Protective Effects of Imeglimin and Metformin Combination Therapy on β-Cells in db/db Male Mice

• Published in: Endocrinology (Philadelphia) Vol. 164; no. 8
• Main Authors: Nishiyama, Kuniyuki, Ono, Masato, Tsuno, Takahiro, Inoue, Ryota, Fukunaka, Ayako, Okuyama, Tomoko, Kyohara, Mayu, Togashi, Yu, Fukushima, Setsuko, Atsumi, Takuto, Sato, Aoi, Tsurumoto, Asuka, Sakai, Chisato, Fujitani, Yoshio, Terauchi, Yasuo, Ito, Shuichi, Shirakawa, Jun
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 26-06-2023
• Subjects: Adipocytes; Adipose tissue; Animals; Antidiabetics; Apoptosis; Beta cells; Blood Glucose - metabolism; Cell culture; Cell death; Cell proliferation; Combination therapy; Computed tomography; CXCL12 protein; Cytology; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - metabolism; Egr-3 protein; Endocrinology; Fatty liver; Gelatinase B; Gene expression; Gene regulation; Genes; Glucose; Glucose - metabolism; Glucose tolerance; Hepatocytes; Hydrogen peroxide; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Insulin; Insulin - metabolism; Insulin-Secreting Cells - metabolism; Lipid metabolism; Lipids; Liver; Locomotor activity; Male; Metformin; Metformin - pharmacology; Metformin - therapeutic use; Mice; Mice, Inbred Strains; Palmitic acid; Snail protein; metformin; imeglimin; type 2 diabetes; pancreatic islets
• ISSN: 1945-7170; 0013-7227; 1945-7170
• DOI: 10.1210/endocr/bqad095

Abstract
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.