Effect of the GSTM1 gene deletion on glycemic variability, sympatho-vagal balance and arterial stiffness in patients with metabolic syndrome, but without diabetes

https://doi.org/10.1016/j.diabres.2018.02.006Get rights and content

Abstract

Aims

An increased rate of cerebrovascular complications in patients with metabolic syndrome (MetS) has been reported. Previous studies demonstrated an association between glycemic variability (GV) and cerebrovascular reactivity (CRV) in MetS, thus suggesting a putative role of GV on cerebrovascular events. Although the pathophysiological mechanism linking GV to damage is still to be elucidated, evidence suggests oxidative stress plays a crucial role. Since functional variants in glutathione S-transferases (GST) genes modulate the cellular detoxification processes, the aim of this study was to elucidate the involvement of GSTs in MetS and investigating the correlation with GV, arterial stiffness, and sympatho-vagal (SV) balance.

Methods

A hundred metabolic syndrome patients without diabetes underwent GST gene polymorphism analysis and a sub-sample 36 patients were randomly selected to investigate the correlation between GST gene polymorphisms and GV, and sympatho-vagal (SV) balance and arterial stiffness.

Results

GSTM1 showed a significant association with several GV, arterial stiffness, and SV balance indexes. In particular, the GSTM1 deletion positively correlates with lower values of these indexes when compared to the presence of the gene.

Conclusions

Therefore, we suggested a global influence of GSTM1 deletion on the GV, arterial stiffness, and SV balance pathways in MetS patients, probably also interacting with AMP-activated protein kinase (AMPK) regulation.

Our novel findings indicate GSTM1 could be a risk locus in MetS development and shed light novel scenarios on the role of glucose fluctuations in neurological impairments.

Introduction

Metabolic syndrome (MetS) is defined as a cluster of risk factors, including dyslipidemias, abdominal obesity, and arterial hypertension leading to an increased risk of cardiovascular events and diabetes [1].

An increased rate of neurological disorders, such as Alzheimer's disease, cognitive decline, impaired autonomic nervous system activity and stroke has been reported in patients with MetS [2], [3], [4]. The molecular pathways underlying the putative relationship between MetS and neurological complications is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in MetS, including impairment of endothelial function, abnormality in fatty acid metabolism and alterations in lipid mediators, along with abnormal insulin/leptin signaling, may represent a pathological link between MetS and neurological disorders [5]. An altered autonomic nervous system activity in MetS has been suggested as a good predictor of cardiovascular events [6]. An alteration of the sympatho-vagal balance, with a prevalence of sympathetic tone, is correlated with insulin resistance, hypertension, dyslipidemia and inflammation and may play a crucial role in the pathogenesis of MetS [7], [8].

Glycemic variability (GV) has been previously suggested to play a role in the development of microvascular complications and neuropathy, in patients with diabetes mellitus (DM) [9], [10], [11], [12]. Additionally, we previously demonstrated an association between GV and cerebrovascular reactivity (CRV) in MetS patients, even before the onset of diabetes, thus suggesting a putative role of GV on cerebrovascular events [13]. Accordingly, Buscemi and collaborators suggested that GV influences endothelial function even in non-diabetic patients and that the fluctuations in glucose concentration may explain the increased cardiovascular risk observed in MetS patients, prior to develop type 2 diabetes (DMT2) [14]. Although the pathophysiological mechanism linking GV to damage is still to be elucidated, a good body of evidence suggests oxidative stress plays a crucial role [15].

Moreover, the high levels of circulating lipids, observed in MetS are responsible for increased lipo-peroxidation processes, and the consequent increase of oxidative metabolites. These, in turn, may affect cell structures and tissues, thus leading to nervous system impairment [16], and diminishing the antioxidant defense systems, such as superoxide dismutase (SOD), glutathione S-transferases (GSTs), and catalase (CAT).

Functional variants in GST genes modulate the enzyme activity in pathways of glutathione conjugation to highly reactive metabolites conferring cellular protection against oxidative stress imbalance and immunogenic alterations [17]. Evidence have shown that GST gene polymorphisms are associated with increased risk of several types of complex diseases, such as cancer [18], allergic rhinitis [19], asthma [20], essential hypertension [21], Alzheimer’s diseases [22], and hypothyroidism [23].

The association between GST polymorphism and diabetes mellitus have been widely investigated [24]. However, only few studies with non-concordant results are available regarding GST gene polymorphisms involvement in MetS [25], [26], although several biochemical studies have highlighted the association between MetS and others detoxifying enzymes, including SOD, CAT, glutathione reductase (GR), and paraoxonase1 (PON1) [27], [28].

Therefore, the aim of this study was to elucidate the involvement of GSTs in MetS, investigating the putative association between GST gene polymorphisms and glycemic variability, arterial function and structure, and sympatho-vagal balance in patients with MetS, but without diabetes.

Section snippets

Sample and laboratory measurements

One hundred patients with MetS were consecutively recruited at the ‘‘San Giovanni Calibita’’ Fatebenefratelli Hospital in Rome. Inclusion criteria were: MetS according to the International Diabetes Federation (IDF) Worldwide Definition of the Metabolic Syndrome (https://www.idf.org/), age from 18 to 75 years old, no diabetes mellitus according to the ADA criteria [29]. Exclusion criteria included pregnancy, end stage renal or liver disease, cancer, arrhythmia or pacemaker implantation.

All

Explorative analysis

The personal, anthropometric, clinical and genetic characteristics of the entire investigated cohort are shown in Table 1. The genotype frequencies were in H–W equilibrium for all the GST gene polymorphisms (p > 0.05).

Fig. 1 shows the results of the genotype/clinical variable association analysis performed by the Kruskal-Wallis test and considering the 100 MetS patients. After Bonferroni adjustment, only the deletion polymorphisms of the GSTM1 and GSTT1 genes were significantly associated with

Discussion

The results of our initial explorative analysis suggest that GSTM1 and GSTT1 deletion polymorphisms, alone or in combination, are significantly associated with glycemia 120 min after the glycemic load (GLY 120′). In particular, we observed that the GLY 120′ values in MetS patients with deleted GSTM1 and GSTT1 was significantly lower when compared to patients with the presence of the respective genes.

Regarding the GSTT1 gene, our preliminary analysis has shown a negative association between the

Acknowledgments

The authors thank the volunteer participants for their cooperation and the collaborators of the ‘San Giovanni Calibita’ Fatebenefratelli Hospital for their valuable contributions.

Author contributions

R.P. and S.F. design the study protocol. A.I. performed the genetic investigations, data analysis, and wrote the manuscript. D.Y. performed the sampling, the clinical evaluation and wrote the manuscript. F.P. performed the sampling. P.M., D.F., and A.A. performed the clinical investigations. A.I., D.Y., R.P., D.M., M.F., and S.F. significantly contributed to the discussion and to the final version of the manuscript.

Funding

This study was supported by RSA Grant 2009 from University of Rome “Tor Vergata”, by PRIN 2009-11 (Project No. 200975T9EW) from the Italian Ministry of Instruction, University and Research (MIUR) (M.F.) and by a grant from the Fatebenefratelli Foundation for Biomedical Research (AFaR division) (D.Y., F.P., D.M., S.F.). The authors declare no conflicts of interest.

Guarantor

A.I. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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    These authors contributed equally to this work.

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