r knockdown mice had blunted responses to a GLP1R agonist but intact glucose lowering with a dipeptidylpeptidase 4 (DPP-4) inhibitor. Thus, in mice, ß cell Glp1rs are required to respond to hyperglycemia and exogenous GLP-1, but other factors compensate for reduced GLP-1 action during meals. These results support a role for extraislet GLP1R in oral glucose tolerance and paracrine regulation of ß cells by islet GLP-1.