Circulating zonulin levels in newly diagnosed Chinese type 2 diabetes patients

https://doi.org/10.1016/j.diabres.2014.08.017Get rights and content

Highlights

  • Association of serum zonulin, a biomarker for gut barrier dysfunction, with T2DM was studied in a Chinese Han population.

  • Zonulin serum levels are significantly elevated in newly diagnosed Chinese T2DM patients.

  • Zonulin is correlated with insulin resistance, dyslipidemia and inflammation.

  • Zonulin levels are an independent predictor for T2DM in Chinese.

Abstract

Aims

Studies suggest that type 2 diabetes mellitus is associated with increased gut permeability. Human zonulin is the only physiological mediator discovered to date that is known to regulate gut permeability reversibly by disassembling intestinal tight junctions. However, the relationship between zonulin and type 2 diabetes remains to be defined, and no Chinese population-based data were reported. The aim of this study was to investigate the association between serum zonulin levels and type 2 diabetes in a Chinese Han population.

Methods

143 newly diagnosed type 2 diabetes patients, 124 patients with impaired glucose tolerance and 121 subjects with normal glucose tolerance were enrolled in this study. Serum zonulin was measured by ELISA.

Results

Patients with type 2 diabetes had higher serum zonulin levels than impaired or normal glucose tolerant subjects. Serum zonulin correlated with body mass index, waist-to-hip ratio, triglyceride, total cholesterol, HDL-C, fasting plasma glucose, 2 h plasma glucose, HbA1c, tumor necrosis factor α, interleukin 6, HOMA-IR and QUICK index using correlation analysis (p < 0.05 for all). Multivariate stepwise regression analysis showed that zonulin levels were independently associated with insulin resistance (β = 0.024, p = 0.005). In logistic regression analysis, zonulin levels were an independent predictor of type 2 diabetes (OR = 1.080, p = 0.037).

Conclusions

Serum zonulin levels are significantly elevated in newly diagnosed Chinese Type 2 diabetes patients, and are associated with dyslipidemia, inflammation and insulin resistance, indicating a potential role of zonulin in the pathophysiology of type 2 diabetes in Chinese.

Introduction

Recently, increasing attention has been paid to the link between gut barrier dysfunction and metabolic diseases, such as obesity [1], [2], nonalcoholic fatty liver disease [3] and type 2 diabetes mellitus (T2DM) [1], [4]. In mouse models, an increased gut permeability has been described in high fat diet induced obese and diabetic mice [1], [2], with improvements in gut barrier integrity of obese mice linked with decreased inflammation markers (e.g. tumor necrosis factor α, interleukin 6, interleukin 1β) and improved glucose tolerance [1], [2]. Very recently, increased gut permeability has also been demonstrated in human T2DM patients [5].

Human zonulin, the eukaryotic counterpart of Vibrio cholerae zonula occludens toxin, is the only physiological mediator discovered to date that is known to regulate gut permeability reversibly by disassembling intestinal tight junctions [6], [7]. It increases intestinal permeability (IP) in the small intestines and participates in intestinal innate immunity. Circulating zonulin in serum correlates with IP and can be used as a biomarker for gut barrier function [8], [9], [10]. Serum zonulin concentrations are strongly correlated with lactulose: mannitol urine ratio – a widely used clinical indicator of IP [11], [12], [13].

Few studies have examined the relationship between zonulin and metabolic diseases. Additionally, there is controversy regarding zonulin's association with insulin resistance – the key feature of metabolic diseases. It has been reported that serum zonulin levels are significantly elevated in obese subjects and in subjects with glucose intolerance, and that zonulin levels closely correlate with obesity-associated insulin resistance [14]. However Zak-Golab et al. [15] found increased zonulin concentration in obese subjects, but did not observe any association between zonulin levels and insulin resistance. With the increasing interest in the roles of gut in T2DM, a better understanding of the role of zonulin is needed. Furthermore, there is currently no data on the relationship between circulating zonulin and T2DM in Chinese.

In the present study, we measured serum zonulin in the Chinese Han population with normal and impaired glucose tolerance, and newly diagnosed type 2 diabetes, as well as investigated zonulin's association with clinical and biochemical measures of glucose, lipid metabolism, insulin resistance and inflammatory markers.

Section snippets

Subjects

A total of 388 subjects were recruited in this study from endocrine outpatient clinic of Xiangya Hospital of Central South University between September 2011 and October 2013. All of them had consulted for problems with either their body weight, menorrhea, and/or glucose concerns. All participants were Chinese Hans from southern China. Subjects were excluded if they had Type 1 diabetes (T1DM), pregnancy, acute or chronic infectious disease, hypertension, heart failure, hepatic or renal disease,

Clinical characteristics of study participants

Table 1 shows the clinical characteristics of subjects. The T2DM group were older by 13 years in average than NGT group (p < 0.01), and by 5 years than IGT group (p < 0.01). Subjects among the three groups had matched BMI, but T2DM patients had higher WHR (p < 0.05). Compared with BMI matched IGT and NGT subjects, patients with T2DM had higher levels of glucose at all time points during OGTT and higher HbA1c. T2DM patients had lower insulin concentrations at 30, 60, 120 min (p < 0.05), lower HOMA-β and

Discussion

Studies have previously focused on the role of zonulin in autoimmune disease. It has been reported that zonulin is involved in the pathogenesis of T1DM in animal models [19], and increased serum zonulin levels are associated with several autoimmune diseases in humans, such as T1DM and Crohn's disease [11], [20]. Since recent evidence suggests a possible role of IP in metabolic diseases, more attention is being given to the relationship of zonulin with metabolic diseases. Studies have shown that

Funding

There is no funding to report for this study.

Conflict of interest

There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Acknowledgments

We are indebted to all subjects for agreeing to participate in this study.

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