{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:24:04Z","timestamp":1790400244649,"version":"4.1.0"},"reference-count":33,"publisher":"The Endocrine Society","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Grants-in-Aid for Young Scientists","award":["20K17503"],"award-info":[{"award-number":["20K17503"]}]},{"name":"Scientific Research","award":["23K08001"],"award-info":[{"award-number":["23K08001"]}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology of Japan","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Japan Diabetes Society Junior Scientist Development Grant"},{"DOI":"10.13039\/100015758","name":"Novo Nordisk Pharma Ltd.","doi-asserted-by":"publisher","award":["2020-2021"],"award-info":[{"award-number":["2020-2021"]}],"id":[{"id":"10.13039\/100015758","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013236","name":"MSD Life Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013236","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Public Interest Incorporated Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>6-Phosphofructo-2-kinase\/fructose-2,6-biphosphatase 3 (PFKFB3) is a key glycolytic regulator involved in the compensation for \u03b2-cell dysfunction under diabetic conditions, but its upstream regulation is incompletely understood. Here, we have characterized the relationship between the underlying pancreatic pathology and PFKFB3 expression in pancreatic \u03b2-cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Pancreatic sections from deceased individuals with and without type 2 diabetes (T2D) were immunostained for PFKFB3. The ratios of PFKFB3-positive \u03b2 and \u03b1 cells were compared, and the relationships with islet amyloid and pancreatic fibrosis were assessed. PFKFB3 expression was also evaluated in caerulein-treated mice and INS-1 832\/13 cells co-cultured with pancreatic stellate cells (PSCs), as models of fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Eighteen individuals with and 18 without T2D were evaluated. The proportion of PFKFB3-positive \u03b2-cells, but not \u03b1-cells, was higher in those with T2D (23.9% \u00b1 16.1% vs 8.7% \u00b1 6.3%, P &amp;lt; .05). PFKFB3 expression negatively correlated with \u03b2-cell mass (\u03c1 = \u22120.34, P &amp;lt; .05). Both the amyloid deposition and area of fibrosis positively correlated with the proportion of PFKFB3-positive \u03b2-cells (\u03c1 = 0.50 and 0.84, respectively; P &amp;lt; .05). In mice, \u03b2-cell PFKFB3 positivity was higher in the fibrosis model vs controls (20.5% \u00b1 10.5% vs 5.6% \u00b1 5.1%, P &amp;lt; .05). Additionally, Pfkfb3 expression in INS-1 cells was significantly higher after co-culture with PSCs. In this co-culture model, RNA sequencing identified transforming growth factor (TGF)-\u03b2-related gene clusters; enzyme-linked immunosorbent assay confirmed high TGF-\u03b2 levels, and western blotting showed greater phosphorylation of Smad.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>PFKFB3-mediated metabolic remodeling occurs in the \u03b2-cells of individuals with T2D, and is linked not only to \u03b2-cell overload, but to pancreatic fibrosis and local TGF-\u03b2\/Smad signaling.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgag315","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T11:45:58Z","timestamp":1785843958000},"source":"Crossref","is-referenced-by-count":2,"title":["Relationship between metabolic remodeling of pancreatic \u03b2-cells and pancreatic histology in type 2 diabetes"],"prefix":"10.1210","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5525-7290","authenticated-orcid":false,"given":"Rimi","family":"Izumihara","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University , Sapporo 060-8638 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0713-221X","authenticated-orcid":false,"given":"Hiroshi","family":"Nomoto","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University , Sapporo 060-8638 ,","place":["Japan"]},{"name":"Division of Endocrinology, Metabolism, and Rheumatology, Department of Internal Medicine, Asahikawa Medical University , Asahikawa 078-8510 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koki","family":"Chiba","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University , Sapporo 060-8638 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1870-6688","authenticated-orcid":false,"given":"Hiraku","family":"Kameda","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University , Sapporo 060-8638 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8192-0006","authenticated-orcid":false,"given":"Akinobu","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University , Sapporo 060-8638 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2920-582X","authenticated-orcid":false,"given":"Hiroki","family":"Mizukami","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine , Hirosaki 036-8562 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5657-962X","authenticated-orcid":false,"given":"Tatsuya","family":"Atsumi","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University , Sapporo 060-8638 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