Abstract and Introduction
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.
Introduction
The worldwide prevalence of metabolic diseases has substantially increased during the last few decades, and projections portend an even greater increase in the future (Finkelstein et al. 2012; Whiting et al. 2011). Although caloric consumption and sedentary lifestyle are surely major contributors to this rise, other nontraditional risk factors (e.g., environmental chemicals, stress, an altered gut microbiome) have been implicated as well (Thayer et al. 2012). The potential involvement of ubiquitous environmental pollutants in metabolic disease etiology, also known as the "metabolic disruptor hypothesis" (Casals-Casas and Desvergne 2011; Casals-Casas et al. 2008), has caught the interest of the scientific community and has been subject of intensive research over the last 5–10 years. At present, many institutions [e.g., U.S. National Institutes of Health (NIH 2011), U.S. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK 2011)] acknowledge and emphasize the need to understand the role of environmental exposures in metabolic disease development in order to inform future prevention and research strategies. Current prevention programs [e.g., U.S. Diabetes Prevention Program (Diabetes Prevention Program Research Group 2002), the European "IMAGE" program (Paulweber et al. 2010)] are aimed mainly at lifestyle interventions such as increasing physical activity and changing diet or, although less effective, pharmacological treatment (e.g., metformin, thiazolidinediones, orlistat). One of the major effects of these interventions and treatments is the management or improvement of insulin resistance (IR) (Nelson et al. 2013), a core pathophysiological process in the development of diabetes and a hallmark of most modern, metabolic diseases (e.g., metabolic syndrome, obesity, nonalcoholic fatty liver disease) (Samuel and Shulman 2012). Nevertheless, despite the central position of IR in metabolic diseases and current prevention strategies, the particular role of environmental chemicals in IR pathogenesis and the responsible molecular mechanisms have not been fully elucidated.
IR is defined as a state wherein normal concentrations of insulin evoke a less-than-normal biological response (Kahn 1978). It manifests itself in metabolically active tissues such as skeletal muscle, adipose tissue (peripheral IR), and liver (hepatic IR). Reduced sensitivity to insulin results in decreased insulin-stimulated glucose uptake together with a decline in glycogen synthesis in skeletal muscle and with impaired inhibition of lipolysis in adipose tissue. Hepatic IR is characterized by its selectivity: insulin fails to suppress glucose production, whereas fatty acid synthesis or lipogenesis is thought to remain intact or to be even hyperstimulated (Brown and Goldstein 2008). Thus, in the face of hyperinsulinemia in insulin-resistant conditions, the liver continues to produce glucose but also synthesizes large amounts of fatty acids and triglycerides, which accumulate in the liver, producing the pathological condition known as hepatic steatosis (Moon et al. 2012). Excess triglycerides are secreted via very low density lipoproteins, augmenting the levels of triglycerides in blood. The increased amount of fatty acids, derived from these triglycerides, may aggravate IR in muscle and adipose tissue and may contribute to β-cell dysfunction, ultimately leading to overt type 2 diabetes. As such, the triad of hypertriglyceridemia, hyperinsulinemia, and hyperglycemia characteristic for type 2 diabetes occurs (Brown and Goldstein 2008). Despite years of intensive research seeking to reveal the molecular pathogenesis underlying IR, the exact mechanisms are yet to be defined (Parker et al. 2011; Samuel and Shulman 2012).
To assess the relevance of the metabolic disruptor hypothesis for the human population, primary information can be derived from epidemiological studies. Given the increasing concern regarding the potential involvement of pollutants in metabolic disease etiology, the U.S. National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP) (NTP 2011) organized a workshop in 2011 that resulted in the generation of a publicly accessible database containing > 200 human studies linking environmental pollutants to diabetes and obesity (NTP 2012). The role of pollutants in diabetes and obesity was compelling in the series of papers published following this workshop (Behl et al. 2013; Maull et al. 2012; Taylor et al. 2013; Thayer et al. 2012) as well as in other reviews (Alonso-Magdalena et al. 2011; Hatch et al. 2010; Hectors et al. 2011; Neel and Sargis 2011; Tang-Péronard et al. 2011). With regard to IR in particular, several studies have investigated the potential association between pollutants and markers of insulin sensitivity (e.g., Barregard et al. 2013; Chang et al. 2010, 2011; Chen et al. 2008; Dirinck et al. 2011; Færch et al. 2012; Kern et al. 2004; Lee et al. 2007, 2011; Nelson et al. 2010; Raafat et al. 2012; Wang et al. 2012). The most convincing evidence for a positive association of exposure to environmental pollutants and IR is with phthalates (James-Todd et al. 2012; Lind et al. 2012; Stahlhut et al. 2007) and air pollutants (Kelishadi et al. 2009; Kim and Hong 2012). Although these reports show a potential role for environmental pollutants in metabolic diseases, all studies emphasized the need for experimental evidence providing proof of causation of IR, diabetes, or obesity by pollutants and recommend the development of a standardized experimental testing strategy for this purpose (e.g., Taylor et al. 2013; Thayer et al. 2012).
Given that IR is a key feature of diabetes and most other metabolic diseases and that IR has a central position in current prevention strategies, the focus of the present review is on the role of environmental pollutants in IR pathogenesis. We aimed a) to summarize experimental studies linking pollutants to IR, and b) to gather information on available IR test models in order to discuss their suitability in IR toxicity testing. The latter is a first important step to streamlining future research on IR-inducing pollutants. In this regard, because metabolic disruptors are included in the group of endocrine-disrupting compounds (EDCs) (Casals-Casas and Desvergne 2011; Casals-Casas et al. 2008), much of the rationale behind EDC screening and toxicity testing also applies to metabolic disruptors. EDC screening is currently based on a tiered approach combining in vitro screening assays and both short-term and long-term in vivo assays [Organisation for Economic Co-operation and Development (OECD) 2012b; U.S. Environmental Protection Agency (EPA) 2013]. To suggest how future testing strategies to evaluate the relationship between metabolic disruptors and IR may look, we describe in vivo and in vitro end points that may be included in a comparable multilevel screening approach for the identification and prioritization of potential metabolic disruptors.