Betagenin ameliorates diabetes by inducing insulin secretion and β-cell proliferation

Tomotaka Yokoo; Kazuhisa Watanabe; Kaoruko Iida; Yutaka Nakachi; Hiroaki Suzuki; Hitoshi Shimano; Seiji Takashima; Yasushi Okazaki; Nobuhiro Yamada; Hideo Toyoshima

doi:10.1016/j.jbc.2025.108202

Betagenin ameliorates diabetes by inducing insulin secretion and β-cell proliferation

J Biol Chem. 2025 Jan 16:108202. doi: 10.1016/j.jbc.2025.108202. Online ahead of print.

Authors

Affiliations

¹ Division of Experimental Animal, Hidaka Branch, Biomedical Research Center, Saitama Medical University, Saitama, Japan; Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
² Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan; Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
³ Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan; Department of Food and Nutrition Science, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan.
⁴ Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan; Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
⁵ Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
⁶ Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Osaka, Japan.
⁷ Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan; Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
⁸ Division of Experimental Animal, Hidaka Branch, Biomedical Research Center, Saitama Medical University, Saitama, Japan; Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan. Electronic address: [email protected].

PMID: 39826690
DOI: 10.1016/j.jbc.2025.108202

Abstract

Recent success with the use of glucagon-like peptide-1 (GLP-1) receptor analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of patients with diabetes has highlighted the role of the intestine as an endocrine organ. Gut-derived hormones, including GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and ghrelin, have important roles in the control of energy metabolism and food intake, and are associated with the metabolic syndrome. In this study, we isolated and identified a new intestine-derived hormone, betagenin, and showed that it stimulates insulin secretion and β-cell proliferation and suppresses β-cell apoptosis. Adenovirus-mediated expression of betagenin restored the blood glucose concentrations and hemoglobin A1c (HbA1c) levels of mice with streptozotocin (STZ)-induced diabetes to normal and increased their β-cell mass. Transgenic mice overexpressing betagenin exhibited more than three-fold higher β-cell mass than wild-type mass, whereas that of knockout mice was four-fold lower. A synthetic peptide representing the sequence of purified and secreted betagenin enhanced glucose-dependent insulin secretion in human and mouse pancreatic islets and stimulated the proliferation of the pancreatic β-cell line MIN6 through extracellular signal-regulated kinase (ERK) 1/2-dependent signaling. The intravenous administration of this peptide to STZ mice stimulated the proliferation of pancreatic β-cells in vivo, and the intraperitoneal administration of betagenin ameliorated diabetes and restored β-cell mass. These results indicate that betagenin may reduce blood glucose concentration and induce β-cell regeneration in patients with diabetes.

Keywords: apoptosis; cell proliferation; diabetes; insulin secretion; pancreatic islet.