Role of lipid droplets and FITM2 in beta-cell physiology and pathophysiology

Hyperlipidemia is a known driving factor of T2DM, with saturated fatty acids (SFAs) pinpointed as the causation of β cell failure. Hence, intracellular handling of these SFAs, in β cells, was thought to be vital in preventing the loss of its function. The biogenesis of lipid droplets (LDs) forms an important arm of lipid handling as the ability to safely sequester these toxic fatty acids as neutral lipids would prevent the harmful effects of SFAs. In our study, we found that loss of FITM2, a protein essential of LD biogenesis, resulted in poor glycemic control β cell function in mice. Further delineation of SFA effects on FITM2 revealed an induction of degradation of FITM2 through S-palmitoylation and ERAD-C pathway. Lastly, every-other-day fasting (EODF) was shown to promote the stability of FITM2 and prevent SFA-induced lipotoxicity, hence suggesting the possibility of EODF as a potential therapeutic intervention for T2DM.Doctor of Philosoph