A gene expression signature for insulin resistance

Article

Konstantopoulos, Nicky, Foletta, Victoria C., Segal, David H., Shields, Katherine A., Sanigorski, Andrew, Windmill, Kelly, Swinton, Courtney, Connor, Tim, Wanyonyi, Stephen, Dyer, Thomas D., Fahey, Richard P., Watt, Rose A., Curran, Joanne E., Molero, Juan C., Krippner, Guy, Collier, Greg R., James, David E., Blangero, John, Jowett, Jeremy B. and Walder, Ken R.. 2011. "A gene expression signature for insulin resistance." Physiological Genomics. 43 (3), pp. 110-120. https://doi.org/10.1152/physiolgenomics.00115.2010
Article Title

A gene expression signature for insulin resistance

ERA Journal ID14629
Article CategoryArticle
AuthorsKonstantopoulos, Nicky (Author), Foletta, Victoria C. (Author), Segal, David H. (Author), Shields, Katherine A. (Author), Sanigorski, Andrew (Author), Windmill, Kelly (Author), Swinton, Courtney (Author), Connor, Tim (Author), Wanyonyi, Stephen (Author), Dyer, Thomas D. (Author), Fahey, Richard P. (Author), Watt, Rose A. (Author), Curran, Joanne E. (Author), Molero, Juan C. (Author), Krippner, Guy (Author), Collier, Greg R. (Author), James, David E. (Author), Blangero, John (Author), Jowett, Jeremy B. (Author) and Walder, Ken R. (Author)
Journal TitlePhysiological Genomics
Journal Citation43 (3), pp. 110-120
Number of Pages11
Year2011
Place of PublicationUnited States
ISSN1094-8341
1531-2267
Digital Object Identifier (DOI)https://doi.org/10.1152/physiolgenomics.00115.2010
Web Address (URL)https://journals.physiology.org/doi/full/10.1152/physiolgenomics.00115.2010
Abstract

Insulin resistance is a heterogeneous disorder caused by a range of genetic and environmental factors, and we hypothesize that its etiology 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 tumor necrosis factor-α (TNF-α) and then reversed with aspirin and troglitazone (“resensitized”). The GES consisted of five genes whose expression levels best discriminated between the insulin-resistant and insulin-resensitized 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 with aspirin and troglitazone. This screen identified both known and new insulin-sensitizing compounds including nonsteroidal anti-inflammatory agents, β-adrenergic antagonists, β-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 the discovery of insulin-sensitizing compounds and the characterization of patients into subtypes of insulin resistance according to GES scores, opening the possibility of developing a personalized medicine approach to type 2 diabetes.

Keywordsmicroarray; screening; diabetes;personalized medicine; tumor-necrosis-factor;
Contains Sensitive ContentDoes not contain sensitive content
ANZSRC Field of Research 2020320208. Endocrinology
320213. Medical genetics (excl. cancer genetics)
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Institution of OriginUniversity of Southern Queensland
Byline AffiliationsDeakin University
Baker Heart and Diabetes Institute, Australia
Texas Biomedical Research Institute, United States
Verva Pharmaceuticals, Australia
ChemGenex Pharmaceuticals, Australia
Garvan Institute of Medical Research, Australia
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