Imeglimin preserves islet β-cell mass in Type 2 diabetic ZDF rats

Objectives Type 2 diabetes (T2D) is driven by progressive dysfunction and loss of pancreatic beta-cell mass. Imeglimin is a first-in-class novel drug candidate that improves glycaemia and glucose-stimulated insulin secretion in preclinical models and patients. Given evidence that imeglimin can attenuate beta-cell dysfunction and protect beta cells in vitro, we postulated that imeglimin could also exert longer term effects to prevent pancreatic beta-cell death and preserve functional beta-cell mass in vivo. Methods Zucker diabetic fatty (ZDF) male rats were treated by oral gavage with imeglimin at a standard dose of 150 mg/kg or vehicle, twice daily for five weeks. At treatment completion, oral glucose tolerance tests were performed in fasted animals before a thorough histomorphometry and immunohistochemical analysis was conducted on pancreas tissue slices to assess cellular composition and disease status. Results Imeglimin treatment significantly improved glucose-stimulated insulin secretion (augmentation of the insulinogenic index) and improved glycaemia. Both basal insulinaemia and pancreatic insulin content were also increased by imeglimin. In ZDF control rats, islet structure was disordered with few beta-cells; after imeglimin treatment, islets appeared healthier with more normal morphology in association with a significant increase in insulin-positive beta-cells. The increase in beta-cell mass was associated with a greater degree of beta-cell proliferation in the presence of reduced apoptosis. Unexpectedly, a decrease in as a alpha-cell mass was also documented due to an apparent antiproliferative effect of imeglimin on this cell type. Conclusion In male ZDF rats, chronic imeglimin treatment corrects a paramount component of type 2 diabetes progression: progressive loss of functional beta-cell mass. In addition, imeglimin may also moderate a-cell turnover to further ameliorate hyperglycaemia. Cumulatively, these cellular effects suggest that imeglimin may provide for disease modifying effects to preserve functional beta-cell mass.