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IG20/MADD gene functional isoform KIAA0358 can promote glucose and insulin secretion in repaglinide-induced pancreatic β-cells

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

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.

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Fig. 1: KIAA0358 associates with insulin granules, and knockout of IG20 induces hyperglycemia.
Fig. 2: Nateglinide, mitiglinide or repaglinide treatment failed to rescue glucose-stimulated insulin secretion in KMA1ko mice.
Fig. 3: KMA1ko mouse islets exhibited defective insulin secretion in response to glucose and repaglinide stimulation.
Fig. 4: KIAA0358 expression rescues the reduced insulin secretion induced by IG20 knockout under glucose and repaglinide stimulation.
Fig. 5: KIAA0358 restores the reduction in insulin exocytosis caused by IG20 deficiency.
Fig. 6: Restoration of KIAA0358 can restore insulin secretion and transport and anchoring of insulin granules to the PM of KMA1ko mice.
Fig. 7: KIAA0358 functions as a Rab GEF to activate Rab3A and Rab27A.
Fig. 8: Model of KIAA0358 functional mechanism in β cells. KIAA0358, a functional splice variant of IG20, serves as a Rab GEF that regulates the activation of Rab3A and Rab27A.

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Acknowledgements

This work was supported in part by the National Natural Science Foundation of China (82073908) to LCL. We thank Li-juan Wang for making Ad-vector and Ad-KIAA0358, and Zhi-yu Liu for generating the anti-mouse KIAA0358 antibody. The authors appreciate the technical assistance by Jun-jie Chen, Ye Yun, from the School of Pharmaceutical Sciences, Xiamen University, and Ya-ying Wu, Qing-feng Liu, from the School of Life Sciences, Xiamen University.

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Authors and Affiliations

  1. Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China

    Yi Sui, Zhao-lei Weng, Li-xia Qian, Wan-jin Hong & Liang-cheng Li

  2. Institute of Molecular and Cell Biology (IMCB), Singapore, 138673, Singapore

    Wan-jin Hong

  3. Scientist Jesse Brown VA Medical Center, Chicago, IL, USA

    Bellur S. Prabhakar

  4. Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Bellur S. Prabhakar

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  1. Yi Sui
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  2. Zhao-lei Weng
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  3. Li-xia Qian
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  4. Wan-jin Hong
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  5. Bellur S. Prabhakar
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  6. Liang-cheng Li
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Contributions

YS designed, conducted the experiments, and drafted the manuscript. ZLW was involved in the investigation and data curation. LXQ analysed the data. BSP, WJH, and LCL conceived the project, designed the experiments, reviewed the results and edited the manuscript.

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Correspondence to Wan-jin Hong, Bellur S. Prabhakar or Liang-cheng Li.

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Sui, Y., Weng, Zl., Qian, Lx. et al. IG20/MADD gene functional isoform KIAA0358 can promote glucose and insulin secretion in repaglinide-induced pancreatic β-cells. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-026-01759-z

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