PMID:18719127

Citation	Ellingsgaard, H, Ehses, JA, Hammar, EB, Van Lommel, L, Quintens, R, Martens, G, Kerr-Conte, J, Pattou, F, Berney, T, Pipeleers, D, Halban, PA, Schuit, FC and Donath, MY (2008) Interleukin-6 regulates pancreatic alpha-cell mass expansion. Proc. Natl. Acad. Sci. U.S.A. 105:13163-8
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.
Links	PubMed PMC2529061 Online version:10.1073/pnas.0801059105
Keywords	Animals; Apoptosis/drug effects; Cell Proliferation/drug effects; Dietary Fats/pharmacology; Feeding Behavior/drug effects; Gene Expression Regulation/drug effects; Glucagon/genetics; Glucagon/metabolism; Glucagon-Secreting Cells/cytology; Glucagon-Secreting Cells/drug effects; Glucose Tolerance Test; Humans; Insulin-Secreting Cells/cytology; Insulin-Secreting Cells/drug effects; Interleukin-6/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation/drug effects; Protein Precursors/genetics; Protein Precursors/metabolism; RNA, Messenger/genetics; RNA, Messenger/metabolism; Rats; Rats, Wistar; Receptors, Interleukin-6/genetics; Receptors, Interleukin-6/metabolism; STAT3 Transcription Factor/metabolism
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