{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:57:28Z","timestamp":1791388648725,"version":"4.3.3"},"reference-count":32,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K02701"],"award-info":[{"award-number":["25K02701"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K22635"],"award-info":[{"award-number":["25K22635"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016573","name":"Japan Association for Diabetes Education and Care","doi-asserted-by":"publisher","award":["2025\u2010YNG\u2010017"],"award-info":[{"award-number":["2025\u2010YNG\u2010017"]}],"id":[{"id":"10.13039\/100016573","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:sec>\n                    <jats:title>Aims\/Introduction<\/jats:title>\n                    <jats:p>Proinsulin is associated with \u03b2\u2010cell stress and has been linked to subsequent deterioration in glucose metabolism in Western populations, but its predictive value in Asian populations remains unclear. We investigated whether proinsulin is associated with future glucose tolerance deterioration in community\u2010dwelling Japanese adults.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>Of 160 individuals who underwent a 75\u2010g oral glucose tolerance test (OGTT) in 2020\u20132021, 88 completed a follow\u2010up OGTT in 2024\u20132025. Fasting proinsulin concentrations were measured using stored baseline serum samples from 84 participants. Associations with glucose tolerance deterioration were examined using Firth's penalized logistic regression, and discriminatory performance was evaluated using receiver operating characteristic (ROC) analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      During the 4\u2010year follow\u2010up, glucose tolerance deteriorated in 16 participants. Fasting proinsulin concentrations were higher in progressors than in non\u2010progressors (5.8 vs. 3.6\u2009pmol\/L;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.009). Each 1\u2010standard deviation increase in fasting proinsulin was associated with glucose tolerance deterioration (odds ratio 2.11, 95% confidence interval 1.31\u20133.72;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.002). In exploratory ROC analysis, the area under the curve was 0.710, and a cutoff of 5.1\u2009pmol\/L yielded 68.8% sensitivity and 83.8% specificity. Participants with elevated fasting proinsulin (\u2265\u20095.1\u2009pmol\/L) and a low disposition index (\u2264\u20091.27) had the highest odds of deterioration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Fasting proinsulin may help identify Japanese adults at risk of future glucose tolerance deterioration, particularly when combined with indices of \u03b2\u2010cell compensation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jdi.70461","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:35:53Z","timestamp":1791387353000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fasting proinsulin as a predictor of future glucose tolerance deterioration in Japanese adults"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4226-5915","authenticated-orcid":false,"given":"Nobuhiro","family":"Kajihara","sequence":"first","affiliation":[{"name":"Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences Kumamoto University  Kumamoto Japan"},{"name":"Department of Metabolic Medicine, Faculty of Life Sciences Kumamoto University  Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3723-3938","authenticated-orcid":false,"given":"Tomonori","family":"Tsuyama","sequence":"additional","affiliation":[{"name":"Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences Kumamoto University  Kumamoto Japan"},{"name":"Department of Medical Biochemistry, Faculty of Life Sciences Kumamoto University  Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3237-9065","authenticated-orcid":false,"given":"Kazuki","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Department of Metabolic Medicine, Faculty of Life Sciences Kumamoto University  Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai","family":"Maekawa","sequence":"additional","affiliation":[{"name":"Kikuchiyojoen Clinic  Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4064-7525","authenticated-orcid":false,"given":"Eiichi","family":"Araki","sequence":"additional","affiliation":[{"name":"Kikuchi Medical Association Hospital  Kumamoto Japan"},{"name":"Research Center for Health and Sports Sciences Kumamoto Health Science University  Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3336-2767","authenticated-orcid":false,"given":"Naoto","family":"Kubota","sequence":"additional","affiliation":[{"name":"Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences Kumamoto University  Kumamoto Japan"},{"name":"Department of Metabolic Medicine, Faculty of Life Sciences Kumamoto University  Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7564-7579","authenticated-orcid":false,"given":"Kazuya","family":"Yamagata","sequence":"additional","affiliation":[{"name":"Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences Kumamoto University  Kumamoto Japan"},{"name":"Department of Medical Biochemistry, Faculty of Life Sciences Kumamoto University  Kumamoto 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Some clues from recent advances made in understanding the proinsulin\u2010processing mechanism","volume":"43","author":"Rhodes CJ","year":"1994","journal-title":"Diabetes"},{"key":"e_1_2_9_28_1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/s00125-002-0995-2","article-title":"Proinsulin and acute insulin response independently predict type 2 diabetes mellitus in men\u2014Report from 27\u2009years of follow\u2010up study","volume":"46","author":"Zethelius B","year":"2003","journal-title":"Diabetologia"},{"key":"e_1_2_9_29_1","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41586-024-07019-6","article-title":"Genetic drivers of heterogeneity in type 2 diabetes pathophysiology","volume":"627","author":"Suzuki K","year":"2024","journal-title":"Nature"},{"key":"e_1_2_9_30_1","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1007\/s001250051271","article-title":"The relation of proinsulin and insulin to insulin sensitivity and acute insulin response in subjects with newly diagnosed type II diabetes: The insulin resistance atherosclerosis study","volume":"42","author":"Mykk\u00e4nen L","year":"1999","journal-title":"Diabetologia"},{"key":"e_1_2_9_31_1","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1007\/s00125-011-2322-2","article-title":"Proinsulin\u2010to\u2010C\u2010peptide ratio versus proinsulin\u2010to\u2010insulin ratio in the prediction of incident diabetes: The insulin resistance atherosclerosis study (IRAS)","volume":"54","author":"Loopstra\u2010Masters RC","year":"2011","journal-title":"Diabetologia"},{"issue":"2","key":"e_1_2_9_32_1","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/dom.13401","article-title":"Islet prohormone processing in health and disease","volume":"20","author":"Chen YC","year":"2018","journal-title":"Diabetes Obes Metab"},{"key":"e_1_2_9_33_1","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1007\/BF00418345","article-title":"Intra\u2010individual variation of glucose, specific insulin and proinsulin concentrations measured by two oral glucose tolerance tests in a general Caucasian population: The Hoorn study","volume":"39","author":"Mooy JM","year":"1996","journal-title":"Diabetologia"}],"container-title":["Journal of Diabetes Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jdi.70461","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jdi.70461","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jdi.70461","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:35:58Z","timestamp":1791387358000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jdi.70461"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":32,"alternative-id":["10.1111\/jdi.70461"],"URL":"https:\/\/doi.org\/10.1111\/jdi.70461","archive":["Portico"],"relation":{},"ISSN":["2040-1116","2040-1124"],"issn-type":[{"value":"2040-1116","type":"print"},{"value":"2040-1124","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]},"assertion":[{"value":"2026-07-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"jdi.70461"}}