Deletion of IRS-1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in rats
Abstract Insulin receptor substrate (IRS)-1 and IRS-2 are major molecules that transduce signals from insulin and insulin-like growth factor-I receptors. The physiological functions of these proteins have been intensively investigated in mice, while little is known in other animals. Our previous stu...
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Nature Portfolio
2025-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-84234-1 |
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| author | Yuka Toyoshima Katsuyuki Nakamura Yusuke Taguchi Reiko Tokita Shiho Takeuchi Hayato Osawa Naomi Teramoto Hidetoshi Sugihara Fumiaki Yoshizawa Keitaro Yamanouchi Shiro Minami |
| author_facet | Yuka Toyoshima Katsuyuki Nakamura Yusuke Taguchi Reiko Tokita Shiho Takeuchi Hayato Osawa Naomi Teramoto Hidetoshi Sugihara Fumiaki Yoshizawa Keitaro Yamanouchi Shiro Minami |
| author_sort | Yuka Toyoshima |
| collection | DOAJ |
| description | Abstract Insulin receptor substrate (IRS)-1 and IRS-2 are major molecules that transduce signals from insulin and insulin-like growth factor-I receptors. The physiological functions of these proteins have been intensively investigated in mice, while little is known in other animals. Our previous study showed that the disruption of IRS-2 impairs body growth but not glucose tolerance or insulin sensitivity in rats, which led us to hypothesize that IRS-1 plays more pivotal roles in insulin functions than IRS-2. Here, we created IRS-1 knockout (KO) rats to elucidate the physiological roles of IRS-1 in rats. The body weight of IRS-1 KO rats at birth was lower than that of wild-type (WT) littermates, and postnatal growth of IRS-1 KO rats was severely impaired. Compared with WT rats, IRS-1 KO rats displayed insulin resistance but maintained euglycemia because of compensatory hyperinsulinemia. In addition, despite the increased activity of insulin-stimulated IRS-2-associated phosphatidylinositol-3 kinase (PI3K), insulin-induced phosphorylation of the kinases downstream of PI3K was suppressed in the liver and skeletal muscle of IRS-1 KO rats. Taken together, these results indicate that in rats, IRS-1 is essential for normal growth and the glucose-lowering effects of insulin. IRS-1 appears to be more important than IRS-2 for insulin functions in rats. |
| format | Article |
| id | doaj-art-f4b1f466c66a43c6ae9f9036fc96b8d9 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-f4b1f466c66a43c6ae9f9036fc96b8d92025-01-12T12:19:25ZengNature PortfolioScientific Reports2045-23222025-01-0115111510.1038/s41598-024-84234-1Deletion of IRS-1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in ratsYuka Toyoshima0Katsuyuki Nakamura1Yusuke Taguchi2Reiko Tokita3Shiho Takeuchi4Hayato Osawa5Naomi Teramoto6Hidetoshi Sugihara7Fumiaki Yoshizawa8Keitaro Yamanouchi9Shiro Minami10Department of Agrobiology and Bioresources, School of Agriculture, Utsunomiya UniversityLaboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of TokyoDepartment of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical SchoolDepartment of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical SchoolLaboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of TokyoDepartment of Agrobiology and Bioresources, School of Agriculture, Utsunomiya UniversityLaboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of TokyoLaboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of TokyoDepartment of Agrobiology and Bioresources, School of Agriculture, Utsunomiya UniversityLaboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of TokyoDepartment of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical SchoolAbstract Insulin receptor substrate (IRS)-1 and IRS-2 are major molecules that transduce signals from insulin and insulin-like growth factor-I receptors. The physiological functions of these proteins have been intensively investigated in mice, while little is known in other animals. Our previous study showed that the disruption of IRS-2 impairs body growth but not glucose tolerance or insulin sensitivity in rats, which led us to hypothesize that IRS-1 plays more pivotal roles in insulin functions than IRS-2. Here, we created IRS-1 knockout (KO) rats to elucidate the physiological roles of IRS-1 in rats. The body weight of IRS-1 KO rats at birth was lower than that of wild-type (WT) littermates, and postnatal growth of IRS-1 KO rats was severely impaired. Compared with WT rats, IRS-1 KO rats displayed insulin resistance but maintained euglycemia because of compensatory hyperinsulinemia. In addition, despite the increased activity of insulin-stimulated IRS-2-associated phosphatidylinositol-3 kinase (PI3K), insulin-induced phosphorylation of the kinases downstream of PI3K was suppressed in the liver and skeletal muscle of IRS-1 KO rats. Taken together, these results indicate that in rats, IRS-1 is essential for normal growth and the glucose-lowering effects of insulin. IRS-1 appears to be more important than IRS-2 for insulin functions in rats.https://doi.org/10.1038/s41598-024-84234-1 |
| spellingShingle | Yuka Toyoshima Katsuyuki Nakamura Yusuke Taguchi Reiko Tokita Shiho Takeuchi Hayato Osawa Naomi Teramoto Hidetoshi Sugihara Fumiaki Yoshizawa Keitaro Yamanouchi Shiro Minami Deletion of IRS-1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in rats Scientific Reports |
| title | Deletion of IRS-1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in rats |
| title_full | Deletion of IRS-1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in rats |
| title_fullStr | Deletion of IRS-1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in rats |
| title_full_unstemmed | Deletion of IRS-1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in rats |
| title_short | Deletion of IRS-1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in rats |
| title_sort | deletion of irs 1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in rats |
| url | https://doi.org/10.1038/s41598-024-84234-1 |
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