Serum retinol binding protein 4 and nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus
Introduction
Yang et al. have proven that retinol binding protein 4 (RBP4) is a protein secreted by adipocytes, and increased in insulin resistant states [1]. Elevated serum RBP4 levels impair postreceptor insulin signaling in muscle and induce the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase in the liver, which lead to insulin resistance, while lowering the serum levels of RBP4 improves insulin resistance and glucose tolerance in mice with obesity [1]. Human studies suggest that serum RBP4 level might contribute to systemic insulin resistance and be associated with diabetes, dyslipidemia, and cardiovascular risk factors [2]. However, RBP4 is also a cytokine that is mainly expressed in hepatocytes as the principal transport protein for retinol (vitamin A) in the circulation, and the pathophysiological roles of serum RBP4 in liver diseases are largely unknown [3].
Insulin resistance is the pathophysiological denominator that links all the components of the metabolic syndrome and may have a major role in the development of nonalcoholic fatty liver disease (NAFLD) [4]. Meanwhile, insulin resistance plays a pivotal role in type 2 diabetes mellitus (T2DM) and glucose intolerance and indeed there is strong association between these disorders and liver disease, and up to 75% of diabetic patients have NAFLD [5], [6], [7]. Diabetic medications that have been shown to correct insulin resistance may prove to be beneficial in NAFLD treatments [8], [9]. Thus, based on the strong association between RBP4 and insulin resistance, we postulate that RBP4 might contribute to the pathogenesis of NAFLD.
To investigate the role of RBP4 in NAFLD, we measured serum RBP4 level as well as adiponectin in type 2 diabetic patients with or without NAFLD.
Section snippets
Subjects
From November 2003 to April 2005, subjects with Han ethnicity in China who consecutively visited the Diabetic Clinic of Shanghai No. 6 People's Hospital for endocrinological and metabolic disorders or physical checkup were studied. One hundred and two diabetic patients (61 men and 41 menopausal women) newly diagnosed, aged 53.3 ± 8.5, were recruited. The diagnosis of type 2 diabetes mellitus (T2DM) was based on the WHO criteria [10]. Patients presenting with symptoms suggestive of type 1
Statistical analysis
The data are shown as the mean ± S.D. All of the statistical analyses were performed by SPSS version 11.5 (Statistical Package for the Social Science, SPSS Inc., Chicago, IL). Each variable was examined for normal distribution and significantly skewed variables were log transformed. For descriptive purposes, mean values were presented on untransformed and unadjusted variables. Since the distribution of diastolic blood pressure, HbA1c, triglycerides, HDL-cholesterol, ALT and γGT values were
Results
The clinical characteristics of the subjects are shown in Table 1. A total of 52 diabetic patients with NAFLD and 50 sex- and age-matched diabetic patients without NAFLD were studied. Diabetic patients with NAFLD had higher BMI, triglyceride, fasting serum insulin, HOMA-IR, ALT, γGT, and uric acid than those of control patients. Serum RBP4 levels were found to be elevated in diabetic patients with NAFLD (32.0 ± 8.9 μg/ml vs. 41.3 ± 9.8 μg/ml, p < 0.001). In contrast, adiponectin decreased (17.4 ± 9.3
Discussion
Individuals with T2DM have increased prevalence of NAFLD [5], [6], [7]. In a population study of patients with T2DM, standardized mortality rates due to liver disease exceed that due to cardiovascular diseases [12]. We demonstrated that RBP4 serum level increased in diabetic patients with NAFLD or in a fully adjusted model. It inferred there was a causal relationship between RBP4 and NAFLD.
Insulin resistance leads to the accumulation of fat in hepatocytes by lipolysis and hyperinsulinemia and
Acknowledgements
We are grateful to all colleagues in Diabetic Clinic of Shanghai No. 6 People's Hospital for assistance in recruiting patients. This work was funded by National Natural Science Foundation of China Project (30670989), Chinese National 973 Project (2006CB503901), and the Foundation of Shanghai Science and Technology Development (012D002(1)).
References (31)
- et al.
Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes
Nature
(2005) - et al.
Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects
N. Engl. J. Med.
(2006) Retinol-binding protein: the serum transport protein for vitamin A
Endocr. Rev.
(1989)- et al.
Association of nonalcoholic fatty liver disease with insulin resistance
Am. J. Med.
(1999) - et al.
Liver diseases and diabetes mellitus
Prog. Liver Dis.
(1970) - et al.
Receiver operating characteristic analysis of glycogenated nuclei in liver biopsy specimens: quantitative evaluation of their relationship with diabetes and obesity
Hum. Pathol.
(1994) - et al.
Prognosis in non-alcoholic steatohepatitis (Letter)
Gastroenterology
(1995) - et al.
Safety and effectiveness of rosiglitazone in type 2 diabetes patients with nonalcoholic Fatty liver disease
J. Formos Med. Assoc.
(2006) - et al.
Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes
Diabetes
(2004) - et al.
Definition, diagnosis and classification of diabetes mellitus and its complications. 1: Diagnosis and classification of diabetes mellitus, provisional report of a WHO consultation
Diab. Med.
(1998)
Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man
Diabetologia
Cause specific mortality in type 2 diabetes. The Verona Diabetes study
Diab. Care
CYP2E1 and CYP4A as microsomal catalysts of lipid peroxidase in murine nonalcoholic steatohepatitis
J. Clin. Invest.
The lipid peroxidation end product 4-hydroxy-2,3-nonenal up regulates transformin growth factor B1 expression in the macrophage lineage: a link between oxidation injury and fibrosclerosis
FASEB J.
Mechanisms of disease. Nonalcoholic fatty liver disease
N. Engl. J. Med.
Cited by (74)
Isotope-dilution liquid chromatography-tandem mass spectrometry for quantification of human retinol binding protein 4 in serum
2022, Analytical BiochemistryCitation Excerpt :Of interest, the varying level in plasma or serum RBP4 might reflect renal impairment in type2 diabetes mellitus patients [5–7]. In addition, RBP4 is a biomarker for a series of metabolism-related diseases, including obesity, cardiovascular diseases, nonalcoholic fatty liver disease, gestational diabetes mellitus and polycystic ovary syndrome [8–12]. Presently, immunological analysis (e.g., RIA and ELISA) is the most commonly adopted method enabling simple and rapid clinical detection of RBP4 [5,6,10].
Vitamin A signaling and homeostasis in obesity, diabetes, and metabolic disorders
2019, Pharmacology and TherapeuticsCitation Excerpt :Human observational studies exploring relationships between serum/plasma RBP4 and NAFLD occurrence are largely in agreement with the conclusion that serum/plasma RBP4 levels are elevated in patients with NAFLD. A representative sample of, but not all correlative studies, include ones involving patients with type II diabetes (Wu et al., 2008), obese children (Romanowska, Lebensztejn, Skia, Trasów, & Kaczmarski, 2011), healthy 6- to 12-year-old children (Huang & Yang, 2013), subjects diagnosed with NAFLD but not type II diabetes (Yan et al., 2013), obese and lean patients diagnosed with NAFLD (Zwolak, Szuster-Ciesielska, Daniluk, Semeniuk, & Dandefer-Szerszen, 2016), postmenopausal women diagnosed with NALFD (Cai et al., 2018) and a community-based cross-sectional study involving 2938 participants 40-70-year-olds (Chen et al., 2017). Each of these studies reported significantly elevated serum/plasma RBP4 concentrations for patients with NAFLD but provided little insight into possible cause/effect relationships.
Irisin in patients with nonalcoholic fatty liver disease
2014, Metabolism: Clinical and ExperimentalThe relationship between NAFLD and retinol-binding protein 4 - an updated systematic review and meta-analysis
2023, Lipids in Health and DiseaseEmerging Links between Nonalcoholic Fatty Liver Disease and Neurodegeneration
2023, Seminars in Liver Disease