Imeglimin Ameliorates β-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway

The effects of imeglimin, a novel antidiabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression o f endoplasmic reticulum (ER)–related molecules, includingChop (Ddit3),Gadd34 (Ppp1r15a),Atf3, andSdf2l1, and decreased eIF2 α phosphorylation after treatment with thapsigargin and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect against ER stress–induced β-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a signifi cant decrease in the number of apoptotic β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell–derived β-like cells. Taken together, imeglimin modulates the ER homeostasis pathway, which results i n the prevention of β-cell apoptosis both in vitro and in vivo.
Source: Diabetes - Category: Endocrinology Source Type: research