{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T09:08:05Z","timestamp":1788858485694,"version":"build-2803163510"},"reference-count":25,"publisher":"The Endocrine Society","issue":"10","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["JP21K08534"],"award-info":[{"award-number":["JP21K08534"]}]},{"name":"JSPS KAKENHI","award":["JP24K11728"],"award-info":[{"award-number":["JP24K11728"]}]},{"DOI":"10.13039\/100016573","name":"Japan Association for Diabetes Education and Care","doi-asserted-by":"publisher","award":["2023-FND-021"],"award-info":[{"award-number":["2023-FND-021"]}],"id":[{"id":"10.13039\/100016573","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007664","name":"Manpei Suzuki Diabetes Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Unprovoked ketosis-prone type 2 diabetes (KPD) is characterized by a male predominance, young age of onset, and abrupt presentation of diabetic ketosis\/ketoacidosis without precipitating factors. Although many individuals regain \u03b2-cell function after insulin therapy, some progress to insulin dependence, suggesting overlap with type 1 diabetes. We previously reported the involvement of insulin-associated peptide-specific T helper 1 (Th1) responses in KPD pathogenesis. Exocrine pancreatic inflammation has been documented in type 1 diabetes, with evidence suggesting its contribution to disease development; however, its relevance to KPD remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This cross-sectional study aimed to elucidate mechanisms underlying KPD by investigating the association between endocrine and exocrine immune responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We recruited 54 participants with KPD, assessed clinical parameters, including human leukocyte antigen (HLA)-DRB1\/DQB1 genotypes, carbonic anhydrase II (CA2) antibody levels, and insulin-associated peptide-specific Th1 responses, and explored their interrelationship.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HLA-DRB1*08:03 frequency was significantly higher in participants with KPD than in historical healthy controls. Elevated exocrine pancreatic enzyme levels were observed in 29.6% (16\/54) of cases. CA2 antibody levels were increased in HLA-DRB1*08:03-positive participants, especially those with elevated exocrine pancreatic enzyme levels, and positively correlated with insulin-associated peptide-specific Th1 responses. Th1 responses were inversely associated with serum C-peptide levels in all participants, reflecting disease activity, but not in HLA-DRB1*08:03-positive participants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>HLA-DRB1*08:03 is possibly associated with endocrine and exocrine immune responses in KPD, mediating exocrine\u2013endocrine immune linkage. However, it is unlikely to be directly involved in \u03b2-cell impairment via insulin-specific Th1 responses, potentially explaining reversible \u03b2-cell dysfunction in early KPD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/jendso\/bvag200","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T08:10:24Z","timestamp":1788250224000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>HLA-DRB1*08:03<\/i>\n                    -associated exocrine\u2013endocrine immune linkage: a pathogenic mechanism in ketosis-prone type 2 diabetes"],"prefix":"10.1210","volume":"10","author":[{"given":"Seiya","family":"Suzuki","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Diabetes, Saitama Medical University , Saitama 350-0495 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1524-6751","authenticated-orcid":false,"given":"Yoichi","family":"Oikawa","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Saitama Medical University , Saitama 350-0495 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Satomura","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Saitama Medical University , Saitama 350-0495 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akifumi","family":"Haisa","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Saitama Medical University , Saitama 350-0495 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumpei","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Saitama Medical University , Saitama 350-0495 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Fujisawa","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Saitama Medical University , Saitama 350-0495 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Saitama Medical University , Saitama 350-0495 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Katsuki","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Tokyo Saiseikai Central Hospital , Tokyo 108-0073 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Shimada","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Saitama Medical University , Saitama 350-0495 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"issue":"1","key":"2026090804165757300_bvag200-B1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s13340-022-00599-6","article-title":"A patient with ketosis-prone type 2 diabetes showing nearly normalized glucose tolerance after recovery from severe diabetic ketoacidosis","volume":"14","author":"Satomura","year":"2023","journal-title":"Diabetol Int"},{"issue":"12","key":"2026090804165757300_bvag200-B2","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.2337\/dc06-1870","article-title":"Ketosis-prone type 2 diabetes: time to revise the classification of diabetes","volume":"29","author":"Umpierrez","year":"2006","journal-title":"Diabetes Care"},{"issue":"11","key":"2026090804165757300_bvag200-B3","doi-asserted-by":"crossref","first-page":"5090","DOI":"10.1210\/jc.2003-030180","article-title":"Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta-cell functional classification, prospective analysis, and clinical outcomes","volume":"88","author":"Maldonado","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"issue":"12","key":"2026090804165757300_bvag200-B4","doi-asserted-by":"crossref","first-page":"2575","DOI":"10.2337\/dc06-0749","article-title":"Accuracy and predictive value of classification schemes for ketosis-prone diabetes","volume":"29","author":"Balasubramanyam","year":"2006","journal-title":"Diabetes Care"},{"issue":"2","key":"2026090804165757300_bvag200-B5","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1111\/jdi.13120","article-title":"Bodyweight threshold for sudden onset of ketosis might exist in ketosis-prone type 2 diabetes patients","volume":"11","author":"Satomura","year":"2020","journal-title":"J Diabetes Investig"},{"issue":"3","key":"2026090804165757300_bvag200-B6","doi-asserted-by":"crossref","first-page":"645","DOI":"10.2337\/diabetes.53.3.645","article-title":"Ketosis-prone type 2 diabetes in patients of sub-saharan African origin: clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance","volume":"53","author":"Mauvais-Jarvis","year":"2004","journal-title":"Diabetes"},{"issue":"5","key":"2026090804165757300_bvag200-B7","doi-asserted-by":"crossref","first-page":"e2124","DOI":"10.1210\/clinem\/dgab912","article-title":"Clinical significance of insulin peptide-specific interferon-gamma-related immune responses in ketosis-prone type 2 diabetes","volume":"107","author":"Satomura","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"issue":"9","key":"2026090804165757300_bvag200-B8","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1016\/j.cmet.2023.06.018","article-title":"The pathogenic \u201csymphony\u201d in type 1 diabetes: a disorder of the immune system, beta cells, and exocrine pancreas","volume":"35","author":"Atkinson","year":"2023","journal-title":"Cell Metab"},{"issue":"6","key":"2026090804165757300_bvag200-B9","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1002\/dvdy.20754","article-title":"Timing and expression pattern of carbonic anhydrase II in pancreas","volume":"235","author":"Inada","year":"2006","journal-title":"Dev Dyn"},{"issue":"3","key":"2026090804165757300_bvag200-B10","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0016-5085(00)70264-2","article-title":"Autoimmune-related pancreatitis is associated with autoantibodies and a Th1\/th2-type cellular immune response","volume":"118","author":"Okazaki","year":"2000","journal-title":"Gastroenterology"},{"issue":"12","key":"2026090804165757300_bvag200-B11","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1007\/s00125-009-1539-9","article-title":"Differential association of HLA with three subtypes of type 1 diabetes: fulminant, slowly progressive and acute-onset","volume":"52","author":"Kawabata","year":"2009","journal-title":"Diabetologia"},{"issue":"8","key":"2026090804165757300_bvag200-B12","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.2337\/diacare.26.8.2345","article-title":"Fulminant type 1 diabetes: a nationwide survey in Japan","volume":"26","author":"Imagawa","year":"2003","journal-title":"Diabetes Care"},{"key":"2026090804165757300_bvag200-B13","doi-asserted-by":"crossref","first-page":"108260","DOI":"10.1016\/j.clim.2019.108260","article-title":"Significance of peripheral mononuclear cells producing interferon-gamma in response to insulin B:9-23-related peptides in subtypes of type 1 diabetes","volume":"208","author":"Oikawa","year":"2019","journal-title":"Clin Immunol"},{"issue":"5","key":"2026090804165757300_bvag200-B14","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1111\/j.1872-034X.2010.00631.x","article-title":"Analysis of HLA-DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC): the HLA-DRB1polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC","volume":"40","author":"Nakamura","year":"2010","journal-title":"Hepatol Res"},{"issue":"6","key":"2026090804165757300_bvag200-B15","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/S0168-8278(05)80617-8","article-title":"DNA typing of HLA class II genes; DRB1*0803 increases the susceptibility of Japanese to primary biliary cirrhosis","volume":"21","author":"Onishi","year":"1994","journal-title":"J Hepatol"},{"key":"2026090804165757300_bvag200-B16","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jaut.2014.11.006","article-title":"The amino acid variation within the binding pocket 7 and 9 of HLA-DRB1 molecules are associated with primary Sjogren's syndrome","volume":"57","author":"Huang","year":"2015","journal-title":"J Autoimmun"},{"issue":"1","key":"2026090804165757300_bvag200-B17","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1097\/00006676-200307000-00004","article-title":"High prevalence of autoantibodies against carbonic anhydrase II and lactoferrin in type 1 diabetes: concept of autoimmune exocrinopathy and endocrinopathy of the pancreas","volume":"27","author":"Taniguchi","year":"2003","journal-title":"Pancreas"},{"issue":"9","key":"2026090804165757300_bvag200-B18","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.2337\/diacare.24.9.1695","article-title":"Presence of autoantibodies to carbonic anhidrase II and lactoferrin in type 1 diabetes: proposal of the concept of autoimmune exocrinopathy and endocrinopathy of the pancreas","volume":"24","author":"Taniguchi","year":"2001","journal-title":"Diabetes Care"},{"issue":"11","key":"2026090804165757300_bvag200-B19","doi-asserted-by":"crossref","first-page":"3880","DOI":"10.2337\/db14-0549","article-title":"Increased immune cell infiltration of the exocrine pancreas: a possible contribution to the pathogenesis of type 1 diabetes","volume":"63","author":"Rodriguez-Calvo","year":"2014","journal-title":"Diabetes"},{"issue":"1","key":"2026090804165757300_bvag200-B20","doi-asserted-by":"crossref","first-page":"e001158","DOI":"10.1136\/bmjdrc-2019-001158","article-title":"Impaired exocrine pancreatic function in different stages of type 1 diabetes","volume":"9","author":"Dozio","year":"2021","journal-title":"BMJ Open Diabetes Res Care"},{"issue":"2","key":"2026090804165757300_bvag200-B21","doi-asserted-by":"crossref","first-page":"248","DOI":"10.2337\/dc18-1507","article-title":"Pancreas volume declines during the first year after diagnosis of type 1 diabetes and exhibits altered diffusion at disease onset","volume":"42","author":"Virostko","year":"2019","journal-title":"Diabetes Care"},{"issue":"1","key":"2026090804165757300_bvag200-B22","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1007\/s12020-025-04338-0","article-title":"Alterations of the pancreas in type 1 diabetes\u2014from prior to diagnosis to long-standing disease","volume":"90","author":"Missima","year":"2025","journal-title":"Endocrine"},{"issue":"4","key":"2026090804165757300_bvag200-B23","doi-asserted-by":"crossref","first-page":"120","DOI":"10.33696\/immunology.5.177","article-title":"Type 1 diabetes: a disorder of the exocrine and endocrine pancreas","volume":"5","author":"Bruggeman","year":"2023","journal-title":"J Cell Immunol"},{"issue":"50","key":"2026090804165757300_bvag200-B24","doi-asserted-by":"crossref","first-page":"19915","DOI":"10.1073\/pnas.0805803105","article-title":"Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth","volume":"105","author":"Inada","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"2026090804165757300_bvag200-B25","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1399-5448.2011.00833.x","article-title":"HLA-class II and class I genotypes among Japanese children with type 1A diabetes and their families","volume":"13","author":"Sugihara","year":"2012","journal-title":"Pediatr Diabetes"}],"container-title":["Journal of the Endocrine Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jes\/advance-article-pdf\/doi\/10.1210\/jendso\/bvag200\/70888921\/bvag200.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jes\/article-pdf\/10\/10\/bvag200\/70888921\/bvag200.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jes\/article-pdf\/10\/10\/bvag200\/70888921\/bvag200.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T08:17:07Z","timestamp":1788855427000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jes\/article\/doi\/10.1210\/jendso\/bvag200\/8777319"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":25,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,9,3]]}},"URL":"https:\/\/doi.org\/10.1210\/jendso\/bvag200","relation":{},"ISSN":["2472-1972"],"issn-type":[{"value":"2472-1972","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,10]]},"published":{"date-parts":[[2026,9,1]]},"article-number":"bvag200"}}