Treatment with Anakinra Improves Disposition Index But Not Insulin Sensitivity in Nondiabetic Subjects with the Metabolic Syndrome: A Randomized, Double-Blind, Placebo-Controlled Study

Context: Obesity induces low-grade inflammation that may promote the development of insulin resistance. IL-1 is one of the key inflammatory factors. Objective: The objective of the study was to demonstrate improvement of insulin sensitivity by blocking IL-1. Design: This was a randomized, double-blind, crossover study. Setting: The study was based on ambulatory care. Participants: Participants included nondiabetic, obese subjects with the metabolic syndrome. Intervention: Intervention included 150 mg anakinra sc once daily or matching placebo for 4 wk. Main Outcome Measure: Insulin sensitivity as measured by euglycemic hyperinsulinemic clamp. Results: A total of 13 of 19 subjects completed the study. Although anakinra treatment resulted in a significantly lower level of inflammation illustrated by a reduction in circulating C-reactive protein concentrations and leukocyte numbers, insulin sensitivity was not significantly different after anakinra treatment (2.8 × 10−2 ± 0.5 × 10−2) compared with placebo treatment (2.4 × 10−2 ± 0.3 × 10−2 μmol/kg−1 · min−1 · pmol−1, P = 0.15). Adipose tissue examination, performed to analyze local effects of IL-1 receptor antagonist, showed an increased influx of macrophages after treatment with anakinra most likely due to an injection site reaction caused by the vehicle (0.28 ± 0.05 vs. 0.11 ± 0.01 macrophages per adipocyte, P = 0.005). The differences in individual subject insulin sensitivity after anakinra as compared with placebo between subjects were negatively correlated with macrophage infiltration into the adipose tissue (r2 = 0.46, P = 0.01). The disposition index increased significantly after anakinra treatment (P = 0.04), reflecting an improvement in β-cell function. Conclusions: Our results suggest that anakinra does not improve insulin sensitivity in obese, insulin-resistant, nondiabetic subjects.