title: 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: BACKGROUND
  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.
  
  
  METHODS
  This was a randomized, double-blind, crossover study.
  
  
  METHODS
  The study was based on ambulatory care.
  
  
  METHODS
  Participants included nondiabetic, obese subjects with the metabolic syndrome.
  
  
  METHODS
  Intervention included 150 mg anakinra sc once daily or matching placebo for 4 wk.
  
  
  METHODS
  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 (r(2) = 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.
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands. e.vanasseldonk@aig.umcn.nl
authors.forename: Edwin J P
authors.initials: EJ
authors.lastname: van Asseldonk
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
authors.forename: Tim B
authors.initials: TB
authors.lastname: Koenen
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Tack
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001786:Blood Glucose / Q000378:metabolism*; D002097:C-Reactive Protein / Q000378:metabolism; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D002097:C-Reactive Protein