| Title: |
Adipocytes desensitized and resensitized to insulin through the combined action of TNF-alpha, aspirin, and troglitazone. [original title: A Gene Expression Signature for Insulin Resistance]
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| Organism(s): |
Mus musculus
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| Description: |
3T3-L1 fibroblasts were cultured and treated in 3 stages. First, they were differentiated into adipocytes with >80% efficiency. Second, they were treated with or without TNF-alpha for 48 hours; treated cells became insulin-resistant. Third, they were treated with or without aspirin and troglitazone for an additional 24 hours; these treated cells became resensitized to insulin. [original description: Insulin resistance is a heterogeneous disorder caused by a range of genetic and environmental factors, and we hypothesise that its aetiology varies considerably between individuals. This heterogeneity provides significant challenges to the development of effective therapeutic regimes for long-term management of type 2 diabetes. We describe a novel strategy, using large-scale gene expression profiling, to develop a gene expression signature (GES) that reflects the overall state of insulin resistance in cells and patients. The GES was developed from 3T3-L1 adipocytes that were made “insulin resistant” by treatment with tumour necrosis factor (TNF-alpha and then reversed with aspirin and troglitazone (“re-sensitized”). The GES consisted of 5 genes whose expression levels best discriminated between the insulin resistant and insulin re-sensitized states. We then used this GES to screen a compound library for agents that affected the GES genes in 3T3-L1 adipocytes in a way that most closely resembled the changes seen when insulin resistance was successfully reversed using aspirin and troglitazone. This screen identified both known and new insulin sensitising compounds including non-steroidal anti-inflammatory agents, beta-adrenergic antagonists, beta-lactams and sodium channel blockers. We tested the biological relevance of this GES in participants in the San Antonio Family Heart Study (n = 1,240) and showed that patients with the lowest GES scores were more insulin resistant (according to HOMA_IR and fasting plasma insulin levels, P < 0.001). These findings show that GES technology can be used for both discovery of insulin sensitising compounds and characterisation of patients into subtypes of insulin resistance according to GES scores, opening the possibility of developing a personalised medicine approach to type 2 diabetes. Three-condition experiment, Vehicle, TNF and TNF+ASA+TGZ with biological replicates: 22 Vehicle, 21 TNF and 21 TNF+ASA+TGZ , independently grown and harvested. One replicate per array.]
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| Design(s): |
transcription profiling by array
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| Publication(s): |
Konstantopoulos N, Foletta VC, Segal DH, Shields KA, Sanigorski A, Windmill K, Swinton C, Connor T, Wanyonyi S, Dyer TD, Fahey RP, Watt RA, Curran JE, Molero JC, Krippner G, Collier GR, James DE, Blangero J, Jowett JB, Walder KR
A gene expression signature for insulin resistance.
PubMed:21081660
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| Sample attribute(s): |
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| TNFalpha
2
recorded
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TNF-alpha; tumor necrosis factor
control condition
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| aspirin
2
recorded
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acetylsalicylic acid
control condition
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| Material Type
1
recorded
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Fully differentiated 3T3-L1 adipocytes
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| cell line type
1
recorded
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differentiated
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| cell line
1
recorded
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3T3-L1 cell
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| differentiated into
1
recorded
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adipocyte
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| Label
2
recorded
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Cy3
Cy5
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| troglitazone
2
recorded
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control condition
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| organism
1
recorded
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Mus musculus
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| Contact(s): |
Ken Walder Nicky KonstantopoulosGreg CollierJuan-Carlos MoleroDavid SegalStephen WanyonyiKatherine ShieldsVictoria FolettaAndrew SanigorskiJohn BlangeroJeremy JowettJoanne CurranThomas DyerGuy KrippnerKelly WindmillTim ConnorDavid JamesAndrew SanigorskiCourtney Swinton
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| Release Date: |
9/10/2010
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| Submission Date: |
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| Metadata Downloads |
Download Study Metadata as ISAtabDownload Study Metadata as ISAtab
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| Assay Downloads |
| transcription profiling using DNA microarray
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| 64 assays |
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