No increased insulin sensitivity after a single intravenous administrationof a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients

Inhibition of tumor necrosis factor (TNF)-alpha results in a marked increas e in insulin sensitivity in obese rodents. We investigated the influence of a TNF antagonist [Ro 45-2081, a recombinant fusion protein that consists o f the soluble TNF-receptor (p55) linked to the Fc portion of human IgG1] on insulin sensitivity of patients with android obesity. Seven patients (five women and two men; mean +/- so age, 41 +/- 4 yr; body mass index, 36.1 +/- 4.7 kg/m(2); waist to hip ratio, 0.99 +/- 0.11) were studied (three patien ts with normal glucose tolerance and four patients with impaired glucose to lerance or mild diabetes; all were hyperinsulinemic). Each patient underwen t two consecutive euglycemic hyperinsulinemic glucose-clamp tests: 48 h aft er injection of placebo and 48 h after a single iv injection of 50 mg Ro 45 -2081. In both tests, steady-state plasma glucose and insulin levels were s imilar. Insulin-mediated glucose disposal (2.23 +/- 0.74 us. 2.38 +/- 0.99 mg/kg(-1).min(-1)) and glucose metabolic clearance rate (2.28 +/- 0.85 vs. 2.48 +/- 1.03 mL/kg(-1)min(-1))were similar alter placebo and after the dru g. Indirect calorimetry showed no difference in substrate oxidation rates b etween the two experimental conditions. In conclusion, under the conditions of this study, no improvement in insulin sensitivity was observed in obese insulin-resistant patients following a single iv administration of a recom binant TNF receptor: Fc fusion protein.