Mesenchymal Stem Cells Ameliorate Mitochondrial Dysfunction in α - cells and Hyperglucagonemia in type 2 Diabetes via SIRT1/FoxO3a Signaling

Abstract Background: Dysregulation of α-cells results in hyperglycemia and hyperglucagonemia in type 2 diabetes mellitus (T2DM). Mesenchymal stem cell (MSC)-based therapy increases oxygen consumption of islets and enhances insulin secretion. However, the underlying mechanism for the protective role of MSCs in α- cell mitochondrial dysfunction remains unclear. Here, we evaluated the efficacy and molecular mechanisms of human umbilical cord MSCs (hucMSCs) on α-cell mitochondrial function and glucagon secretion in T2DM.Methods: hucMSCs were used to treat two kinds of T2DM mice and αTC1-6 cells to explore the role of hucMSCs in improving α-cell mitochondrial dysfunction and hyperglucagonemia. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay (ELISA). Mitochondrial function of α-cells was assessed by the Seahorse Analyzer. To investigate the underlying mechanisms, Sirtuin 1 (SIRT1), Forkhead box O3a (FoxO3a), glucose transporter type1 (GLUT1), and glucokinase (GCK) were assessed by western blotting analysis.Results: In vivo, hucMSC infusion improved glucose and insulin tolerance, as well as hyperglycemia and hyperglucagonemia in T2DM mice. Meanwhile, hucMSC intervention rescued islet structure and decreased α- to β-cell ratio. Consistently, glucagon secretion from αTC1-6 cells was inhibited by hucMSCs in vitro. Meanwhile, hucMSC treatment activated intracellular SIRT1/FoxO3a signaling, promoted glucose uptake and activation, alleviated mitochondrial dysfunction, and enhanced ATP production. However, transfection of SIRT1 small interfering RNA (siRNA) or the application of SIRT1 inhibitor EX-527 weakened the therapeutic effects of hucMSCs on mitochondrial function and glucagon secretion.Conclusions: Our observations indicate that hucMSCs mitigate mitochondrial dysfunction and glucagon hypersecretion of α-cells in T2DM via SIRT1/FoxO3a signaling, which provides novel evidence demonstrating the potential for hucMSCs in treating T2DM.