title: A gene expression signature for insulin resistance.
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.
authors.affiliation: Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia. nicky.konstantopoulos@deakin.edu.au
authors.forename: Nicky
authors.initials: N
authors.lastname: Konstantopoulos
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Foletta
authors.forename: David H
authors.initials: DH
authors.lastname: Segal
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Shields
authors.forename: Andrew
authors.initials: A
authors.lastname: Sanigorski
authors.forename: Kelly
authors.initials: K
authors.lastname: Windmill
authors.forename: Courtney
authors.initials: C
authors.lastname: Swinton
authors.forename: Tim
authors.initials: T
authors.lastname: Connor
authors.forename: Stephen
authors.initials: S
authors.lastname: Wanyonyi
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.forename: Richard P
authors.initials: RP
authors.lastname: Fahey
authors.forename: Rose A
authors.initials: RA
authors.lastname: Watt
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Molero
authors.forename: Guy
authors.initials: G
authors.lastname: Krippner
authors.forename: Greg R
authors.initials: GR
authors.lastname: Collier
authors.forename: David E
authors.initials: DE
authors.lastname: James
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Jowett
authors.forename: Ken R
authors.initials: KR
authors.lastname: Walder
mesh_terms: D041721:3T3-L1 Cells; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D021381:Protein Transport / Q000187:drug effects; D015203:Reproducibility of Results; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D055815:Young Adult
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha