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Ras-related C3 botulinum toxin substrate 1 (RAC1) regulates glucose-stimulated insulin secretion via modulation of F-actin |
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| Authors: | S Asahara Y Shibutani K Teruyama H Y Inoue Y Kawada H Etoh T Matsuda M Kimura-Koyanagi N Hashimoto M Sakahara W Fujimoto H Takahashi S Ueda T Hosooka T Satoh H Inoue M Matsumoto A Aiba M Kasuga Y Kido |
| Institution: | 1. Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan 2. Division of Medical Chemistry, Kobe University Graduate School of Health Sciences, Kobe, 654-0142, Japan 3. Cancer Institute, Japanese Foundation of Cancer Research, Tokyo, Japan 4. Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan 5. Kobe University Graduate School of Agricultural Science, Kobe, Japan 6. Division of Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan 7. Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan 8. Research Institute, National Center for Global Health and Medicine, Tokyo, Japan 9. Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan |
| Abstract: | Aims/hypothesisThe small G-protein ras-related C3 botulinum toxin substrate 1 (RAC1) plays various roles in mammalian cells, such as in the regulation of cytoskeletal organisation, cell adhesion, migration and morphological changes. The present study examines the effects of RAC1 ablation on pancreatic beta cell function.MethodsIsolated islets from pancreatic beta cell-specific Rac1-knockout (betaRac1 ?/?) mice and RAC1 knockdown INS-1 insulinoma cells treated with small interfering RNA were used to investigate insulin secretion and cytoskeletal organisation in pancreatic beta cells.ResultsBetaRac1 ?/? mice showed decreased glucose-stimulated insulin secretion, while there were no apparent differences in islet morphology. Isolated islets from the mice had blunted insulin secretion in response to high glucose levels. In RAC1 knockdown INS-1 cells, insulin secretion was also decreased in response to high glucose levels, consistent with the phenotype of betaRac1 ?/? mice. Even under high glucose levels, RAC1 knockdown INS-1 cells remained intact with F-actin, which inhibits the recruitment of the insulin granules, resulting in an inhibition of insulin secretion.Conclusions/interpretationIn RAC1-deficient pancreatic beta cells, F-actin acts as a barrier for insulin granules and reduces glucose-stimulated insulin secretion. |
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