Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function
Abstract We aimed to determine the mechanism by which the sodium glucose co-transporter 2 inhibitor, luseogliflozin, preserves pancreatic beta-cell mass and function in db/db mice. Six-week-old db/db mice were fed to standard chow or standard chow containing 0.01% luseogliflozin. After 4 weeks, DNA...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-13888-6 |
| _version_ | 1811343652454137856 |
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| author | Yuki Yamauchi Akinobu Nakamura Takashi Yokota Kiyohiko Takahashi Shinichiro Kawata Kazuhisa Tsuchida Kazuno Omori Hiroshi Nomoto Hiraku Kameda Kyu Yong Cho Toshihisa Anzai Shinya Tanaka Yasuo Terauchi Hideaki Miyoshi Tatsuya Atsumi |
| author_facet | Yuki Yamauchi Akinobu Nakamura Takashi Yokota Kiyohiko Takahashi Shinichiro Kawata Kazuhisa Tsuchida Kazuno Omori Hiroshi Nomoto Hiraku Kameda Kyu Yong Cho Toshihisa Anzai Shinya Tanaka Yasuo Terauchi Hideaki Miyoshi Tatsuya Atsumi |
| author_sort | Yuki Yamauchi |
| collection | DOAJ |
| description | Abstract We aimed to determine the mechanism by which the sodium glucose co-transporter 2 inhibitor, luseogliflozin, preserves pancreatic beta-cell mass and function in db/db mice. Six-week-old db/db mice were fed to standard chow or standard chow containing 0.01% luseogliflozin. After 4 weeks, DNA microarray analysis, real-time PCR analysis, and measurement of mitochondrial respiratory capacity and reactive oxygen species (ROS) generation were performed using isolated islets. Immunohistochemistry and electron microscopic analysis were performed using pancreatic tissues. Metabolites extracted from the islets were measured by capillary electrophoresis mass spectrometry. The expression of genes involved in the tricarboxylic acid (TCA) cycle and electron transport chain was upregulated by luseogliflozin. Luseogliflozin improved the mitochondrial complex II-linked oxidative phosphorylation capacity and reduced ROS generation. Mitochondrial morphology was normally maintained by luseogliflozin. Luseogliflozin increased NK6 homeobox 1 (NKX6.1) expression and TCA cycle metabolites. Relief of glucotoxicity by luseogliflozin may involve lower mitochondrial ROS generation and an improvement in complex II-linked mitochondrial respiration. Reducing ROS generation through preventing complex II damage likely increases NKX6.1 expression and ameliorate glucose metabolism in the TCA cycle, contributing to the protection of pancreatic beta-cells. Protection of complex II in pancreatic beta-cells represents a novel therapeutic target for type 2 diabetes. |
| first_indexed | 2024-04-13T19:33:44Z |
| format | Article |
| id | doaj.art-c1a2036c306a49faa4f57882e630c63f |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-13T19:33:44Z |
| publishDate | 2022-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-c1a2036c306a49faa4f57882e630c63f2022-12-22T02:33:07ZengNature PortfolioScientific Reports2045-23222022-06-0112111210.1038/s41598-022-13888-6Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial functionYuki Yamauchi0Akinobu Nakamura1Takashi Yokota2Kiyohiko Takahashi3Shinichiro Kawata4Kazuhisa Tsuchida5Kazuno Omori6Hiroshi Nomoto7Hiraku Kameda8Kyu Yong Cho9Toshihisa Anzai10Shinya Tanaka11Yasuo Terauchi12Hideaki Miyoshi13Tatsuya Atsumi14Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityDepartment of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityClinical Research and Medical Innovation Center, Hokkaido University HospitalDepartment of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityDepartment of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityDepartment of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityDepartment of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityDepartment of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityDepartment of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityDepartment of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityDepartment of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityDepartment of Cancer Pathology, Faculty of Medicine, Hokkaido UniversityDepartment of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City UniversityDepartment of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityDepartment of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityAbstract We aimed to determine the mechanism by which the sodium glucose co-transporter 2 inhibitor, luseogliflozin, preserves pancreatic beta-cell mass and function in db/db mice. Six-week-old db/db mice were fed to standard chow or standard chow containing 0.01% luseogliflozin. After 4 weeks, DNA microarray analysis, real-time PCR analysis, and measurement of mitochondrial respiratory capacity and reactive oxygen species (ROS) generation were performed using isolated islets. Immunohistochemistry and electron microscopic analysis were performed using pancreatic tissues. Metabolites extracted from the islets were measured by capillary electrophoresis mass spectrometry. The expression of genes involved in the tricarboxylic acid (TCA) cycle and electron transport chain was upregulated by luseogliflozin. Luseogliflozin improved the mitochondrial complex II-linked oxidative phosphorylation capacity and reduced ROS generation. Mitochondrial morphology was normally maintained by luseogliflozin. Luseogliflozin increased NK6 homeobox 1 (NKX6.1) expression and TCA cycle metabolites. Relief of glucotoxicity by luseogliflozin may involve lower mitochondrial ROS generation and an improvement in complex II-linked mitochondrial respiration. Reducing ROS generation through preventing complex II damage likely increases NKX6.1 expression and ameliorate glucose metabolism in the TCA cycle, contributing to the protection of pancreatic beta-cells. Protection of complex II in pancreatic beta-cells represents a novel therapeutic target for type 2 diabetes.https://doi.org/10.1038/s41598-022-13888-6 |
| spellingShingle | Yuki Yamauchi Akinobu Nakamura Takashi Yokota Kiyohiko Takahashi Shinichiro Kawata Kazuhisa Tsuchida Kazuno Omori Hiroshi Nomoto Hiraku Kameda Kyu Yong Cho Toshihisa Anzai Shinya Tanaka Yasuo Terauchi Hideaki Miyoshi Tatsuya Atsumi Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function Scientific Reports |
| title | Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function |
| title_full | Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function |
| title_fullStr | Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function |
| title_full_unstemmed | Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function |
| title_short | Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function |
| title_sort | luseogliflozin preserves the pancreatic beta cell mass and function in db db mice by improving mitochondrial function |
| url | https://doi.org/10.1038/s41598-022-13888-6 |
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