Metformin Preserves ß-Cell Compensation in Insulin Secretion and Mass Expansion in Prediabetic Nile Rats.

ABSTRACT

Prediabetes is a high-risk condition for type 2 diabetes (T2D). Pancreatic ß-cells adapt to impaired glucose regulation in prediabetes by increasing insulin secretion and ß-cell mass expansion. In people with prediabetes, metformin has been shown to prevent prediabetes conversion to diabetes. However, emerging evidence indicates that metformin has negative effects on ß-cell function and survival. Our previous study established the Nile rat (NR) as a model for prediabetes, recapitulating characteristics of human ß-cell compensation in function and mass expansion. In this study, we investigated the action of metformin on ß-cells in vivo and in vitro. A 7-week metformin treatment improved glucose tolerance by reducing hepatic glucose output and enhancing insulin secretion. Although high-dose metformin inhibited ß-cell glucose-stimulated insulin secretion in vitro, stimulation of ß-cell insulin secretion was preserved in metformin-treated NRs via an indirect mechanism. Moreover, ß-cells in NRs receiving metformin exhibited increased endoplasmic reticulum (ER) chaperones and alleviated apoptotic unfold protein response (UPR) without changes in the expression of cell identity genes. Additionally, metformin did not suppress ß-cell mass compensation or proliferation. Taken together, despite the conflicting role indicated by in vitro studies, administration of metformin does not exert a negative effect on ß-cell function or cell mass and, instead, early metformin treatment may help protect ß-cells from exhaustion and decompensation.