Trace elements concentration in adipose tissue and the risk of incident type 2 diabetes in a prospective adult cohort☆
Graphical abstract
Introduction
Type 2 diabetes (T2DM) is characterized by increased blood glucose levels caused by a reduced insulin secretion from pancreatic β-cells and/or insulin resistance (Franks and McCarthy, 2016). In addition, T2DM is closely related to highly-prevalent comorbidities such as cardiovascular disease, hypertension, obesity or dyslipidemia (Petrie et al., 2018). The World Health Organization (WHO) estimated that 422 million adults worldwide (nearly 9%) suffered from diabetes (WHO, 2016).
Although far from been completely understood, the etiology of T2DM is considered a complex mixture of internal and external risk factors, many of them susceptible of modification e.g., sedentary lifestyle or unbalanced diet (Zheng et al., 2018). In this regard, most studies have focused their research on the macronutrient's status e.g., increasing the intake of complex carbohydrates to the detriment of simple sugars as a strategy to prevent T2DM. However, micronutrients and, specifically, some trace elements (TEs) have been postulated as determinants of T2DM risk (Pasula and Sameera, 2013; Tinkov et al., 2015). TEs are present at very low concentrations in natural and perturbed environments, and are required at low amounts by humans (usually ≤ 100 mg/day). However, TEs are essential for a number of physiological processes, mainly involved in immunity and metabolism, since they serve as cofactors for multiple enzyme systems (Wiernsperger and Rapin, 2010; Dubey et al., 2020). Specifically, the imbalance of chromium (Cr), vanadium (V), zinc (Zn), copper (Cu), iron (Fe) and selenium (Se) seems to be linked to T2DM development and progression, as well as to T2DM-derived complications (Kazi et al., 2008; Moreno-Navarrete et al., 2014; Wiernsperger and Rapin, 2010). It has been proposed that both TE deficiencies or overload could be associated with oxidative stress, which is closely related to insulin resistance and diabetes (Dubey et al., 2020). In addition, Cr, Zn, Cu, Fe and Se exert antioxidant effects and, therefore, might ultimately enhance insulin action by the activation of insulin receptor sites or increment of insulin sensitivity (Hussain et al., 2009).
According to Kruse-Jarres and Rükgauer (2000), the most accurate information on the potential contribution of TEs to disease prevention/onset comes from the tissues that reflect the immediate biochemical processes. Nevertheless, most of the researches have been focused on TE concentrations in blood (plasma or serum) and urine. In this regard, adipose tissue has been overlooked, despite being considered a metabolically active tissue closely related to T2DM onset. Adipose tissue also intervenes in metabolic homeostasis through the synthesis of biologically active substances, sending and responding to signals that modulate energy intake or insulin sensitivity, among other functions (Abranches et al., 2015; Coelho et al., 2013). In fact, the adipose tissue dysfunction observed under obesity conditions can cause impaired insulin action or even insulin resistance (Abranches et al., 2015). Additionally, it has been hypothesized that an unbalance of some TE concentrations in adipose tissue could lead to insulin resistance and further metabolic disruption (Kazi et al., 2008; Tinkov et al., 2015), although there is scant epidemiological research in the field. Indeed, we evidenced negative associations of adipose tissue concentrations of cobalt (Co), Cu, molybdenum (Mo) and Se with the degree of obesity in adults from GraMo cohort (Rodríguez-Pérez et al., 2018). Thus, further studies are warranted to elucidate the potential influence of TEs in adipose tissue dysfunction.
Based on the foregoing, the present work, which is encompassed in a largely characterized adult cohort from Southern Spain, aims to study the associations of adipose tissue concentrations of Cr, Zn, Cu, V, Se and Fe with T2DM incidence over a 16-year follow-up period. Complementary cross-sectional analysis with markers of glucose homeostasis at recruitment were also performed.
Section snippets
Study area and GraMo cohort
This research is part of a wider investigation focused on identifying environmental factors affecting the development of several chronic diseases in an adult cohort from Southern Spain (GraMo cohort). The design and population recruitment have been described elsewhere (Arrebola et al. 2010, 2009, 2015; Rodríguez-Pérez et al., 2018). Briefly, study participants were recruited in two public hospitals in Granada province: San Cecilio University Hospital in the city of Granada (considered urban
Results
Main characteristics of the participants, including a comparison between those who developed T2DM during follow-up vs T2DM-free, are summarized in Table 1. Out of 214 participants, 25 males (64.1%) and 14 females (35.9%) developed T2DM during the follow-up. Compared to participants free of incident T2DM, there was a higher proportion of smokers/ex-smokers and uncompleted primary studies in those that developed T2DM over follow-up. Noteworthy, those participants who developed T2DM during the
Discussion
This is the first epidemiologic study addressing the associations of TEs accumulated in adipose tissue with the risk of T2DM, which appears to be of relevance for the ethology of insulin resistance and other metabolic disturbances, as previously suggested elsewhere (Tinkov et al., 2015). We evidenced positive associations of adipose tissue Fe, Cr and Cu with T2DM incidence.
Laboratory studies have evidenced diabetogenic and obesogenic effects of low adipose tissue Cr concentrations (Tinkov et
Conclusions
To date, this is the first study exploring the relationship between levels of TEs in adipose tissue and incidence of T2DM in an adult cohort. Our findings suggest a potential role of Fe, Cr and Cu as potential risk factors for T2DM, as well as a protective role of V and Zn for the prevention of T2DM. Furthermore, our results emphasize the relevance of adipose tissue as a matrix for the assessment of the metabolic implications of certain TEs, which could complement current prediction algorithms
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We would like to acknowledge the collaboration of the patients taking part in it.
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This paper has been recommended for acceptance by Payam Dadvand.