MDM2 inhibitor nutlin-3a impairs glucose homeostasis and insulin secretion in mice

Abstract

Introduction: Mdm2, an E3 ubiquitin ligase, regulates the tumour suppressor p53 by enhancing its proteasomemediated degradation through the protein-protein interaction. A small molecule Nutlin-3a has been shown to disrupt the interaction between p53 and MDM2, thereby up-regulating expression of p53 in cancer cells. Therefore, this small molecular represents a promising therapeutic agent for cancer. However, the effect of nutlin-3a on glucose homeostasis has never been explored so far. In this study, we aimed to investigate whether nutlin-3a affects glucose metabolism using both in-vivo and in-vitro approaches. Methods: Twelve-week male C57BL/6 mice were treated with nutlin-3 or DMSO (as a vehicle control) by oral gavage 2 hours before the experiment. Glucose tolerance and insulin sensitivity were assessed by intraperitoneal glucose tolerance test (GTT) or insulin tolerance test (ITT). Insulin secretion during GTT was examined. Effect of nutlin-3a on glucose or non-glucose secretagogues-stimulated insulin secretion was determined in mouse pancreatic islets and beta cell lines. Results: The mice treated with nutlin-3 exhibited glucose intolerance which is accompanied with blunted insulin secretion, but similar insulin sensitivity compared to the DMSO control group. Further analysis revealed that beta cells treated with nutlin-3a exhibited impairment of glucose-stimulated insulin secretion (GSIS), which was associated with diminished ATP production and calcium influx. Furthermore, nutlin-3a treatment also suppresses insulin secretion induced by non-glucose secretagogues, including the mitochondria activators, the potassium channel blockers and the cell membrane depolarisation agents. Conclusion: These findings demonstrated that disruption of the interaction between MDM2 and p53 by nutlin-3 leads to glucose intolerance, owing to defective insulin secretory capacity. Such inhibitory effects on insulin secretion may attribute to impaired glucose metabolism, mitochondria activation and/or calcium mobilisation.