Interleukin-1-receptor antagonist in type 2 diabetes mellitus.
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Interleukin-1-receptor antagonist in type 2 diabetes mellitus. / Larsen, Claus M; Faulenbach, Mirjam; Vaag, Allan; Vølund, Aage; Ehses, Jan A; Seifert, Burkhardt; Mandrup-Poulsen, Thomas; Donath, Marc Y.
In: New England Journal of Medicine, Vol. 356, No. 15, 2007, p. 1517-26.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Interleukin-1-receptor antagonist in type 2 diabetes mellitus.
AU - Larsen, Claus M
AU - Faulenbach, Mirjam
AU - Vaag, Allan
AU - Vølund, Aage
AU - Ehses, Jan A
AU - Seifert, Burkhardt
AU - Mandrup-Poulsen, Thomas
AU - Donath, Marc Y
N1 - Keywords: Blood Glucose; Body Mass Index; C-Reactive Protein; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Gene Expression Regulation; Glucose Tolerance Test; Glucose Transporter Type 4; Heat-Shock Proteins; Hemoglobin A, Glycosylated; Humans; Insulin Resistance; Insulin-Secreting Cells; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Male; Middle Aged; RNA, Messenger; Receptors, Interleukin-1; Recombinant Proteins; Transcription Factors
PY - 2007
Y1 - 2007
N2 - 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].).
AB - 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].).
U2 - 10.1056/NEJMoa065213
DO - 10.1056/NEJMoa065213
M3 - Journal article
C2 - 17429083
VL - 356
SP - 1517
EP - 1526
JO - New England Journal of Medicine
JF - New England Journal of Medicine
SN - 0028-4793
IS - 15
ER -
ID: 8465605