The relationship between Statins, the NLRP3 Inflammasome, and Type 2 Diabetes control. (360G-Wellcome-211426_Z_18_Z)

Recent reports have implicated statins in the risk of developing Type 2 Diabetes Mellitus (T2DM). Statins are very successful in the management of cardiovascular disease but can also alter the immune response. The immune altering abilities of statins are thought largely dependent on statin type and dose. The NLRP3 inflammasome appears to be a key regulator of statin-mediated alterations of immune function. Hyperglycaemia can activate NLRP3 and in macrophages leads to the production of IL-1beta, which exerts detrimental paracrine effects on pancreatic beta cells leading to apoptosis. The mechanism of action of statins in inducing the NLRP3 inflammasome and resultant beta cell death is yet to be fully elucidated. Furthermore, it is not known whether statin-induced NLRP3 activation is exacerbated under hyperglycaemic conditions. Statins have also been associated with poor response to sulphonylureas, a front line therapy for T2DM. Sulphonylureas act by blocking potassium efflux (leading eventually to insulin exocytosis from the beta cell), which is a major mechanism for NLRP3 activation. In this study, pancreatic beta cell lines and macrophages will be used to investigate the mechanisms of statin induced NLRP3 activation in vitro, and to determine if specific statins compete with sulphonylureas resulting in altered insulin secretion.