{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T00:37:55Z","timestamp":1793407075789,"version":"4.5.0"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"35","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,9,2]]},"abstract":"<jats:p>\n                    Interleukin-6 (IL-6) is systemically elevated in obesity and is a predictive factor to develop type 2 diabetes. Pancreatic islet pathology in type 2 diabetes is characterized by reduced \u03b2-cell function and mass, an increased proportion of \u03b1-cells relative to \u03b2-cells, and \u03b1-cell dysfunction. Here we show that the \u03b1 cell is a primary target of IL-6 actions. Beginning with investigating the tissue-specific expression pattern of the IL-6 receptor (IL-6R) in both mice and rats, we find the highest expression of the IL-6R in the endocrine pancreas, with highest expression on the \u03b1-cell. The islet IL-6R is functional, and IL-6 acutely regulates both pro-glucagon mRNA and glucagon secretion in mouse and human islets, with no acute effect on insulin secretion. Furthermore, IL-6 stimulates \u03b1-cell proliferation, prevents apoptosis due to metabolic stress, and regulates \u03b1-cell mass\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Using IL-6 KO mice fed a high-fat diet, we find that IL-6 is necessary for high-fat diet-induced increased \u03b1-cell mass, an effect that occurs early in response to diet change. Further, after high-fat diet feeding, IL-6 KO mice without expansion of \u03b1-cell mass display decreased fasting glucagon levels. However, despite these \u03b1-cell effects, high-fat feeding of IL-6 KO mice results in increased fed glycemia due to impaired insulin secretion, with unchanged insulin sensitivity and similar body weights. Thus, we conclude that IL-6 is necessary for the expansion of pancreatic \u03b1-cell mass in response to high-fat diet feeding, and we suggest that this expansion may be needed for functional \u03b2-cell compensation to increased metabolic demand.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0801059105","type":"journal-article","created":{"date-parts":[[2008,8,21]],"date-time":"2008-08-21T21:40:27Z","timestamp":1219354827000},"page":"13163-13168","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":256,"title":["Interleukin-6 regulates pancreatic \u03b1-cell mass expansion"],"prefix":"10.1073","volume":"105","author":[{"given":"Helga","family":"Ellingsgaard","sequence":"first","affiliation":[{"name":"*Division of Endocrinology and Diabetes and Center for Integrated Human Physiology, University Hospital of Z\u00fcrich, 8091 Z\u00fcrich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan A.","family":"Ehses","sequence":"additional","affiliation":[{"name":"*Division of Endocrinology and Diabetes and Center for Integrated Human Physiology, University Hospital of Z\u00fcrich, 8091 Z\u00fcrich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva B.","family":"Hammar","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine and Development, University Medical Center, CH-1211 Geneva 4, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leentje","family":"Van Lommel","sequence":"additional","affiliation":[{"name":"Gene Expression Unit, Department of Molecular Cell Biology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roel","family":"Quintens","sequence":"additional","affiliation":[{"name":"Gene Expression Unit, Department of Molecular Cell Biology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert","family":"Martens","sequence":"additional","affiliation":[{"name":"Diabetes Research Center, Brussels Free University, Laarbeeklaan 103, B-1090 Brussels, Belgium; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Kerr-Conte","sequence":"additional","affiliation":[{"name":"**Cell Therapy of Diabetes, ERIT-M 0106, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Faculty of Medicine, 1 Place de Verdun, 59045 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Pattou","sequence":"additional","affiliation":[{"name":"**Cell Therapy of Diabetes, ERIT-M 0106, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Faculty of Medicine, 1 Place de Verdun, 59045 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Berney","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine and Development, University Medical Center, CH-1211 Geneva 4, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Pipeleers","sequence":"additional","affiliation":[{"name":"Diabetes Research Center, Brussels Free University, Laarbeeklaan 103, B-1090 Brussels, Belgium; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe A.","family":"Halban","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine and Development, University Medical Center, CH-1211 Geneva 4, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans C.","family":"Schuit","sequence":"additional","affiliation":[{"name":"Gene Expression Unit, Department of Molecular Cell Biology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc Y.","family":"Donath","sequence":"additional","affiliation":[{"name":"*Division of Endocrinology and Diabetes and Center for Integrated Human Physiology, University Hospital of Z\u00fcrich, 8091 Z\u00fcrich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,9,2]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(75)92375-2"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.3.624"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2002-020735"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.suppl_2.S108"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00251826"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2006-0007"},{"key":"e_1_3_3_7_2","first-page":"1","article-title":"IL-6 signal transduction and its physiological roles: The signal orchestration model","volume":"149","author":"Kamimura D","year":"2003","unstructured":"D Kamimura, K Ishihara, T Hirano, IL-6 signal transduction and its physiological roles: The signal orchestration model. 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