{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:44:31Z","timestamp":1786628671493,"version":"build-2736575974"},"reference-count":19,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000646","name":"Japan Society for the Promotion of Science London","doi-asserted-by":"publisher","award":["26K02463"],"award-info":[{"award-number":["26K02463"]}],"id":[{"id":"10.13039\/501100000646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Diabetes Invest"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Currently, diabetes is defined as \u201ca chronic hyperglycemic state resulting from the absolute or relative insufficiency of insulin action,\u201d emphasizing its characterization as an insulin\u2010related disease. However, glucagon dysregulation should also play a critical role in the pathophysiology of type 2 diabetes. The pathophysiological relevance of glucagon in type 2 diabetes has long remained uncertain, largely owing to the lack of a reliable assay for measuring plasma glucagon concentrations. We recently developed a highly accurate glucagon sandwich enzyme\u2010linked immunosorbent assay, demonstrating its utility in characterizing patients with type 2 diabetes and its potential for near\u2010term clinical application. In parallel, glucagon has emerged as a promising therapeutic target. Although glucagon receptor antagonists produce potent glucose\u2010lowering effects without increasing the risk of hypoglycemia, their clinical development has not progressed to phase 3 trials because of adverse effects, including weight gain and worsening hepatic steatosis. In contrast, we demonstrated that \u03b1\u2010methyl D\u2010glucopyranoside, an endogenous glucagon secretagogue, reduces body weight and improves hepatic steatosis and glucose intolerance in an obese diabetic mouse model. Furthermore, dual glucagon\/glucagon\u2010like peptide 1 (GLP\u20101) receptor agonists and triple glucagon\/GLP\u20101\/glucose\u2010dependent insulinotropic polypeptide receptor agonists are currently undergoing phase 3 clinical trials for the treatment of obesity and metabolic dysfunction\u2010associated steatotic liver disease. Taken together, glucagon plays a key role in the pathophysiology, diagnosis, and treatment of metabolic diseases.<\/jats:p>","DOI":"10.1111\/jdi.70416","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:24:56Z","timestamp":1786627496000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Role of glucagon in metabolic diseases"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8809-8740","authenticated-orcid":false,"given":"Tadahiro","family":"Kitamura","sequence":"first","affiliation":[{"name":"Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University  3\u201039\u201015 Showa\u2010machi Maebashi Gunma 371\u20108512 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0692-8224","authenticated-orcid":false,"given":"Yoko","family":"Tabei","sequence":"additional","affiliation":[{"name":"Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University  3\u201039\u201015 Showa\u2010machi Maebashi Gunma 371\u20108512 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University  3\u201039\u201015 Showa\u2010machi Maebashi Gunma 371\u20108512 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"crossref","first-page":"391","DOI":"10.2337\/db10-0426","article-title":"Glucagon receptor knockout prevents 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available\u00a0immunoassays","volume":"409","author":"Miyachi A","year":"2017","journal-title":"Anal Bioanal Chem"},{"key":"e_1_2_13_6_1","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1007\/s00125-014-3283-z","article-title":"Hyperglucagonaemia analyzed by glucagon sandwich ELISA: Nonspecific interference or truly elevated levels?","volume":"57","author":"Wewer Albrechtsen NJ","year":"2014","journal-title":"Diabetologia"},{"key":"e_1_2_13_7_1","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1111\/jdi.12400","article-title":"Postabsorptive hyperglucagonemia in patients with type 2 diabetes mellitus analyzed with a novel enzyme\u2010linked immunosorbent assay","volume":"7","author":"Matsuo T","year":"2016","journal-title":"J Diabetes Investig"},{"key":"e_1_2_13_8_1","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1111\/jdi.13325","article-title":"Pseudo\u2010hyperglucagonemia was observed in pancreatectomized patients when measured by glucagon sandwich enzyme\u2010linked immunosorbent assay","volume":"12","author":"Kobayashi M","year":"2021","journal-title":"J Diabetes Investig"},{"key":"e_1_2_13_9_1","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1111\/jdi.13986","article-title":"A newly developed glucagon sandwich ELISA is useful for more accurate glucagon evaluation than the currently used sandwich ELISA in subjects with elevated plasma proglucagonderived peptide levels","volume":"14","author":"Kobayashi M","year":"2023","journal-title":"J Diabetes Investig"},{"key":"e_1_2_13_10_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molmet.2018.10.009","article-title":"SGLT1 in pancreatic \u03b1 cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels","volume":"19","author":"Suga M","year":"2019","journal-title":"Mol 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