Puerarin ameliorates hyperglycemia in HFD diabetic mice by promoting β-cell neogenesis via GLP-1R signaling activation

Diabetes is characterized by β-cell loss and dysfunction. A strategy for diabetes treatment is to promote new β-cell formation. Puerarin is an isoflavone from the root of Pueraria lobata (Willd.) Ohwi. Our previous study demonstrated puerarin could ameliorate hyperglycemia in diabetic mice. However, related mechanisms and potential roles of puerarin in β-cell neogenesis have not been elucidated. The present study aims to investigate whether anti-diabetic effect of puerarin is dependent on promoting β-cell neogenesis via GLP-1R signaling activation. A high-fat diet (HFD) induced diabetic mouse model was applied to investigate effects of puerarin in vivo, exendin-4 (GLP-1R agonist) and metformin were used as positive controls. Moreover, related mechanisms and GLP-1R downstream signal transduction were explored in isolated cultured mouse pancreatic ductal cells. Puerarin improved glucose homeostasis in HFD diabetic mice significantly. Markers of new β-cell formation (insulin, PDX1 and Ngn3) were observed in pancreatic ducts of HFD mice treated by puerarin. Of note, efficacy of puerarin in vivo was suppressed by GLP-1R antagonist exendin9-39, but enhanced by exendin-4 respectively. In cultured mouse pancreatic ductal cells, puerarin induced expressions of insulin and PDX1, upregulated GLP-1R expression and activated β-catenin and STAT3 subsequently. Expressions of insulin and PDX1 in ductal cells could be blocked by exendin9-39, or β-catenin inhibitor ICG001, or JAK2 inhibitor AG490. These data clarified puerarin ameliorated hyperglycemia of HFD mice via a novel mechanism involved promoting β-cell neogenesis. Our finding highlights the potential value of puerarin developing as an anti-diabetic agent.