Dataset: Increased SRF Transcriptional Activity is a Novel Signature of Insulin Resistance in Humans and Mice
Insulin resistance in skeletal muscle is a key phenotype associated with type 2 diabetes (T2D) and is even present in offspring of...
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. 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.
- Species:
- human
- Samples:
- 50
- Source:
- E-GEOD-25462
- Updated:
- Dec.12, 2014
- Registered:
- Sep.15, 2014
| Sample | FASTING GLUCOSE (IV0GAVG) | AGE (YEARS) | BODY MASS INDEX (KG/M2) | GENDER | SI | 2 HOUR GLUCOSE (OGTT) | HEMOGLOBIN A1C | FAMILY HISTORY | FASTING GLUCOSE (OGTT) | WAIST HIP RATIO | FASTING INSULIN (IV0INAVG) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| GSM624925 | 90 | 39 | 20 | female | 11.91 | 125.0 | 5.6 | Family history negative | 85.0 | 1.364 | 2.7 |
| GSM624926 | 87 | 23 | 23 | male | 8.31 | 112.0 | 5.0 | Family history negative | 84.5 | 0.792 | 4.4 |
| GSM624927 | 79 | 42 | 21 | female | 1.59 | 124.0 | 4.6 | Family history negative | 67.0 | 0.824 | 6.1 |
| GSM624928 | 91 | 40 | 27 | male | 8.38 | 150.0 | 5.1 | Family history negative | 103.0 | 0.981 | 5.6 |
| GSM624929 | 94 | 57 | 22 | female | 4.06 | 95.0 | 5.5 | Family history negative | 81.5 | 0.0 | 5.0 |
| GSM624930 | 91 | 23 | 25 | female | 6.53 | 90.0 | 4.3 | Family history negative | 77.0 | 0.833 | 8.0 |
| GSM62493 | 88 | 46 | 26 | female | 10.39 | 77.0 | 5.4 | Family history negative | 85.5 | 0.845 | 4.4 |
| GSM624932 | 83 | 28 | 24 | male | 14.28 | 58.0 | 4.7 | Family history negative | 78.5 | 0.865 | 1.7 |
| GSM624933 | 88 | 38 | 25 | male | 10.29 | 38.0 | 5.1 | Family history negative | 91.5 | 0.902 | 4.6 |
| GSM624934 | 109 | 50 | 33 | male | 1.7 | 146.0 | 5.4 | Family history negative | 105.0 | 1.018 | 15.9 |
| GSM624935 | 95 | 24 | 24 | female | 4.19 | 99.0 | 4.2 | Family history negative | 92.0 | 0.832 | 4.8 |
| GSM624936 | 85 | 32 | 25 | female | 6.95 | 105.0 | 5.3 | Family history negative | 86.5 | 0.836 | 5.3 |
| GSM624937 | 83 | 24 | 30 | female | 5.66 | 94.0 | 5.0 | Family history negative | 89.0 | 0.892 | 8.5 |
| GSM624938 | 96 | 45 | 36 | female | 9.64 | 106.0 | 5.0 | Family history positive - 1 parent | 91.5 | 0.836 | 4.6 |
| GSM624939 | 93 | 43 | 30 | male | 3.04 | 97.0 | 5.3 | Family history positive - 1 parent | 91.5 | 0.925 | 4.8 |
| GSM624940 | 95 | 37 | 25 | female | 2.56 | 141.0 | 5.4 | Family history positive - 1 parent | 102.5 | 0.805 | 3.7 |
| GSM62494 | 96 | 31 | 20 | female | 7.61 | 128.0 | 4.9 | Family history positive - 1 parent | 93.0 | 0.745 | 5.1 |
| GSM624942 | 92 | 26 | 26 | female | 4.5 | 169.0 | 5.0 | Family history positive - 1 parent | 86.5 | 0.755 | 2.1 |
| GSM624943 | 93 | 25 | 39 | female | 1.06 | 149.0 | 5.7 | Family history positive - 1 parent | 100.5 | 0.957 | 22.0 |
| GSM624944 | 85 | 31 | 26 | male | 6.02 | 115.0 | 4.9 | Family history positive - 1 parent | 85.5 | 0.824 | 1.9 |
| GSM624945 | 86 | 47 | 23 | female | 3.18 | 123.0 | 4.7 | Family history positive - 1 parent | 91.0 | 0.805 | 5.6 |
| GSM624946 | 94 | 44 | 31 | female | 4.45 | 72.0 | 5.0 | Family history positive - 1 parent | 98.5 | 0.914 | 14.3 |
| GSM624947 | 98 | 44 | 25 | male | 1.77 | 151.0 | 4.8 | Family history positive - 1 parent | 93.5 | 0.905 | 10.0 |
| GSM624948 | 83 | 21 | 27 | male | 1.34 | 114.0 | 4.5 | Family history positive - 1 parent | 84.5 | 0.948 | 14.3 |
| GSM624949 | 81 | 25 | 22 | female | 6.9 | 127.0 | 4.9 | Family history positive - 1 parent | 90.5 | 0.885 | 6.5 |
| GSM624950 | 86 | 27 | 24 | male | 5.65 | 148.0 | 4.7 | Family history positive - 1 parent | 87.0 | 0.865 | 4.2 |
| GSM62495 | 98 | 51 | 26 | female | 4.21 | 146.0 | 4.8 | Family history positive - 1 parent | 101.0 | 0.8 | 5.4 |
| GSM624952 | 112 | 25 | 42 | female | 1.62 | 170.0 | 5.6 | Family history positive - 2 parents | 99.5 | 0.808 | 15.6 |
| GSM624953 | 89 | 24 | 20 | male | 3.84 | 148.0 | 5.4 | Family history positive - 2 parents | 94.5 | 0.791 | 5.2 |
| GSM624954 | 91 | 46 | 23 | male | 6.11 | 105.0 | 5.2 | Family history positive - 2 parents | 90.0 | 0.953 | 7.7 |
| GSM624955 | 102 | 60 | 32 | female | 0.91 | 163.0 | 5.7 | Family history positive - 2 parents | 94.5 | 0.911 | 16.7 |
| GSM624956 | 88 | 25 | 22 | female | 4.02 | 36.0 | 4.6 | Family history positive - 2 parents | 90.0 | 0.71 | 8.6 |
| GSM624957 | 77 | 43 | 25 | female | 8.43 | 90.0 | 4.6 | Family history positive - 2 parents | 83.5 | 0.784 | 1.5 |
| GSM624958 | 98 | 46 | 31 | male | 2.02 | 144.0 | 4.8 | Family history positive - 2 parents | 99.5 | 0.968 | 10.5 |
| GSM624959 | 90 | 52 | 30 | male | 1.71 | 118.0 | 5.4 | Family history positive - 2 parents | 91.5 | 0.985 | 11.0 |
| GSM624960 | 101 | 40 | 35 | male | 2.2 | 155.0 | 5.4 | Family history positive - 2 parents | 98.0 | 0.958 | 13.8 |
| GSM62496 | 105 | 62 | 28 | male | 0.49 | nan | 5.9 | DM | nan | 0.88 | 24.75 |
| GSM624962 | 94 | 52 | 37 | female | 1.34 | nan | 5.5 | DM | nan | 0.923 | 21.1 |
| GSM624963 | 88 | 55 | 44 | female | 1.22 | nan | 5.3 | DM | nan | 0.905 | 12.9 |
| GSM624964 | 119 | 60 | 27 | male | nan | nan | 8.5 | DM | nan | 0.94 | 5.3 |
| GSM624965 | 121 | 36 | 29 | male | 1.43 | nan | 6.6 | DM | nan | 1.085 | 15.7 |
| GSM624966 | 222 | 59 | 25 | male | 2.07 | nan | 9.2 | DM | nan | 0.953 | 10.95 |
| GSM624967 | 185 | 26 | 49 | female | nan | nan | 7.8 | DM | nan | 0.886 | 94.38 |
| GSM624968 | 213 | 35 | 28 | female | 3.6 | nan | 8.5 | DM | nan | 0.906 | 10.93 |
| GSM624969 | 101 | 51 | 27 | female | 3.79 | nan | 6.6 | DM | nan | 0.822 | 33.0 |
| GSM624970 | 102 | 67 | 34 | female | 0.58 | nan | 6.4 | DM | nan | 0.963 | 17.8 |
| GSM62497 | 93 | 50 | 25 | male | 4.67 | 65.0 | 5.4 | Family history negative | 84.0 | 0.929 | 5.3 |
| GSM624972 | 105 | 34 | 24 | male | 3.25 | 146.0 | 4.7 | Family history positive - 2 parents | 99.5 | 0.903 | 9.8 |
| GSM624973 | 94 | 52 | 27 | male | 6.28 | 117.0 | 4.9 | Family history negative | 91.5 | 0.828 | 4.2 |
| GSM624974 | 94 | 49 | 36 | female | 6.76 | 99.0 | 5.3 | Family history positive - 1 parent | 88.5 | 0.853 | 4.5 |