In the current study we found that serum RBP4 levels were inversely associated with β cell function in a cohort of Chinese women NAFLD patients without known diabetes mellitus. To the best of our knowledge, this study is the first showing a quantitative correlation between serum RBP4 levels and beta cell function assessed not only by HOMA-β but also by hyperglycemic clamp in Chinese NAFLD patients. Our study added to the growing evidences that serum RBP4,which secreted mainly by liver and adipose tissue, was a potential adverse impact factor for beta cell function and diabetes mellitus mellitus. In addition, the serum RBP4 might be one of cytokines involved in the cross-talk between adipose tissue and beta cell function in patients with fatty liver.
So far, a total of 3 articles reported the relationship between circulating RBP4 and β cell insulin secretion. Similarly, two studies have found that RBP4 negatively related to beta cell function. But the study population and methods to assess insulin secretion were different. Broch et al. reported that  circulating RBP4 was negatively associated with acute insulin response (AIRg) (r = -0.48, P = 0.007), calculated as the insulin area during the first 10 min of the frequently sampled intravenous glucose tolerance test, in 107 Spanish men without diabetes mellitus, especially in obese subjects. In multiple regression analyses to predict insulin secretion, RBP4 emerged as an independent factor that contributed independently to AIRg variance (23%) in obese but not in nonobese subjects. There were no related information about women in this study. Another study investigated 867 non-obese Chinese patients with NGT  and showed that serum RBP4 correlated with glucose-stimulated insulin secretion, assessed by ΔI30/ΔG30 (increment in plasma insulin concentration plasma glucose concentration 30 min after the oral administration of 75 g glucose) and the total area under the curve for insulin over 180 min (AUC-I), in NGT non-visceral obesity subjects, but not in NGT visceral obesity subjects and T2DM patients.
This study and the two studies mentioned above all demonstrated that circulating RBP4 may negatively affect β cell function in different subjects. On the contrary, Stefan et al. found that  circulating RBP4 did not correlate with insulin secretion (measured by the IVGTT and OGTT) before or after adjustment for age, sex, and insulin sensitivity in a total of 75 Caucasians without type 2 diabetes mellitus. One of the reasons for this difference may due to different study subjects, another reason may be the excessive adjustment for gender. If the author analyzed the relationship of RBP4 and β cell function in men or women respectively, there might be different results.
It is well known that retinol is pathophysiologically linked to β cell function [18, 19]. On the other hand, retinol-binding protein circulates in serum, forming a complex with transthyretin (TTR), a transport protein for thyroxine. An investigation disclosed that TTR constitutes a functional component in pancreatic β cell stimulus-secretion coupling . TTR inhibits the binding of RBP to the receptor . Thus, it is possible that increased serum RBP4 prevents TTR from exerting its β-cell stimulus-secretion effects. In fact, circulating RBP4 is highly bound to TTR in a one-for-one stoichiometric ratio, and there is little or no “free RBP4” in circulation . In a recent study  using gel filtration chromatography to analyze the RBP4-TTR complex, it was found that increased serumRBP4 remains bound to TTR in insulin resistant states. Because the affinity of RBP4-TTR binding is very strong , the relative stoichiometry and affinity of the two proteins in serum could conceivably influence kinetics of RBP4-antibody binding.
The concentration of serum RBP4 varies by gender, generally lower in women than in men, both among adults and children [2, 24, 25]. Several previous studies hypothesized that sex hormones may play a role in the gender discrepancy. In support of this hypothesis, RBP4 levels were shown to be different between premenopausal and postmenopausal women  and vary according to pubertal status . Although serum RBP4 concentration was higher in men than in women, whereas serum RBP4 didn’t show adverse effect on β cell function of men, which suggested there may be some protective factors, such as testosterone, against RBP4 adverse effect on β cell. McInnes et al. found that androgen receptor (AR) signaling in adipocytes not only protects against high-fat diet induced visceral obesity but also regulates insulin action and glucose homeostasis, independent of adiposity. Androgen deficiency in adipocytes in mice resembles human type 2 diabetes mellitus, with early insulin resistance and evolving insulin deficiency . Palomar et al. found  that testosterone, other than progesterone nor estradiol, protects the β cells of men pancreas against STZ-induced apoptosis, which is sex specific and could be mediated through the induction of catalase and Cu/Zn-SOD. It demonstrated that androgens may protect β cell function in men.
The relationship about RBP4 negatively related to beta cell function, restricted to some, but not all of the study population, which suggested that their relationship was complicated and influenced by many other confounding factors and deserved further research.
Firstly, the cross-sectional design of the study represents a limitation, implicating that cause-and-effect relationships cannot be discerned. Secondly, we used CT as a tool to determine the hepatic fat content, and its diagnostic accuracy is inferior to pathological diagnosis by liver biopsy. Thirdly, we did not measure blood glucose and insulin at 30 min, so we could not analyze the relationship of serum RBP4 and early phase of insulin secretion. Finally, due to the limitation of conditions, there were only 17 NGT patients undertook clamps in this study. Hence, correlation analysis of serum RBP4 and the increment of 1PH was underpowered because the sample size was too small. So, the data came from hyperglycemic clamp could just be considered as a clue, the real relationship of RBP4 and 1PH or increment of 1PH needs further verification by large-scale studies.
In summary, our results suggest that serum RBP4 may negatively affect β-cell function in Chinese women NAFLD patients without known diabetes mellitus.