Kuniyuki Nishiyama1, Masato Ono2, Takahiro Tsuno1, Ryota Inoue1, Ayako Fukunaka3, Tomoko Okuyama2, Mayu Kyohara2, Yu Togashi2, Setsuko Fukushima1, Takuto Atsumi1, Aoi Sato1, Asuka Tsurumoto1, Chisato Sakai1, Yoshio Fujitani3, Yasuo Terauchi2, Shuichi Ito2, and Jun Shirakawa12* (1. Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University; 2. Graduate School of Medicine, Yokohama City University; 3. Laboratory of Developmental Biology and Metabolism, IMCR, Gunma University; *Corresponding Author)
About
Imeglimin and metformin act in metabolic organs, including β-cells, via different mechanisms. In the present study, we investigated the impacts of imeglimin, metformin, or their combination (Imeg+Met) on β-cells, the liver, and adipose tissues in db/db mice. Imeglimin, metformin, or Imeg+Met treatment had no significant effects on glucose tolerance, insulin sensitivity, respiratory exchange ratio, or locomotor activity in db/db mice. The responsiveness of insulin secretion to glucose was recovered by Imeg+Met treatment. Furthermore, Imeg+Met treatment increased β-cell mass by enhancing β-cell proliferation and ameliorating β-cell apoptosis in db/db mice. Hepatic steatosis, the morphology of adipocytes, adiposity assessed by computed tomography, and the expression of genes related to glucose or lipid metabolism and inflammation in the liver and fat tissues showed no notable differences in db/db mice. Global gene expression analysis of isolated islets indicated that the genes related to regulation of cell population proliferation and negative regulation of cell death were enriched by Imeg+Met treatment in db/db islets. In vitro culture experiments confirmed the protective effects of Imeg+Met against β-cell apoptosis. The expression of Snai1, Tnfrsf18, Pdcd1, Mmp9, Ccr7, Egr3, and Cxcl12, some of which have been linked to apoptosis, in db/db islets was attenuated by Imeg+Met. Treatment of a β-cell line with Imeg+Met prevented apoptosis induced by hydrogen peroxide or palmitate. Thus, the combination of imeglimin and metformin is beneficial for the maintenance of β-cell mass in db/db mice, probably through direct action on β-cells, suggesting a potential strategy for protecting β-cells in the treatment of type 2 diabetes.
Paper information
Kuniyuki Nishiyama, Masato Ono, Takahiro Tsuno, Ryota Inoue, Ayako Fukunaka, Tomoko Okuyama, Mayu Kyohara, Yu Togashi, Setsuko Fukushima, Takuto Atsumi, Aoi Sato, Asuka Tsurumoto, Chisato Sakai, Yoshio Fujitani, Yasuo Terauchi, Shuichi Ito, and Jun Shirakawa. Protective effects of imeglimin and metformin combination therapy on β-cells in db/db male mice. Endocrinology. 2023 Jun 14:bqad095. doi: 10.1210/endocr/bqad095.
Online URL
https://doi.org/10.1210/endocr/bqad095
