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This Article Full Text Full Text (PDF) All Versions of this Article: JOE-09-0413v1 204/3/265    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fosgerau, K Articles by Steensberg, A Search for Related Content PubMed PubMed Citation Articles by Fosgerau, K Articles by Steensberg, A

¹ Rheoscience, Department of In Vivo Pharmacology, 2730 Herlev, Denmark
² Department of Infectious Diseases, Faculty of Health Sciences, Centre of Inflammation and Metabolism
³ Department of Clinical Immunology, Faculty of Health Sciences, Rigshospitalet, 2100 Copenhagen, Denmark
⁴ Department of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, 2000 Copenhagen, Denmark
⁵ Steno Diabetes Center, 2820 Gentofte, Denmark
⁶ Faculty of Health Sciences, University of Aarhus, 8000 Aarhus, Denmark

(Correspondence should be addressed to A Steensberg; Email: asee{at}novonordisk.com)

Interleukin-6 (IL6) is critically involved in inflammation and metabolism. About 1% of people produce IL6 autoantibodies (aAb-IL6) that impair IL6 signaling in vivo. We tested the hypothesis that the prevalence of such aAb-IL6 is increased in type 2 diabetic patients and that aAb-IL6 plays a direct role in causing hyperglycemia. In humans, the prevalence of circulating high-affinity neutralizing aAb-IL6 was 2.5% in the type 2 diabetic patients and 1% in the controls (odds ratio 2.5, 95% confidence interval 1.2–4.9, P=0.01). To test for the role of aAb-IL6 in causing hyperglycemia, such aAb-IL6 were induced in mice by a validated vaccination procedure. Mice with plasma levels of aAb-IL6 similar to the 2.5% type 2 diabetic patients developed obesity and impaired glucose tolerance (area under the curve (AUC) glucose, 2056±62 vs 1793±62, P=0.05) as compared with sham-vaccinated mice, when challenged with a high-fat diet. Mice with very high plasma levels of aAb-IL6 developed elevated fasting plasma glucose (mM, 4.8±0.4 vs 3.3±0.1, P<0.001) and impaired glucose tolerance (AUC glucose, 1340±38 vs 916±25, P<0.001) as compared with sham-control mice on normal chow. In conclusion, the prevalence of plasma aAb-IL6 at levels known to impair IL6 signaling in vivo is increased 2.5-fold in people with type 2 diabetes. In mice, matching levels of aAb-IL6 cause obesity and hyperglycemia. These data suggest that a small subset of type 2 diabetes may in part evolve from an autoimmune attack against IL6.