IL-1 receptor antagonism and muscle gene expression in patients with type 2 diabetes.
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.
Berchtold
Lukas A
LA
Hagedorn Research Institute, Gentofte, Denmark, Steno Diabetes Center, Gentofte, Denmark.
Larsen
Claus M
CM
Vaag
Allan
A
Faulenbach
Mirjam
M
Workman
Christopher T
CT
Kruhøffer
Mogens
M
Donath
Marc
M
Mandrup-Poulsen
Thomas
T
D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology* / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors*; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D052097:Quadriceps Muscle / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
C508600:IL6 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D009124:Muscle Proteins