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In this study, we evaluated the effect of imeglimin on pancreatic \u03b2-cells. First, single-dose administration of imeglimin enhanced insulin secretion from \u03b2-cells and decreased blood glucose levels in type 2 diabetic db\/db mice. In addition, single-dose administration of imeglimin significantly augmented insulin secretion in response to glucose from islets isolated from non-diabetic db\/m mice. Second, during an oral glucose tolerance test 4-week chronic treatment with imeglimin enhanced insulin secretion and ameliorated glycemic control in diabetic db\/db mice. Furthermore, the examination with electron microscope image showed that imeglimin exerted favorable effects on morphology in \u03b2-cell mitochondria and substantially increased the number of insulin granules in type 2 diabetic db\/db and KK-Ay mice. Finally, imeglimin reduced the percentage of apoptotic \u03b2-cell death which was accompanied by reduced expression levels of various genes related to apoptosis and inflammation in \u03b2-cells. Taken together, imeglimin directly enhances insulin secretion in response to glucose from \u03b2-cells, increases the number of insulin granules, exerts favorable effects on morphology in \u03b2-cell mitochondria, and reduces apoptotic \u03b2-cell death in type 2 diabetic mice, which finally leads to amelioration of glycemic control.<\/jats:p>","DOI":"10.1038\/s41598-022-17657-3","type":"journal-article","created":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T09:05:41Z","timestamp":1659431141000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Imeglimin exerts favorable effects on pancreatic \u03b2-cells by improving morphology in mitochondria and increasing the number of insulin granules"],"prefix":"10.1038","volume":"12","author":[{"given":"Junpei","family":"Sanada","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Obata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiro","family":"Fushimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Shimoda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Ikeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Nogami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Obata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Yamasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhei","family":"Nakanishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoatsu","family":"Mune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Kaku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Kaneto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,8,2]]},"reference":[{"key":"17657_CR1","volume-title":"Global Report on Diabetes","author":"World Health Organization","year":"2016","unstructured":"World Health Organization. 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Diabetes 52, 102\u2013110. https:\/\/doi.org\/10.2337\/diabetes.52.1.102 (2003).","journal-title":"Diabetes"},{"issue":"Suppl 4","key":"17657_CR4","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1111\/j.1463-1326.2008.00939.x","volume":"10","author":"AV Matveyenko","year":"2008","unstructured":"Matveyenko, A. V. & Butler, P. C. Relationship between beta-cell mass and diabetes onset. Diabetes Obes. Metab. 10(Suppl 4), 23\u201331. https:\/\/doi.org\/10.1111\/j.1463-1326.2008.00939.x (2008).","journal-title":"Diabetes Obes. Metab."},{"key":"17657_CR5","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1038\/ni.1935","volume":"11","author":"SL Masters","year":"2010","unstructured":"Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1\u03b2 in type 2 diabetes. Nat. Immunol. 11, 897\u2013904. https:\/\/doi.org\/10.1038\/ni.1935 (2010).","journal-title":"Nat. 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Diabetes Care 44, 952\u2013959. https:\/\/doi.org\/10.2337\/dc20-0763 (2021).","journal-title":"Diabetes Care"},{"key":"17657_CR14","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1111\/dom.14613","volume":"24","author":"J Dubourg","year":"2022","unstructured":"Dubourg, J., Fouqueray, P., Quinslot, D., Grouin, J. M. & Kaku, K. Long-term safety and efficacy of imeglimin as monotherapy or in combination with existing antidiabetic agents in Japanese patients with type 2 diabetes (TIMES 2): A 52-week, open-label, multicentre phase 3 trial. Diabetes Obes. Metab. 24, 609\u2013619. https:\/\/doi.org\/10.1111\/dom.14613 (2022).","journal-title":"Diabetes Obes. Metab."},{"key":"17657_CR15","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1111\/dom.14642","volume":"24","author":"C Reilhac","year":"2022","unstructured":"Reilhac, C. et al. 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Diabetologia 53, 1656\u20131668. https:\/\/doi.org\/10.1007\/s00125-010-1733-9 (2010).","journal-title":"Diabetologia"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-17657-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-17657-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-17657-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T05:22:13Z","timestamp":1669353733000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-17657-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,2]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["17657"],"URL":"https:\/\/doi.org\/10.1038\/s41598-022-17657-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,2]]},"assertion":[{"value":"6 May 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 July 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 August 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"H.K. has received honoraria for lectures, received scholarship grants, and received research grant from Novo Nordisk Pharma, Sanofi, Eli Lilly, Boehringer Ingelheim, Taisho Pharma, Sumitomo Pharma, Takeda Pharma, Ono Pharma, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Kissei Pharma, MSD, AstraZeneca, Astellas, Novartis, Kowa, Abbott. K.K. has been an advisor to, received honoraria for lectures from, and received scholarship grants from Novo Nordisk Pharma, Sanwa Kagaku, Takeda, Taisho Pharma, MSD, Kowa, Sumitomo Pharma, Novartis, Mitsubishi Tanabe Pharma, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Sanofi. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"13220"}}