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Series GSE25462 Query DataSets for GSE25462
Status Public on Mar 01, 2011
Title Increased SRF Transcriptional Activity is a Novel Signature of Insulin Resistance in Humans and Mice
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Insulin 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.
 
Overall design 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.
 
Contributor(s) Patti M, Jin W, Goldfine A, Boes T, Henry RR, Ciaraldi T, Kim E, Emecan M, Fitzpatrick C, Sen A, Shah A, Mun E, Vokes M, Schroeder J, Tatro E, Jiminez-Chillaron J
Citation(s) 21393865, 27689005
Submission date Nov 17, 2010
Last update date Mar 25, 2019
Contact name Mary Elizabeth Patti
E-mail(s) mary.elizabeth.patti@joslin.harvard.edu
Phone 6177351966
Fax 6177322593
Organization name Joslin Diabetes Center
Department Research Division
Street address 1 Joslin Place
City Boston
State/province MA
ZIP/Postal code 02215
Country USA
 
Platforms (1)
GPL570 [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array
Samples (50)
GSM624925 Muscle-FamilyHistoryNegative-1
GSM624926 Muscle-FamilyHistoryNegative-2
GSM624927 Muscle-FamilyHistoryNegative-3
Relations
BioProject PRJNA134597

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE25462_RAW.tar 237.3 Mb (http)(custom) TAR (of CEL)
Raw data provided as supplementary file
Processed data included within Sample table

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