Diabetes Metab J.  2014 Feb;38(1):13-24. 10.4093/dmj.2014.38.1.13.

The Hijacking of Cellular Signaling and the Diabetes Epidemic: Mechanisms of Environmental Disruption of Insulin Action and Glucose Homeostasis

• Sargis RM

• KMID: 2174180
• DOI: http://doi.org/10.4093/dmj.2014.38.1.13

Abstract

The burgeoning epidemic of metabolic disease causes significant societal and individual morbidity and threatens the stability of health care systems around the globe. Efforts to understand the factors that contribute to metabolic derangements are critical for reversing these troubling trends. While excess caloric consumption and physical inactivity superimposed on a susceptible genetic background are central drivers of this crisis, these factors alone fail to fully account for the magnitude and rapidity with which metabolic diseases have increased in prevalence worldwide. Recent epidemiological evidence implicates endocrine disrupting chemicals in the pathogenesis of metabolic diseases. These compounds represent a diverse array of chemicals to which humans are exposed via multiple routes in adulthood and during development. Furthermore, a growing ensemble of animal- and cell-based studies provides preclinical evidence supporting the hypothesis that environmental contaminants contribute to the development of metabolic diseases, including diabetes. Herein are reviewed studies linking specific endocrine disruptors to impairments in glucose homeostasis as well as tying these compounds to disturbances in insulin secretion and impairments in insulin signal transduction. While the data remains somewhat incomplete, the current body of evidence supports the hypothesis that our chemically polluted environment may play a contributing role in the current metabolic crisis.

Keyword

Diabetes mellitus; Endocrine disrupting chemicals; Endocrine disruptors; Insulin; Insulin resistance; Insulin signaling; Pollution

MeSH Terms

Delivery of Health Care
Diabetes Mellitus
Endocrine Disruptors
Glucose*
Homeostasis*
Humans
Insulin Resistance
Insulin*
Metabolic Diseases
Prevalence
Signal Transduction
Endocrine Disruptors
Glucose
Insulin

Figure

• 

  Fig. 1 Insulin signaling targets of endocrine disrupting chemicals (EDCs). Multiple studies have examined the effects of EDCs on various aspects of insulin synthesis, release, and cellular action. The molecular targets identified from these various studies are summarized. Of note, this figure synthesizes data from various model systems, including multiple different targets of insulin action (i.e., adipose tissue, liver, and muscle). The data has been combined for clarity but should not be understood to mean that the EDCs shown exert similar effects in all biological tissues or in all species. TCDD, 2,3,7,8-tetrachlorodibenzodioxin; BPA, bisphenol A; DEHP, diethylhexylphthalate; PCB, polychlorinated biphenyl; PDK, phosphoinositide-dependent kinase; mTORC2, mammalian target of rapamycin complex 2; POP, persistent organic pollutant; GLUT4, glucose transporter 4.

• 

  Fig. 2 Endocrine disrupting chemical (EDC) modulation of glucocorticoid activity. The effects of multiple studies examining the effects of EDCs on the glucocorticoid signaling pathway are summarized, including effects at various concentrations and in different model systems. As such, these studies should not be interpreted to mean that each EDCs operates similarly in all tissues; however, pooling of the data suggests potential mechanisms of synergy among various EDCs that modulate activity of this signaling pathway. 11β-HSD, 11β-hydroxysteroid dehydrogenase; BPA, bisphenol A; PCB, polychlorinated biphenyl; GR-GRE, glucocorticoid receptor-glucocorticoid response element.

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