Treatment with Anakinra improves disposition index but not insulin sensitivity in nondiabetic subjects with the metabolic syndrome: a randomized, double-blind, placebo-controlled study

Abstract

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 x 10(-2) +/- 0.5 x 10(-2)) compared with placebo treatment (2.4 x 10(-2) +/- 0.3 x 10(-2) mumol/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 (r(2) = 0.46, P = 0.01). The disposition index increased significantly after anakinra treatment (P = 0.04), reflecting an improvement in beta-cell function. CONCLUSIONS: Our results suggest that anakinra does not improve insulin sensitivity in obese, insulin-resistant, nondiabetic subjects.