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Friday, December 23, 2016

Serum GGT activity as a marker of exposure to POPs and diabetes risk

Effects of the Dietary Detoxification Program on Serum γ-glutamyltransferase, Anthropometric Data and Metabolic Biomarkers in Adults

Persistent Organic Pollutants (POPs) are well-known environmental contaminants including polychlorinated bisphenyls (PCBs) and organochlorine pesticides (OCPs). These chemical compounds bioaccumulate in adipose tissue and come into toxins in body [1–3]. Furthermore, POPs have long-lasting adverse effects in our body from food chains. POPs increase reactive oxygen species (ROS), and lead to cell inflammations and oxidative stress [4–6]. It has been documented that POPs are associated with chronic diseases such as cancers, cardiovascular diseases, neuro-degenerative disease, and respiratory diseases [7,8]. Particularly, there are emerging evidences that these xenobiotics alter metabolic mechanism and elevate insulin resistance. It can be resulted in obesity, dyslipidemia, and type 2 diabetes [9–14]. In other words, POPs aggravate many chronic conditions through ingestion, and respiration. To our healthy life, it is important to reduce accumulating chemical agents in the human body.

Unfortunately, people are consistently exposed to various chemicals and these compounds accumulate in our body for several decades [15]. Accordingly, it is vital to avoid chemical materials exposure as well as to remove from the body. However, few studies on reducing POPs effectively from the body have been found in the literature. Traditionally, detoxification, toxin elimination intervention, has become well-used therapy to clean of intestine, alleviate toxic symptoms and lose weight [16]. As the pathway of removal of chemical agents is through urine and fecal elimination, detoxification approach diverse methods using fasting, laxatives and enzyme for specific period [1]. Though, it is preferable to natural methods than strict calorie restriction, intestine cleansing and using certain food or enzyme to discard noxious chemicals for health. As foods are the major sources of human toxic pollutants, detoxification intervention is an effective way of intaking foods containing lower POPs and decomposing toxin from the body naturally [17]. Therefore, we developed an integrated dietary and education program for toxin elimination.

Although these extensive therapies widespread utilizing remove toxins, it is controversy on effects and remedies of detoxification [1,18]. Since physiological biomarkers which reflect body toxin level and objective outcome indicators were not measured, it is insufficient to prove the effects of intervention to remove toxins [18]. Thus, physiological indicators which confirmed to body’s toxin level are necessary to measure the outcomes. It is widely established that serum γ-glutamyltransferase (GGT) is a biomarker of alcohol consumption, heart disease, hypertension and type 2 diabetes [19–21]. In addition, several studies suggested that increased GGT within its normal range can be predicted environmental pollutants [22,23]. Glutathione as an antioxidant combine xenobiotics intracellular and move toward extracellular to metabolite (phase II). GGT which located in cell membrane get involved in glutathione activities which conjugated various environmental pollutants [24]. Thus, the overall burden of toxicants can measure by GGT. Considering numerous synthetic chemicals to which we are exposed, measuring of certain manufactured materials does not understand to identify accumulating toxins in human body.

As environmental pollutants bioaccumulate in fatty tissue, it is essential to investigate the relationship between serum GGT and body fat indicators. Therefore, the present study was conducted to explore the effects of dietary detoxification program on serum GGT, weight, body fat percentage, body fat mass, waist circumference, lipid profiles, blood pressure and fasting blood glucose in adults.

J Lifestyle Med. 2016 Sep;6(2):49-57. Epub 2016 Sep 30.
Effects of the Dietary Detoxification Program on Serum γ-glutamyltransferase, Anthropometric Data and Metabolic Biomarkers in Adults.
Kim JA1, Kim JY2, Kang SW3.


Serum GGT activity as a marker of exposure to POPs

Serum GGT activity as a cumulative exposure marker for various xenobiotics

Although the aforementioned study on Korean men [1] revealed much lower serum GGT activity than that observed in CARDIA and FinMONICA participants [2, 3], there was a striking secular trend in serum GGT [15]. After statistical adjustment, we concluded that the secular trend was not caused by changes in health behaviours or obesity, suggesting that other environmental factors play a role.

Another avenue of thought arose from the observation that serum GGT demonstrated dose–response relationships with blood concentrations of lead and urinary levels of cadmium [16]. This work brought into focus the important function of GSH as a conjugating ligand for the phase II reactions that occur during xenobiotic metabolism. Many xenobiotics are eliminated from cells by phase I biotransformation, followed by phase II conjugation to an anionic group, such as GSH, and transportation into the extracellular space [17]. The first necessary step for further metabolism of GSH conjugates is to break γ-carboxyl linkage of GSH by cellular GGT (Fig. 1, right of the dotted line) [18]. Thus, GGT activity may increase with an increased exposure to xenobiotics, including environmental pollutants, which require conjugation with GSH [17]. Our updated viewpoint on serum GGT as a marker of exposure to xenobiotics is a more comprehensive interpretation, which includes our earlier proposal that serum GGT reflects oxidative stress. Exposure of cells to xenobiotics directly increases the production of ROS [19]. ROS are also conjugated with GSH [17], and consumption of GSH by conjugation with xenobiotics is related to the depletion of intracellular GSH [17]. Based on these propositions, we hypothesised that the associations between serum GGT activity and type 2 diabetes might be explained by exposure to environmental pollutants.

Serum GGT activity as a marker of exposure to POPs

For our hypothesis to be true, the environmental pollutants involved have to satisfy several conditions. First, human exposure to the presumed xenobiotics should be through food consumption, most likely meat. For example, the Korean secular trend of increasing serum GGT activity was similarly observed among all subgroups stratified by various factors, such as age, sex, smoking, alcohol drinking, obesity or job category [15], suggesting some common environmental exposures, such as food. Indeed, serum GGT was positively associated with meat intake in the CARDIA dataset [20]. Second, the xenobiotics should be associated with adipose tissue, because serum GGT activity is strongly associated with obesity. Considering the importance of adipose tissue in the pathogenesis of type 2 diabetes, pollutants stored in adipose tissue could be important. Third, the xenobiotics should be metabolised by GSH conjugation.

Following this logic, POPs, endocrine disruptors stored in adipose tissue, represented the most plausible candidate. POPs include hundreds of different chemical compounds with common properties, such as long-term persistence in the environment and bioaccumulation through the food chain. POPs are detectable in virtually everyone, with exposure occurring through fatty animal food in particular [21]. Some POPs are conjugated to GSH for their metabolism [22–24], and exposure to high amounts of certain POPs in occupational or accidental settings increase serum GGT activity [25, 26].

We tested this hypothesis in the NHANES dataset and found graded associations between serum concentrations of POPs and serum GGT [27]. We also found strong dose–response relationships between POPs and the prevalence of type 2 diabetes [28]. Parallel to the interactions of obesity and diabetes with serum GGT activity, the association between POPs and type 2 diabetes was stronger among obese persons, but type 2 diabetes was nearly absent, irrespective of obesity when POPs concentrations were very low [28]. This observation led us to hypothesise that POPs stored in adipose tissue might be more critical than obesity itself to understanding the pathogenesis of type 2 diabetes.

The studies described above focused on type 2 diabetes risk, reflecting our original hypothesis. However, serum GGT activity within its normal range has also been shown to prospectively predict other clinical outcomes [29–33]. Similarly, in the NHANES dataset, serum POP concentrations were positively associated with the prevalence of the metabolic syndrome, insulin resistance, hypertension, and cardiovascular diseases [34, 36].

Mitochondrial dysfunction has recently emerged as a mechanism unifying the pathogenesis of insulin resistance and type 2 diabetes [37]. Interestingly, it has long been reported that POPs can decrease mitochondrial oxidative capacity in various organs [38, 39]. Even though POPs are mainly stored in adipose tissue, physiological fatty acid release from adipose tissue between meals may be accompanied by some release of POPs, and they may keep redistributing to various organs, such as muscle, liver, or pancreas, even under normal physiological control of adipose tissue [40]. Furthermore, the lipolytic potential of some POPs may disturb normal adipose tissue metabolism and lead to an excessive release of POPs [41]. Thus, continuous chronic exposure to POPs may diminish mitochondrial function in various organs, eventually leading to insulin resistance and type 2 diabetes.

Diabetologia. 2008 Mar;51(3):402-7. Epub 2007 Dec 11.
Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes?
Lee DH1, Steffes MW, Jacobs DR Jr.


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