Interleukin-1-receptor antagonist in type 2 diabetes mellitus

N Engl J Med. 2007 Apr 12;356(15):1517-26. doi: 10.1056/NEJMoa065213.

Abstract

Background: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis.

Methods: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic-euglycemic clamp study. The primary end point was a change in the level of glycated hemoglobin, and secondary end points were changes in beta-cell function, insulin sensitivity, and inflammatory markers.

Results: At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 percentage point lower than in the placebo group (P=0.03); C-peptide secretion was enhanced (P=0.05), and there were reductions in the ratio of proinsulin to insulin (P=0.005) and in levels of interleukin-6 (P<0.001) and C-reactive protein (P=0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was not observed, and there were no apparent drug-related serious adverse events.

Conclusions: The blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation. (ClinicalTrials.gov number, NCT00303394 [ClinicalTrials.gov].).

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Glucose / metabolism
  • Body Mass Index
  • C-Reactive Protein / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Double-Blind Method
  • Female
  • Gene Expression Regulation / drug effects
  • Glucose Tolerance Test
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Glycated Hemoglobin A / metabolism
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Humans
  • Insulin Resistance / physiology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Interleukin 1 Receptor Antagonist Protein / adverse effects
  • Interleukin 1 Receptor Antagonist Protein / pharmacology
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use*
  • Interleukin-6 / blood
  • Male
  • Middle Aged
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-1 / antagonists & inhibitors*
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Blood Glucose
  • Glucose Transporter Type 4
  • Glycated Hemoglobin A
  • Heat-Shock Proteins
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-6
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • RNA, Messenger
  • Receptors, Interleukin-1
  • Recombinant Proteins
  • Transcription Factors
  • C-Reactive Protein

Associated data

  • ClinicalTrials.gov/NCT00303394