Insulin resistance and environmental pollutants: experimental evidence and future perspectives

Abstract

Background: The metabolic disruptor hypothesis postulates that environmental pollutants may be risk factors for metabolic diseases. Because insulin resistance is involved in most metabolic diseases and current health care prevention programs predominantly target insulin resistance or risk factors thereof, a critical analysis of the role of pollutants in insulin resistance might be important for future management of metabolic diseases.

Objectives: We aimed to critically review the available information linking pollutant exposure to insulin resistance and to open the discussion on future perspectives for metabolic disruptor identification and prioritization strategies.

Methods: We searched PubMed and Web of Science for experimental studies reporting on linkages between environmental pollutants and insulin resistance and identified a total of 23 studies as the prime literature.

Discussion: Recent studies specifically designed to investigate the effect of pollutants on insulin sensitivity show a potential causation of insulin resistance. Based on these studies, a summary of viable test systems and end points can be composed, allowing insight into what is missing and what is needed to create a standardized insulin resistance toxicity testing strategy.

Conclusions: It is clear that current research predominantly relies on top-down identification of insulin resistance-inducing metabolic disruptors and that the development of dedicated in vitro or ex vivo screens to allow animal sparing and time- and cost-effective bottom-up screening is a major future research need.

Figure 1

Schematic representation of an example of how an insulin-resistance pathway of toxicity (IR PoT) may be obtained. Steps 1–2: Exposure of in vitro models to three different inducers of IR followed by transcriptome analysis is expected to result in overlapping toxicogenomic profiles with “common genes” (CG) among the IR subtypes. This group of common genes is suggested to contain transcripts that are related to stress responses, to pathways of defense (PoD), as well as to the IR PoT. Steps 3–5: To separate the IR PoT genes, insulin-resistant cells may be treated with a sensitizer mix (S) containing drugs that improve insulin sensitivity. Transcriptome analysis of resensitized cells is expected to reveal which of the common genes among the IR subtypes expression is changed by resensitization. Those genes may then represent or define insulin sensitivity/resistance and, as such, reflect the IR PoT. Step 6: Further evaluation and validation steps are needed to assess how representative the IR PoT is and whether it is able to predict potential adverse in vivo effects. Steps 7–8: When IR PoT-based cellular assays can be developed, they should be integrated in a conceptual framework such as suggested in Table 1. Combined with single–end point or target-based assays, PoT-based cellular assays could be used as a mechanistic basis to identify and prioritize potential metabolic disruptors for further in-depth in vivo analysis.