GPCR-Dependent IP6K1 Phosphorylation Function In Regulation Of Insulin Secretion

Insulin,a peptide hormone synthesized and secreted by beta cells of the pancreatic islets,exerts its function in tightly regulating blood glucose concentration and thus reaching glucose homeostasis.One of the primary reasons for diabetes mellitus is the abnormal blood insulin levels.Inositol hexaphosphate(IP6)is an abundant endogenous metabolite that can be diphosphorylated by inositol hexaphosphate kinase(IP6Ks),generating inositol pyrophosphate(IP7).It is reported that IP6K1 and IP7 can promote the exocytotic ability of pancreatic beta cells.Besides,mice with IP6K1 deletion display low serum insulin levels.These results together indicate that IP6K1 play a role in regulating insulin homeostasis.However,the mechanism of which is still unclear.Inspired by the identification of IP6K1 phosphorylation sites from protein post-transcriptional modification databases,this thesis examined the hypothesis that phosphorylation regulates IP6K1 enzyme activity,with change in IP7 levels,improving the exocytosis of pancreatic beta cells.To validate the hypothesis,we set up in vitro and in vivo systems to detect the influence of phosphorylation to IP6K1 enzyme activity.We then employed HEK293,Ins-IE and C57/BL27 mice as models to investigate the stimulus that triggers physiologic IP6K1 phosphorylation and signaling pathway involved.Based on these findings,we figured out whether the stimulus is from nerve system,and the findings suggest that IP6K1 mediates exocytotic activities controlled by parasympathetic innervation.The data showed that parasympathetic system receives input from the dorsal motor nucleus of vagus(DMV),which,through the vagus nerve,leads to acetylcholine release in pancreatic islets when the body needs more insulin to maintain glucose homeostasis.The acetycholine are recognized by M3R on beta cell surface to initiate the M3R-Gq/i1-PLC-DAG-nPKC-IP6Kl signaling pathway,promoting IP6K1 phosphorylation,enhancing its enzyme activity and thus producing more IP7.This axis of signaling events culminates on insulin secretion.Such neural regulation of insulin secretion works with glucose-triggered insulin secretion,maintaining physiological glucose homeostasis.