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• W4243399160 abstract "POINT-COUNTERPOINTREBUTTAL FROM DR. MOONEYPublished Online:01 Feb 2007https://doi.org/10.1152/japplphysiol.01208c.2006MoreSectionsPDF (41 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmail As anticipated, Drs. Pedersen and Febbraio do not view IL-6 as a bad guy in insulin action. Let's examine their argument. Acute IL-6 infusions in healthy adults have little or no effect on hepatic glucose metabolism while promoting utilization in skeletal muscle. The critical limitation of these infusion studies, however, is that they do not replicate the chronic elevation of IL-6 in obesity-associated insulin resistance. To date, no human studies adequately address chronic effects of IL-6 on insulin action. A polymorphism in the human IL-6 gene promoter at −174 may chronically affect circulating IL-6 and alter risk of insulin resistance and diabetes, but conclusions are conflicting. My colleagues cite one study (8) to support their arguments, but the report actually concludes that the C-174C genotype alone is not associated with diabetic risk. In another recent study, the G-174G genotype was associated with increased plasma IL-6 and reduced insulin sensitivity (2). My colleagues also cite human studies with IL-6 receptor blocking antibodies (1, 4, 9), but the articles actually make no mention of glucose levels. Unfortunately, no clinical studies with these antibodies have analyzed glucose metabolism.Without definitive human studies, an understanding of the effects of chronic IL-6 must come from animal and in vitro studies. Depletion of circulating IL-6 in obese mice improved hepatic insulin responsiveness but had no effect in lean mice (7). This supports the conclusion that IL-6 is an important mediator of obesity-associated insulin resistance and is more than the marker of obesity that my colleagues contend (3). This is further supported by Kern et al. (6) who demonstrated that circulating IL-6 levels correlate with insulin resistance independent of BMI.Finally, tissue-specific differences in response to IL-6 may underlie the two faces of IL-6. My colleagues link IL-6-dependent activation of AMP kinase in L6 myotubes to beneficial metabolic effects of IL-6 in skeletal muscle (6). Interestingly, they had questioned in vitro approaches, particularly those using supraphysiological IL-6 concentrations, yet 100 ng/ml IL-6 was used in their study. We have shown IL-6- dependent inhibition of insulin signaling and increased expression of SOCS-3, a potential mediator of insulin resistance, in hepatocytes in response to fivefold less IL-6 (10). Additionally, IL-6 induces little SOCS-3 in myotubes and is not an effective activator of AMP kinase in liver (5). This supports the conclusion that the liver is a major site for IL-6-dependent dysregulation of insulin action while skeletal muscle may not be a target for this effect.REFERENCES1 Atlizumab: anti-IL6 receptor antibody-Chugai, anti-interleukin-6 receptor antibody-Chugai, MRA-Chugai. BioDrugs 17: 369–372, 2003.Crossref | PubMed | ISI | Google Scholar2 Cardellini M, Perego L, D'Adamo M, Marini MA, Procopio C, Hribal ML, Andreozzi F, Frontoni S, Giacomelli M, Paganelli M, Pontiroli AE, Lauro R, Folli F, Sesti G. C-174G polymorphism in the promoter of the interleukin-6 gene is associated with insulin resistance. Diabetes Care 28: 2007–2012, 2005.Crossref | PubMed | ISI | Google Scholar3 Carey AL, Bruce CR, Sacchetti M, Anderson MJ, Olsen DB, Saltin B, Hawley JA, Febbraio MA. Interleukin-6 and tumor necrosis factor-alpha are not increased in patients with Type 2 diabetes: evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness. Diabetologia 47: 1029–1037, 2004.Crossref | PubMed | ISI | Google Scholar4 Choy EH, Isenberg DA, Garrood T, Farrow S, Ioannou Y, Bird H, Cheung N, Williams B, Hazleman B, Price R, Yoshizaki K, Nishimoto N, Kishimoto T, Panayi GS. Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum 46: 3143–3150, 2002.Crossref | PubMed | Google Scholar5 Kelly M, Keller C, Avilucea PR, Keller P, Luo Z, Xiang X, Giralt M, Hidalgo J, Saha AK, Pedersen BK, Ruderman NB. AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem Biophys Res Commun 320: 449–454, 2004.Crossref | PubMed | ISI | Google Scholar6 Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 280: E745–E751, 2001.Link | ISI | Google Scholar7 Klover PJ, Clementi AH, Mooney RA. Interleukin-6 depletion selectively improves hepatic insulin action in obesity. Endocrinology 146: 3417–3427, 2005.Crossref | PubMed | ISI | Google Scholar8 Kubaszek A, Pihlajamaki J, Komarovski V, Lindi V, Lindstrom J, Eriksson J, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Tuomilehto J, Uusitupa M, Laakso M. Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. Diabetes 52: 1872–1876, 2003.Crossref | PubMed | ISI | Google Scholar9 Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Hashimoto J, Azuma J, Kishimoto T. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 50: 1761–1769, 2004.Crossref | PubMed | Google Scholar10 Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes 51: 3391–3399, 2002.Crossref | PubMed | ISI | Google Scholar Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 102Issue 2February 2007Pages 818-819 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.01208c.2006History Published online 1 February 2007 Published in print 1 February 2007 PDF download Metrics Downloaded 75 times" @default.
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