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.

Using Gene Expression Signatures to Dissect Insulin Resistance Subtypes

“…This was tested for association with HOMA measures of insulin resistance for each subject. Those patients whose expression profiles were most similar to the TNF GES showed a higher degree of insulin resistance as indicated by the HOMA score (P<0.001) (Konstantopoulos et al, 2011). This correlation is consistent with the use of GES technology to characterise an insulin resistant subtype in this population.…”

“…As proof of principle, we recently developed a GES for TNF -induced insulin resistance (Konstantopoulos et al, 2011). Using 3T3-L1 adipocytes as the cell-based model, we identified 3325 genes whose expression was altered by the induction of insulin resistance by TNF .…”

“…5). Screening for those compounds whose effects on the target genes mirrored the expression profile observed in the gene expression signature was successful in identifying known and novel insulin sensitising agents such as non-steroidal anti-inflammatory agents, -adrenergic antagonists, beta-lactams and sodium channel blockers (Konstantopoulos et al, 2011). Investigation of the GES genes, and their role in insulin resistance has also yielded positive outcomes.…”

3T3-L1 adipocytes display phenotypic characteristics of multiple adipocyte lineages

“…17 Adipogenesis was monitored by oil-red O staining, as previously described. 22 For acute norepinephrine treatments, cells were exposed to 1mM norepinephrine or vehicle (H 2 O) for 20 min for signaling analyses, or for 60 min for gene expression analyses.…”

Insulin Resistance and Environmental Pollutants: Experimental Evidence and Future Perspectives

“…Separating these stress response and PoD genes from the core insulin-sensitivity determining genes requires an additional step. One plausible method, previously described by Hayward et al (2011) and Konstantopoulos et al (2011), would be to resensitize cells to insulin by exposing resistant cells to drugs commonly applied in the treatment of IR [e.g., biguanides (metformin), thiazolidinediones (pioglitazone), nonsteroidal anti-inflammatory drugs]. The strength of this approach lies within the coverage of the multifactorial nature of hepatic IR and selection of a common, inducer-aspecific PoT.…”