Cisplatin exposure dysregulates pancreatic islet function in male mice

Cancer survivors have an increased risk of developing new-onset Type 2 diabetes compared to the general population. Moreover, patients treated with cisplatin, a commonly used chemotherapeutic agent, are more likely to develop metabolic syndrome and Type 2 diabetes compared to age- and sex-matched controls. Insulin-secreting β-cells—located within pancreatic islets—are critical for maintaining glucose homeostasis, and dysregulated insulin secretion is central to Type 2 diabetes pathophysiology. Surprisingly, the impact of cisplatin treatment on pancreatic islets has not been reported. In this study, we aimed to determine if murine islet function is adversely affected by direct or systemic exposure to cisplatin. In vivo cisplatin exposure led to deficits in glucose-stimulated insulin secretion in both male and female mice. In vitro cisplatin exposure to both male and female mouse islets profoundly dysregulated insulin release and reduced oxygen consumption in a non-sex specific manner. Male mouse islets exposed to cisplatin had altered the expression of genes related to insulin production, oxidative stress, and the Bcl-2 family and numerous DEGs related to the insulin secretion pathway. Our data suggest both direct and systemic cisplatin exposure cause acute defects in insulin secretion and may have lasting effects on islet health in mice. To investigate the effects of cisplatin on gene expression, pancreatic islets were isolated from 3 male C57Bl/6 mice. Half of the islets isolated from each mouse were treated with vehicle control, and the other half with 10 uM cisplatin for 48 hours, leading to 3 biological replicates per treatment group. Islets were then collected for TempO-Seq analysis.