Trace elements concentration in adipose tissue and the risk of incident type 2 diabetes in a prospective adult cohort

Highlights

• Fe, Cu and Cr adipose tissue concentrations were positively associated with T2DM.

• Adipose tissue Cr, Cu and Fe levels might be indicative of an increased risk of T2DM.

• V and Zn concentrations were positively associated with β-pancreatic cell function.

• V and Zn adipose tissue levels might have a protective effect on T2DM incidence.

Abstract

The aim of this work was to study the associations of adipose tissue trace element concentrations with type 2 diabetes (T2DM) incidence over a 16-year follow-up period in an adult cohort from Southern Spain. 16-year T2DM incidence was gathered from hospital records. Chemical analyses of Cr, V, Zn, Fe, Cu and Se in adipose tissue were performed using inductively coupled plasma mass spectrometry. Multivariable Cox-regression models were used. Complementary cross-sectional analyses with markers of glucose homeostasis at recruitment were performed by multivariable linear regression. Out of 214 participants, 39 developed T2DM during the follow-up. Adipose tissue concentrations of Fe (HR = 1.97, 95% CI: 0.99 to 2.58, p = 0.057), Cr (HR = 1.58, 95% CI: 1.07–2.33, p = 0.022) and Cu (HR = 1.61, 95% CI: 1.01–2.58, p = 0.046) were individually associated with T2DM incidence. When Fe, Cr and Cu were simultaneously entered in a model, only Cr was significantly associated with T2DM incidence (HR = 1.68, 95% CI: 1.02–2.76, p = 0.041). Furthermore, adipose tissue V (β = 0.283, p = 0.004) and Zn (β = 0.217, p = 0.028) concentrations were positively associated with β-pancreatic cell function (HOMA-β), while Se showed an inverse association (β = −0.049, p = 0.027). Although further research is warranted on the potential mechanisms of action, our results suggest that adipose tissue concentrations of certain trace elements (particularly Fe, Cr and Cu) are associated with the risk of incident T2DM, while V and Zn might have a protective effect. These biomarkers might complement prediction algorithms and contribute to identify patients with an increased risk of T2DM.

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.