ArrayExpress Uploader0human90205.6female125.011.9139Family history negative85.01.3642.787235.0male112.08.3123Family history negative84.50.7924.479214.6female124.01.5942Family history negative67.00.8246.191275.1male150.08.3840Family history negative103.00.9815.694225.5female95.04.0657Family history negative81.50.05.091254.3female90.06.5323Family history negative77.00.8338.088265.4female77.010.3946Family history negative85.50.8454.483244.7male58.014.2828Family history negative78.50.8651.788255.1male38.010.2938Family history negative91.50.9024.6109335.4male146.01.750Family history negative105.01.01815.995244.2female99.04.1924Family history negative92.00.8324.885255.3female105.06.9532Family history negative86.50.8365.383305.0female94.05.6624Family history negative89.00.8928.596365.0female106.09.6445Family history positive - 1 parent91.50.8364.693305.3male97.03.0443Family history positive - 1 parent91.50.9254.895255.4female141.02.5637Family history positive - 1 parent102.50.8053.796204.9female128.07.6131Family history positive - 1 parent93.00.7455.192265.0female169.04.526Family history positive - 1 parent86.50.7552.193395.7female149.01.0625Family history positive - 1 parent100.50.95722.085264.9male115.06.0231Family history positive - 1 parent85.50.8241.986234.7female123.03.1847Family history positive - 1 parent91.00.8055.694315.0female72.04.4544Family history positive - 1 parent98.50.91414.398254.8male151.01.7744Family history positive - 1 parent93.50.90510.083274.5male114.01.3421Family history positive - 1 parent84.50.94814.381224.9female127.06.925Family history positive - 1 parent90.50.8856.586244.7male148.05.6527Family history positive - 1 parent87.00.8654.298264.8female146.04.2151Family history positive - 1 parent101.00.85.4112425.6female170.01.6225Family history positive - 2 parents99.50.80815.689205.4male148.03.8424Family history positive - 2 parents94.50.7915.291235.2male105.06.1146Family history positive - 2 parents90.00.9537.7102325.7female163.00.9160Family history positive - 2 parents94.50.91116.788224.6female36.04.0225Family history positive - 2 parents90.00.718.677254.6female90.08.4343Family history positive - 2 parents83.50.7841.598314.8male144.02.0246Family history positive - 2 parents99.50.96810.590305.4male118.01.7152Family history positive - 2 parents91.50.98511.0101355.4male155.02.240Family history positive - 2 parents98.00.95813.8105285.9malenan0.4962DMnan0.8824.7594375.5femalenan1.3452DMnan0.92321.188445.3femalenan1.2255DMnan0.90512.9119278.5malenannan60DMnan0.945.3121296.6malenan1.4336DMnan1.08515.7222259.2malenan2.0759DMnan0.95310.95185497.8femalenannan26DMnan0.88694.38213288.5femalenan3.635DMnan0.90610.93101276.6femalenan3.7951DMnan0.82233.0102346.4femalenan0.5867DMnan0.96317.893255.4male65.04.6750Family history negative84.00.9295.3105244.7male146.03.2534Family history positive - 2 parents99.50.9039.894274.9male117.06.2852Family history negative91.50.8284.294365.3female99.06.7649Family history positive - 1 parent88.50.8534.53873arrayexpress_sid4Insulin resistance in skeletal muscle is a key phenotype associated with type 2 diabetes (T2D) and is even present in offspring of...E-GEOD-25462/profile/8773/arrayexpressuploader1150actinactin cytoskeletoncytoskeletongenomeglucoseinsulinmuscleserumDec.12, 2014Falseincreased-srf-transcriptional-activity-is-a-novelE-GEOD-25462_A-AFFY-44Increased SRF Transcriptional Activity is a Novel Signature of Insulin Resistance in Humans and MiceSep.15, 2014Insulin resistance in skeletal muscle is a key phenotype associated with type 2 diabetes (T2D) and is even present in offspring of diabetic parents. However, molecular mediators of insulin resistance remain unclear. We find that the top-ranking gene set in expression analysis of muscle from humans with T2D and normoglycemic insulin resistant subjects with parental family history (FH+) of T2D is increased expression of actin cytoskeleton genes regulated by serum response factor (SRF) and its coactivator MKL1. Furthermore, the SRF activator STARS is upregulated in FH+ and T2D and inversely correlated with insulin sensitivity. These patterns are recapitulated in insulin resistant mice, and linked to alterations in two other regulators of this pathway: reduced G-actin and increased nuclear localization of MKL1. Both genetic and pharmacologic manipulation of STARS/MKL1/SRF pathway significantly alter insulin action: 1) Overexpression of MKL1 or reduction in G-actin decreased insulin-stimulated Akt phosphorylation; 2) reduced STARS expression increased insulin signalling and glucose uptake, and 3) SRF inhibition by CCG-1423 reduced nuclear MKL1, improved glucose uptake, and improved glucose tolerance in insulin resistant mice in vivo. Thus, SRF pathway alterations are a signature of insulin resistance which may also contribute to T2D pathogenesis and be a novel therapeutic target. Skeletal muscle samples were obtained from 10 subjects with type 2 diabetes, 25 subjects with a family history of type 2 diabetes (one or both parents), and 15 subjects with no family history of type 2 diabetes. In this analysis RNA was isolated for cRNA preparation and hybridized to Affymetrix Human Genome U133 Plus 2.0 microarrays.http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-25462http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-25462/samples/