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

Hui Huang,Catherine B Chan,Paula Horn Zelmanovitz,Bradi R Lorenz

doi:10.3390/ijms22010421

Abstract

Prediabetes is a high-risk condition for type 2 diabetes (T2D). Pancreatic β-cells adapt to impaired glucose regulation in prediabetes by increasing insulin secretion and β-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 β-cell function and survival. Our previous study established the Nile rat (NR) as a model for prediabetes, recapitulating characteristics of human β-cell compensation in function and mass expansion. In this study, we investigated the action of metformin on β-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 β-cell glucose-stimulated insulin secretion in vitro, stimulation of β-cell insulin secretion was preserved in metformin-treated NRs via an indirect mechanism. Moreover, β-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 β-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 β-cell function or cell mass and, instead, early metformin treatment may help protect β-cells from exhaustion and decompensation.

Highlights

Prediabetes, a high-risk condition for type 2 diabetes (T2D), is defined by impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) [1]
Data collected in the Diabetes Prevention Program (DPP) outcomes study suggests that, other than lifestyle intervention, metformin is a cost-effective pharmaceutical option to delay the progression of T2D in prediabetic subjects [4,5,6]
In the intraperitoneal glucose tolerance test at six weeks, Nile rat (NR) on the chow diet (Chow) diet displayed a moderate impairment in glucose tolerance and a marked increase in insulin secretion, which confirms the presence of prediabetes in this model

Summary

Introduction

Prediabetes, a high-risk condition for T2D, is defined by impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) [1]. Much effort has been made to identify effective interventions to prevent or even reverse prediabetes conversion to T2D [3,4]. Data collected in the Diabetes Prevention Program (DPP) outcomes study suggests that, other than lifestyle intervention, metformin is a cost-effective pharmaceutical option to delay the progression of T2D in prediabetic subjects [4,5,6]. Metformin is a biguanide anti-diabetic medication that has been used to treat T2D for decades. It exerts its glucose-lowering effect by inhibiting hepatic glucose production and increasing glucose utilization [7]. Evidence from in vitro studies reveals that metformin protects β-cells from dysfunction and apoptosis against glucolipotoxicity [8,9,10,11]. With little evidence regarding in vivo metformin actions on β-cells during

Methods

Results

Conclusion