Inverse associations of serum bilirubin with high sensitivity C-reactive protein, glycated hemoglobin, and prevalence of type 2 diabetes in middle-aged and elderly Japanese men and women

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Abstract

Aim

The aim of this study was to examine the association of serum bilirubin, an endogenous antioxidant, with serum high sensitivity C-reactive protein (hs-CRP) level, HbA1c, and the prevalence of type 2 diabetes in middle-aged and elderly Japanese men and women (n = 12,400).

Methods

Analysis of covariance and logistic regression analysis were used to estimate geometric means of hs-CRP and HbA1c and odds ratios of prevalent diabetes according to bilirubin concentrations, respectively, with statistical adjustment for behavioral factors and liver enzymes.

Results

Geometric means of hs-CRP and HbA1c were progressively lower with increasing concentrations of serum bilirubin in men and women each. An inverse association between serum bilirubin and HbA1c was slightly attenuated after adjustment for hs-CRP, but still remained highly significant (trend P = 0.0004 in men and trend P = 10−5 in women). Multivariate-adjusted odds ratios of prevalent diabetes for the lowest to highest quintiles of serum total bilirubin were 1.00, 1.00, 0.73, 0.80, and 0.73 (trend P = 0.002), without adjustment for hs-CRP, and 1.00, 1.04, 0.76, 0.86, and 0.79 (trend P = 0.01), with adjustment for hs-CRP.

Conclusions

Higher concentrations of serum bilirubin probably confer protection against the development of type 2 diabetes.

Introduction

Oxidative stress has been implicated in the pathogenesis of type 2 diabetes. In in vitro studies and animal models, antioxidants have been shown to improve insulin sensitivity [1], [2], [3]. Molecular biology studies support the possibility that oxidative stress alters the intracellular signaling pathways including insulin sensitivity [4], [5]. In addition, there is a body of evidence that oxidative stress is increased in pancreatic beta-cells in animal models and patients with type 2 diabetes [6], [7], implicating that oxidative stress may also contribute to progressive beta-cell damage. These findings have suggested that oxidative stress is closely associated with the development of type 2 diabetes. However, the causative role of oxidative stress still remains to be controversial, because there has been very little human evidence indicating beneficial effects of antioxidants on the development of type 2 diabetes.

Bilirubin is an end product of heme catabolism and has long been used in clinical practice as a marker of hepato-biliary and hematopoietic diseases [8]. Anti-oxidative and anti-inflammatory effects of bilirubin have recently drawn much interest particularly in relation to atherosclerotic diseases [9], [10]. Higher concentrations of serum bilirubin were related to decreased risk of coronary artery disease [11], [12], [13], [14], stroke [15], and diabetic vascular complications [16], [17]. Notably, recent reports have shown that enhancement of bilirubin formation by induction of heme oxygenase-1 ameliorates glucose metabolism and insulin sensitivity in rodents [18], [19]. Few studies have also suggested an inverse association between serum bilirubin and C-reactive protein (CRP) [20], [21]. We therefore hypothesized that higher level of serum bilirubin might affect the development of type 2 diabetes through its anti-oxidative and/or anti-inflammatory effect. In this study, we investigated the relation of serum bilirubin concentrations to serum high sensitivity CRP (hs-CRP) levels, glycated hemoglobin (HbA1c), and the prevalence of type 2 diabetes in a middle-aged and elderly population in Japan.

Section snippets

Subjects

The study subjects were participants in the baseline survey of the Kyushu University Fukuoka Cohort Study. Residents aged 50–74 years in the East Ward of Fukuoka City, excluding some areas with sparse population or in remote distance, were invited to participate in the study by mail. The study was approved by the Ethics Committee of Kyushu University Faculty of Medical Sciences. All the study subjects gave written informed consent prior to their participation in this study.

During the period

Characteristics of study subjects

Behavioral factors and laboratory data of the study subjects are summarized for men and women separately (Table 1). Smoking and alcohol use was much less frequent in women than in men. Serum concentrations of hs-CRP and liver enzyme activities were lower in women, while HbA1c levels did not differ much by sex. Median of serum total bilirubin concentrations did not differ by sex, but men had higher values of total, unconjugated, and conjugated bilirubin more frequently than women. Unconjugated

Discussion

In a fairly large population of Japanese men and women, the present study demonstrated a strong inverse association of serum bilirubin concentrations with HbA1c as well as hs-CRP. The association between serum bilirubin and HbA1c was attenuated after adjustment for hs-CRP, but remained highly statistically significant. Furthermore, the present study demonstrated for the first time an inverse association between serum bilirubin concentrations and the prevalence of type 2 diabetes. Since

Conflict of interest

There are no conflicts of interest.

Acknowledgement

This study was supported by a grant for the 21st Century Center of Excellence (COE) Program (Kyushu University) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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