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TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome.

Author(s): Stanley TL, Zanni MV, Johnsen S, Rasheed S, Makimura H, Lee H, Khor VK, Ahima RS, Grinspoon SK

Affiliation(s): Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.

Publication date & source: 2011-01, J Clin Endocrinol Metab., 96(1):E146-50. Epub 2010 Nov 3.

Publication type: Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

CONTEXT AND OBJECTIVE: Obesity is associated with activation of the TNF-alpha system, increased inflammatory markers, and insulin resistance. Although studies in rodents suggest that attenuation of TNF activity improves glucose homeostasis, the effect of prolonged inhibition of TNF-alpha with etanercept on inflammation and glucose homeostasis in a human model of obesity is not known. DESIGN AND PARTICIPANTS: Forty obese subjects with features of metabolic syndrome were randomized to etanercept or placebo, 50 mg twice weekly for 3 months, followed by 50 mg once weekly for 3 months. OUTCOME MEASURES: Subjects underwent oral glucose tolerance testing and measurement of serum inflammatory biomarkers and adipokines. Subcutaneous fat biopsy was performed in a subset for measurement of adipokine and TNF-alpha mRNA expression. RESULTS: Visceral adiposity was significantly associated with serum concentrations of TNF receptor 1 (TNFR1), TNFR2, and vascular cell adhesion molecule-1 and adipose tissue expression of TNF-alpha and SOCS-3 (all P < 0.05). Insulin resistance as assessed by homeostasis model assessment was significantly associated with TNFR1, C-reactive protein, IL-6, and soluble intracellular adhesion molecule-1 (sICAM-1) (all P < 0.05). Etanercept significantly improved fasting glucose (treatment effect vs. placebo over 6 months, -10.8 +/- 4.4%, P = 0.02). Etanercept also increased the ratio of high molecular weight adiponectin to total adiponectin (+22.1 +/- 9.2% vs. placebo, P = 0.02), and decreased levels of sICAM-1 (-11 +/- 2% vs. placebo, P < 0.0001). In contrast, body composition, lipids, C-reactive protein, and IL-6 were unchanged after 6 months. CONCLUSIONS: Prolonged therapy with etanercept improved fasting glucose, increased the ratio of high molecular weight to total adiponectin, and decreased sICAM-1 in obese subjects with abnormal glucose homeostasis and significant subclinical inflammation.

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