Kuniyuki Nishiyama, Masato Ono, Takahiro Tsuno, Ryota Inoue, Ayako Fukunaka, Tomoko Okuyama, Mayu Kyohara, Yu Togashi, Setsuko Fukushima, Takuto Atsumi, Aoi Satoh, 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, 164, 8, 2023.
(要約)
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.
Ryota Inoue, Takahiro Tsuno, Yu Togashi, Tomoko Okuyama, Aoi Satoh, Kuniyuki Nishiyama, Mayu Kyohara, Jinghe Li, Setsuko Fukushima, Tatsuya Kin, Daisuke Miyashita, Yusuke Shiba, Yoshitoshi Atobe, Hiroshi Kiyonari, Kana Bando, James A M Shapiro, Kengo Funakoshi, N Rohit Kulkarni, Yasuo Terauchi and Jun Shirakawa : Uncoupling protein 2 and aldolase B impact insulin release by modulating mitochondrial function and Ca2+ release from the ER., iScience, 25, 7, 2022.
(要約)
Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of this increase in UCP2 expression is unclear. In this study, we highlight the molecular link between the increase in UCP2 expression in β-cells and β-cell failure by using genetically engineered mice and human islets. β-cell-specific UCP2-overexpressing transgenic mice (βUCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion. Decreased mitochondrial function and increased aldolase B (AldB) expression through oxidative-stress-mediated pathway were observed in βUCP2Tg islets. AldB, a glycolytic enzyme, was associated with reduced insulin secretion via mitochondrial dysfunction and impaired calcium release from the endoplasmic reticulum (ER). Taken together, our findings provide a new mechanism of β-cell dysfunction by UCP2 and AldB. Targeting the UCP2/AldB axis is a promising approach for the recovery of β-cell function.
Jinghe Li, Ryota Inoue, Yu Togashi, Tomoko Okuyama, Aoi Satoh, Mayu Kyohara, Kuniyuki Nishiyama, Takahiro Tsuno, Daisuke Miyashita, Tatsuya Kin, M.James A. Shapiro, Ern Resilind Su Chew, Keong Adrian Kee Teo, Seiichi Oyadomari, Yasuo Terauchi and Jun Shirakawa : Imeglimin Ameliorates β-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway, Diabetes, 71, 3, 424-439, 2022.
(要約)
The effects of imeglimin, a novel antidiabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules, including Chop (Ddit3), Gadd34 (Ppp1r15a), Atf3, and Sdf2l1, and decreased eIF2α phosphorylation after treatment with thapsigargin and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect against ER stress-induced β-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell-derived β-like cells. Taken together, imeglimin modulates the ER homeostasis pathway, which results in the prevention of β-cell apoptosis both in vitro and in vivo.
Kenta Takei, Yoshimi Nakagawa, Yunong Wang, iee Song Han, Aoi Satoh, Motohiro Sekiya, Takashi Matsuzaka and Hitoshi Shimano : Effects of K-877, a novel selective PPARα modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockout mice, Journal of Pharmacological Sciences, 133, 4, 214-222, 2017.
Yuri Fujimoto, Yoshimi Nakagawa, Akiko Shingyouchi, Naoko Tokushige, Noriko Nakanishi, Aoi Satoh, Takashi Matsuzaka, aki Kiyo Ishii, Hitoshi Iwasaki, Kazuto Kobayashi, Shigeru Yatoh, Hiroaki Suzuki, Naoya Yahagi, Osamu Urayama, Nobuhiro Yamada and Hitoshi Shimano : Dicer has a crucial role in the early stage of adipocyte differentiation, but not in lipid synthesis, in 3T3-L1 cells, Biochemical and Biophysical Research Communications, 420, 4, 931-936, 2012.