The selective NOX4 inhibitor GLX7013159 decreases blood glucose concentrations and human beta-cell apoptotic rates in diabetic NMRI nu/nu mice transplanted with human islets

NADPH oxidase 4 (NOX4) inhibition has been reported to mitigate diabetes induced beta-cell dysfunction and improve survival in vitro, as well as counteract high fat diet induced glucose intolerance in mice. We investigated the anti-diabetic effects of the selective NOX4 inhibitor GLX7013159 in vivo in athymic diabetic mice transplanted with human islets over a period of 4 weeks.The GLX7013159-treated mice achieved lower blood glucose and water consumption throughout the treatment period. Furthermore, GLX7013159 treatment resulted in improved insulin and c-peptide levels, better insulin secretion capacity, as well as in greatly reduced apoptotic rates of the insulin-positive human cells, measured as co-localization of insulin and cleaved caspase-3. We conclude that the anti-diabetic effects of NOX4 inhibition by GLX7013159 are observed also during a prolonged study period in vivo, and are likely to be due to an improved survival and function of the human beta-cells.