Sleeve gastrectomy activates the GLP-1 pathway in pancreatic β cells and promotes GLP-1-expressing cells differentiation in the intestinal tract.

Db/db mouse was used to study the underlying mechanisms by which Sleeve gastrectomy (SG) improves β-cell function. We investigated β-cell function, plasma active GLP-1 levels, the GLP-1R pathway in β cells and L cell differentiation. After SG, β-cell function was significantly increased, and the GLP-1R-PKCζ-PDX-1 pathway was active in β cells. Plasma active GLP-1 levels, as well as the number of L cells in the jejunum, were significantly increased after SG. The expression of early transcription factors (TF), including Ngn3, FoxA1 and Nkx2.2, was not compromised by chronic hyperglycemia. In contrast, the expression of the downstream TF PAX6 was affected, and this down-regulation could be reversed by SG. So, SG can maintain L cell differentiation, increase plasma active GLP-1 level, sustain the activation of the GLP-1R pathway and improve β cell function in Db/db mice. Our results show that SG can overall improve the function of the entero-insular axis.