TY - JOUR

T1 - IL-1 receptor antagonism and muscle gene expression in patients with type 2 diabetes

AU - Berchtold, Lukas A

AU - Larsen, Claus M

AU - Vaag, Allan

AU - Faulenbach, Mirjam

AU - Workman, Christopher T

AU - Kruhøffer, Mogens

AU - Donath, Marc

AU - Mandrup-Poulsen, Thomas

PY - 2009

Y1 - 2009

N2 - Background. We have previously reported that systemic blockade of IL-1beta in patients with type 2 diabetes with anakinra (a recombinant human interleukin-1-receptor antagonist, IL-1Ra), lowered glycated hemoglobin improved beta-cell function and reduced circulating levels of IL-6 and CRP (7). To investigate the effects of IL-1Ra in insulin-sensitive tissue, gene expression levels in skeletal muscle from type 2 diabetic patients treated with IL-1Ra were analysed. Methods. Gene expression profiles in vastus lateralis muscle biopsies from five obese patients (BMI >27) were determined before and after 13 weeks of treatment with IL-1Ra (anakinra) using Affymetrix U133Plus2.0 GeneChips. Microarray data were normalized and analysed independently using four different algorithms; RMA, GCRMA, dChip and GCOS. Hypothesis tests were applied to the microarray data for each gene, and protein network analysis was used to identify biological networks/pathways affected by the treatment. Gene expression levels for candidate genes (COL1A1, CDKN1C, HSP70, HLA-A, IL-1 and IL-6) were determined by qRT-PCR in muscles of placebo- (n = 12) and anakinra-treated patients (n = 11). Results. The concordance of the variations of the transcripts identified as significantly regulated after IL-1Ra treatment was low. No significantly altered expression levels could be demonstrated after false discovery rate correction. The protein interaction network did not reveal any altered networks/pathways. None of the candidate genes, quantified by qRT-PCR, were significantly altered when comparing the number of transcripts before and after treatment for each individual. Conclusion. Treatment with IL-1Ra did not significantly affect gene expression levels in skeletal muscle in this limited and selected sample of obese patients with type 2 diabetes. Larger studies might confirm the lack of effect of anakinra on muscle tissue gene expression.

AB - Background. We have previously reported that systemic blockade of IL-1beta in patients with type 2 diabetes with anakinra (a recombinant human interleukin-1-receptor antagonist, IL-1Ra), lowered glycated hemoglobin improved beta-cell function and reduced circulating levels of IL-6 and CRP (7). To investigate the effects of IL-1Ra in insulin-sensitive tissue, gene expression levels in skeletal muscle from type 2 diabetic patients treated with IL-1Ra were analysed. Methods. Gene expression profiles in vastus lateralis muscle biopsies from five obese patients (BMI >27) were determined before and after 13 weeks of treatment with IL-1Ra (anakinra) using Affymetrix U133Plus2.0 GeneChips. Microarray data were normalized and analysed independently using four different algorithms; RMA, GCRMA, dChip and GCOS. Hypothesis tests were applied to the microarray data for each gene, and protein network analysis was used to identify biological networks/pathways affected by the treatment. Gene expression levels for candidate genes (COL1A1, CDKN1C, HSP70, HLA-A, IL-1 and IL-6) were determined by qRT-PCR in muscles of placebo- (n = 12) and anakinra-treated patients (n = 11). Results. The concordance of the variations of the transcripts identified as significantly regulated after IL-1Ra treatment was low. No significantly altered expression levels could be demonstrated after false discovery rate correction. The protein interaction network did not reveal any altered networks/pathways. None of the candidate genes, quantified by qRT-PCR, were significantly altered when comparing the number of transcripts before and after treatment for each individual. Conclusion. Treatment with IL-1Ra did not significantly affect gene expression levels in skeletal muscle in this limited and selected sample of obese patients with type 2 diabetes. Larger studies might confirm the lack of effect of anakinra on muscle tissue gene expression.

U2 - 10.1684/ecn.2009.0152

DO - 10.1684/ecn.2009.0152

M3 - Journal article

C2 - 19541594

VL - 20

SP - 81

EP - 87

JO - European Cytokine Network

JF - European Cytokine Network

SN - 1148-5493

IS - 2

ER -