IG20/MADD gene functional isoform KIAA0358 can promote insulin secretion in glucose and...

Deletion of IG20 (also known as MADD), which can encode multiple isoforms, causes diabetes in mice by impairing glucose-stimulated insulin secretion. To evaluate the role of IG20 in mediating the therapeutic potential of glinide-class insulin secretagogues, we tested their effects in Ig20/Madd-knockout (KMA1ko) mice. Glucose tolerance tests revealed that repaglinide, mitiglinide, and nateglinide failed to lower blood glucose levels or enhance insulin secretion in KMA1ko mice, suggesting that IG20 deficiency significantly diminishes the therapeutic efficacy of glinides. The functional relevance of at least 6 IG20 isoforms remains to be defined. Interestingly, among the six IG20 splicing isoforms re-expressed in IG20-deficient Min6 cells, only KIAA0358 was capable of restoring glucose-stimulated insulin secretion. Notably, KIAA0358 re-expression also rescued repaglinide-induced insulin secretion in vivo. Further transmission electron microscopy and total internal reflection fluorescence microscopy analyses showed that KIAA0358 significantly promoted insulin granule transport and docking impaired by IG20 knockout. Furthermore, guanine nucleotide exchange assay and GST pull-down demonstrated that KIAA0358 functions as a Rab GEF to convert Rab3A and Rab27A from the GDP-bound to the active GTP-bound state, thereby restoring their interactions with the downstream effector proteins Rim2α and Slac-2a that were impaired by IG20 deficiency. Therefore, by regulating the activation states of Rab3A and Rab27A, KIAA0358 mediated the transport and docking of insulin granules to the plasma membrane. This study also highlights that the genes encoding non-drug target proteins can influence drug efficacy and provides a novel conceptual foundation for precision medicine strategies aimed at reducing drug resistance and enhancing the clinical efficacy of glinides.