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Interleukin-6 regulates pancreatic alpha-cell mass expansion

Ellingsgaard, Helga
Ehses, Jan A.
Hammar, Eva B.
Van Lommel, Leentje
Quintens, Roel
Martens, Geert
Kerr-Conte, Julie
Pattou, Francois
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Published in Proceedings of the National Academy of Sciences. 2008, vol. 105, no. 35, p. 13163-8
Abstract 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 beta-cell function and mass, an increased proportion of alpha-cells relative to beta-cells, and alpha-cell dysfunction. Here we show that the alpha 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 alpha-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 alpha-cell proliferation, prevents apoptosis due to metabolic stress, and regulates alpha-cell mass in vivo. Using IL-6 KO mice fed a high-fat diet, we find that IL-6 is necessary for high-fat diet-induced increased alpha-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 alpha-cell mass display decreased fasting glucagon levels. However, despite these alpha-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 alpha-cell mass in response to high-fat diet feeding, and we suggest that this expansion may be needed for functional beta-cell compensation to increased metabolic demand.
Keywords AnimalsApoptosis/drug effectsCell Proliferation/drug effectsDietary Fats/pharmacologyFeeding Behavior/drug effectsGene Expression Regulation/drug effectsGlucagon/genetics/metabolismGlucagon-Secreting Cells/cytology/drug effectsGlucose Tolerance TestHumansInsulin-Secreting Cells/cytology/drug effectsInterleukin-6/metabolismMaleMiceMice, Inbred C57BLMice, KnockoutPhosphorylation/drug effectsProtein Precursors/genetics/metabolismRNA, Messenger/genetics/metabolismRatsRats, WistarReceptors, Interleukin-6/genetics/metabolismSTAT3 Transcription Factor/metabolism
PMID: 18719127
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Other version: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18719127
Research groups Fonction de l'îlot de Langerhans (324)
La transplantation d'îlots de Langerhans (623)
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ELLINGSGAARD, Helga et al. Interleukin-6 regulates pancreatic alpha-cell mass expansion. In: Proceedings of the National Academy of Sciences of the United States of America, 2008, vol. 105, n° 35, p. 13163-8. doi: 10.1073/pnas.0801059105 https://archive-ouverte.unige.ch/unige:1828

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Deposited on : 2009-05-28

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