A gene expression signature for insulin resistance

Nicky Konstantopoulos, Victoria C. Foletta, David H. Segal, Katherine A. Shields, Andrew Sanigorski, Kelly Windmill, Courtney Swinton, Tim Connor, Stephen Wanyonyi, Thomas D. Dyer, Richard P. Fahey, Rose A. Watt, Joanne E. Curran, Juan Carlos Molero, Guy Krippner, Greg R. Collier, David E. James, John Blangero, Jeremy B. Jowett, Ken R. Walder

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 largescale 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.

Original languageEnglish (US)
Pages (from-to)110-120
Number of pages11
JournalPhysiological Genomics
Volume43
Issue number3
DOIs
StatePublished - Feb 2011
Externally publishedYes

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Transcriptome
Insulin Resistance
Insulin
troglitazone
Adipocytes
Type 2 Diabetes Mellitus
Aspirin
Sodium Channel Blockers
Lactams
Precision Medicine
Adrenergic Antagonists
Gene Expression Profiling
Non-Steroidal Anti-Inflammatory Agents
Libraries
Fasting
Tumor Necrosis Factor-alpha
Technology
Gene Expression
Therapeutics
Genes

Keywords

  • Diabetes
  • Microarray
  • Personalized medicine
  • Screening

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Konstantopoulos, N., Foletta, V. C., Segal, D. H., Shields, K. A., Sanigorski, A., Windmill, K., ... Walder, K. R. (2011). A gene expression signature for insulin resistance. Physiological Genomics, 43(3), 110-120. https://doi.org/10.1152/physiolgenomics.00115.2010

A gene expression signature for insulin resistance. / 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 Carlos; Krippner, Guy; Collier, Greg R.; James, David E.; Blangero, John; Jowett, Jeremy B.; Walder, Ken R.

In: Physiological Genomics, Vol. 43, No. 3, 02.2011, p. 110-120.

Research output: Contribution to journalArticle

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 2011, 'A gene expression signature for insulin resistance', Physiological Genomics, vol. 43, no. 3, pp. 110-120. https://doi.org/10.1152/physiolgenomics.00115.2010
Konstantopoulos N, Foletta VC, Segal DH, Shields KA, Sanigorski A, Windmill K et al. A gene expression signature for insulin resistance. Physiological Genomics. 2011 Feb;43(3):110-120. https://doi.org/10.1152/physiolgenomics.00115.2010
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 Carlos ; Krippner, Guy ; Collier, Greg R. ; James, David E. ; Blangero, John ; Jowett, Jeremy B. ; Walder, Ken R. / A gene expression signature for insulin resistance. In: Physiological Genomics. 2011 ; Vol. 43, No. 3. pp. 110-120.
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