Study On The Mechanism Of Stress Granules Involved In The Effect Of Saturated Fatty Acids On The Beta Cell Function

PurposeProgressive degeneration of pancreatic islet beta cell function is considered to be the central pathological mechanism of type 2 diabetes(T2DM),which is the main type of diabetes.Studies have shown that prolonged exposure to saturated fatty acids(SFAs)impedes glucose-stimulated insulin secretion(GSIS),impairs insulin gene expression and increases apoptosis in beta cell.Pancreatic and duodenal homeobox 1(PDX1)is the main modulator of insulin transcription and secretion.In the presence of pathological levels of SFAs,PDX1 fails to localize in the nucleus,which may account for beta cell dysfunction in T2 DM.Stress granules(SGs)are membraneless dense particulate matter formed in the cytoplasm when eukaryotic cells respond to stimulation such as oxidative stress,viral infection and arsenate.The study revealed that many nucleocytoplasmic transport factors are localized to SGs following exposure to stress,resulting in damaged nucleocytoplasmic transport.In this study,we investigated whether SGs could form in beta cell and the effects of SGs on PDX1 localisation and beta cell function,to explore the mechanism of beta cell dysfunction induced by palmitic acid(PA;C16:0).Methods(1)The effect of PA on cytoplasmic transport was studied using S-tdTomato and S-GFP reporters.(2)The assembly of SGs in INS1 cells of rat insulinoma cell line was analyzed by immunofluorescence and western blotting.(3)SGs Protein composition were identified by mass spectrometry.(4)The localization of PDX1 and beta cell function were investigated after specific inhibitors were used to inhibit or knock down the proteins necessary for SGs formation.Results(1)PA is an endogenous stressor that disrupts PDX1 nucleocytoplasmic transport.(2)PA induces the formation of SGs,and both PDX1 and nucleocytoplasmic transport factors are sequestered in SGs.(3)Inhibition of SGs formation rescues PA-induced beta cell dysfunction.(4)PI3K is involved in the formation of PA-induced SGs.ConclusionPA inhibits GSIS by disrupting nucleocytoplasmic transport and detaining PDX1 in SGs,suggesting that there is a link between SGs formation and SFAs-induced beta cell dysfunction.Preventing SG formation may be a potential therapeutic strategy for treating T2 DM.