Study On The Mechanism Of KIAA0358 Regulating Glucose-Stimulated Insulin Secretion In Pancreatic Beta-Cells

Type 2 diabetes is a major chronical disease threatening human health.Its clinical manifestations are mainly insulin secretion defect and insulin resistance.It is of great significance to find out the specific pathogenesis of diabetes and then carry out targeted treatment.MADD/IG20 inhibits glucose-stimulated insulin secretion(GSIS),but the mechanism is not clear.In this study,conditioned knockout Madd/Ig20(KMA1 ko)of C57BL/6 mice and CRISPR-Cas9 knockout Madd/Ig20 of mouse pancreatic tumor Min6 cells(Min6Ig20)were as study subjects.Through high glucose stimulation,it was found that the absence of Madd/Ig20 not only inhibit the secretion of GSIS in the first phase,but also inhibit the secretion of GSIS in the second phase.We stimulated KMA1 ko mice and Min6Ig20 cell with the insulin secretagogues repaglinide targeting potassium channels and found that:After absence of Madd/Ig20 the repaglinide does not promote insulin secretion.It is concluded that the regulation of GSIS by MADD/IG20 may be downstream of KATP channel.There are at least six splicing isomers of MADD/IG20,KIAA0358 has the longest sequence of known splicing isomers and containing all the structures of other splicing isomers.At present,it is known that KIAA0358 is the guanosine exchange factor(GEF)of Rab3A,which has regulatory effects on the transport of insulin granules and membrane fusion.We hypothesized that KIAA0358 plays a major role in the regulation of GSIS,so we conducted a rescue experiment and proved this view.However,the absence of MADD/IG20 has a significantly stronger inhibitory effect on insulin secretion than the absence of Rab3A,so we have reasons to believe that KIAA0358 has a regulatory effect on other proteins to regulate insulin secretion.Follow-up studies in this subject will focus on KIAA0358 regulating GSIS through the regulation of other proteins.This study revealed the regulatory mechanism of MADD/IG20 on GSIS,and further proved the role of KIAA0358 on GSIS,which has certain reference significance for the treatment of diabetes.