Diabetes Metab J.  2011 Jun;35(3):207-215. 10.4093/dmj.2011.35.3.207.

Mitochondrial Dysfunction and Insulin Resistance: The Contribution of Dioxin-Like Substances

• Lee HK

• KMID: 2175418
• DOI: http://doi.org/10.4093/dmj.2011.35.3.207

Abstract

Persistent organic pollutants (POPs) are known to cause mitochondrial dysfunction and this in turn is linked to insulin resistance, a key biochemical abnormality underlying the metabolic syndrome. To establish the cause and effect relationship between exposure to POPs and the development of the metabolic syndrome, Koch's postulates were considered. Problems arising from this approach were discussed and possible solutions were suggested. In particular, the difficulty of establishing a cause and effect relationship due to the vagueness of the metabolic syndrome as a disease entity was discussed. Recently a bioassay, aryl-hydrocarbon receptor (AhR) trans-activation activity using a cell line expressing AhR-luciferase, showed that its activity is linearly related with the parameters of the metabolic syndrome in a population. This finding suggests the possible role of bioassays in the analysis of multiple pollutants of similar kinds in the pathogenesis of several closely related diseases, such as type 2 diabetes and the metabolic syndrome. Understanding the effects of POPs on mitochondrial function will be very useful in understanding the integration of various factors involved in this process, such as genes, fetal malnutrition and environmental toxins and their protectors, as mitochondria act as a unit according to the metabolic scaling law.

Keyword

Arylhydrocarbon receptor; Dioxin-like substance; Doubly labeled water test; Insulin resistance; Metabolic scaling law; Metabolic syndrome; Mitochondria; Persistent organic pollutants

MeSH Terms

Biological Assay
Cell Line
Fetal Nutrition Disorders
Insulin
Insulin Resistance
Jurisprudence
Mitochondria
Insulin

Figure

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  Fig. 1 Pathogenesis of the metabolic syndrome as a special state of mitochondrial dysfunction. Various phenotypes, such as insulin deficiency and insulin resistance are pathophysiologically defined states, while type 2 diabetes, hypertension and obesity are well-defined specific disease states. Coronary heart disease and cancer might be considered either specific diseases or complications (or more appropriately, later stages) of preceding disease states. In this model, diabetes and CADs are not results of obesity, but its later stage phenotypes. CVD, cardiovascular disease; NMD, neuromuscular disease; NAFLD, nonalcoholic fatty liver disease.

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  Fig. 2 Metabolic scaling relation between body size and metabolic rate. Panel (A) shows metabolic rate increases (watt) with increasing body mass (kg) across animal species, from mitochondrion to elephant. In Panel (B), the logarithm of the mass-specific metabolic rate, W/g, versus the body mass, M (g), for mammals is plotted in a logarithmic scale. The mass-specific metabolic rate declines as body mass increases. Panel (C) shows the relationship between changes in 24-hour energy expenditure (Δ 24-EE) and Δ weight after adjustment of 24-EE for fat-free mass (FFM), fat mass (FM), waist to thigh ratio (WTR), and age. Weight change is accompanied by a change in energy expenditure in Pima Indians. A long-term adaptation process normalizes the relationship between body mass and metabolic rate, suggesting that an adaptive process is operating (Panel D). Arrows 1A and 2A depicts metabolic adaptation, which leads to a quick decrease in the metabolic drive and a small weight change. Arrows 1B and 2B depict poor metabolic adaptation, which leads to a sustained metabolic drive and a larger weight change.

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  Fig. 3 In whole-body metabolism, energy supply and energy demand are tightly linked, and the metabolism of its parts is quantitatively related (allometry) to whole-body mass. The larger the body, the bigger the parts, but the mass specific metabolic rate decreases (From Weibel ER. Nature 2002;417:131-2, with permission from Nature Publishing Group) [4].

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