Recent epidemiologic studies suggest a possible association between dioxin-like compounds (DLCs) and diabetes in human populations, although experimental links between DLCs and diabetes are lacking. The public health significance of such an association is that all populations are exposed to small but measurable levels of DLCs, chronic low-dose exposure to which may hasten the onset of adult-onset diabetes in susceptible individuals. In this article, we review the epidemiologic studies and propose biologically plausible connections between dioxins and diabetes. Specifically, we suggest that aryl hydrocarbon (Ah) receptor functions may antagonize peroxisome proliferator-activated receptor (PPAR) functions, and hence that the Ah receptor may promote diabetogenesis through a mechanism of PPAR antagonism. Key words: Ah receptor, diabetes, noninsulin-dependent diabetes mellitus, peroxisome proliferator-activated receptors, PPAR[gamma], 2,3,7,8-tetrachlorodibenzo-p-dioxin, type 2 diabetes. Environ Health Perspect 110:853-858 (2002). [Online 17 July 2002] http://ehpnet1.niehs.nih.gov/docs/2002/110p853-858remillard/abstract.html

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The term dioxin can refer both specifically to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and more generally to other polychlorodibenzo-p-dioxin congeners, polychlorinated dibenzofurans, and coplanar polychlorinated biphenyls. Like other organochlorine compounds, dioxin-like compounds (DLCs) are persistent, lipophilic, and prone to bioaccumulation. Most toxicologic work has been carried out with TCDD, and the toxicologic behavior of other DLCs is usually assumed to be similar. The total dioxin concentration is estimated as its toxic equivalence (TEQ), where TEQ = [SIGMA][(DLC).sub.i] x [(TEF).sub.i] and the TEFs are toxic equivalency factors that normalize the toxic potencies of the various DLCs to that of the reference toxicant TCDD, with TEF = 1 (1).

When the toxicity of TCDD was first discovered, attention was directed toward its acutely lethal effects (2-4) in highly sensitive rodents such as guinea pigs (5). The realization that human beings are less susceptible to these acute effects shifted the focus to low-level chronic effects such as carcinogenicity (6) and reproductive toxicity (7,8), both of which can be induced in animal models at concentrations close to those to which humans are exposed (9).

Humans are exposed to DLCs either occupationally or environmentally. Environmental sources of DLCs include combustion by-products that form whenever organic materials are burned in the presence of chlorine sources and, in the case of coplanar PCBs, improper disposal and accidental contamination (9).

Occupations that formerly led to exposure included the manufacture and use of 2,4,5-trichlorophenol and associated products such as herbicides, and bleaching of wood pulp with chlorine (10,11). Releases of dioxins from these activities have greatly declined (12). In the general population, exposure comes mostly from fatty foods such as meat, fish, and dairy products, at the rate of some 3-6 pg of TEQ/kg body weight/day (9). Almost all human subjects have detectable body burdens of DLCs, mostly stored in adipose tissue, and because DLCs have long whole-body half-lives, levels in the general population have probably not yet kept pace with lower rates of release to the environment.

Low levels of dioxin exposure have recently become a focus of interest in the context of their possible link with the incidence of diabetes. Adult-onset diabetes (13,14), whose incidence continues to rise in Western countries, is a metabolic disorder involving abnormal energy metabolism (15,16). Perhaps significantly, lethal poisoning by dioxins also involves disruption of energy metabolism, characterized by depletion of lipid stores of the affected animal (the "wasting syndrome") (17). In rats, Rozman (18) demonstrated nearly identical dose-response behavior by TCDD for suppression of food intake and inhibition of the enzyme phosphoenolpyruvate carboxykinase (PEPCK) involved in gluconeogenesis [although later work (19) with a wider range of rodents did not consistently affirm this correlation]. …