视黄醇结合蛋白4与糖尿病血管并发症

糖尿病血管并发症的发生机制复杂,与高血糖及胰岛素抵抗、炎性反应、氧化应激密切相关.视黄醇结合蛋白4(RBP4)作为一种脂肪细胞因子,可通过胰岛素抵抗、脂代谢紊乱、氧化应激、炎性反应导致动脉粥样硬化的发生及血管扩张,参与糖尿病大血管病变的发生.RBP4也与糖尿病微血管并发症的发生相关,但其具体机制有待进一步研究.运动、减重手术、贝特类调脂药、格列酮类的干预可降低RBP4水平,有望成为治疗糖尿病血管病变的新策略.     

视黄醇结合蛋白4和心血管疾病危险因素

脂肪组织不仅是一个储备能量、提供能量的器官,更是重要的内分泌器官。2005年美国哈佛大学医学中心鉴定出一种新的参与胰岛素抵抗的脂肪细胞因子——视黄醇结合蛋白4（RetinolBindingprotein,RBP4）。随后多项研究表明其可诱导胰岛素抵抗,并且发现血浆RBP4水平在2型糖尿病、肥胖、代谢综合征以及心血管疾病中均有升高。同时国内外一些研究报道了它与脂质代谢、动脉粥样硬化、糖代谢、胰岛素抵抗、高血压、心力衰竭等心血管疾病相关危险因素的相关性。本文综述RBP4的结构、功能、测定及其在心血管疾病中的研究进展。     

新的脂肪细胞因子与糖尿病肾病

Chemerin、visfatin、vaspin、视黄醇结合蛋白 4(RBP4 )是近几年新发现的脂肪细胞因子,它们参与体内物质和能量代谢、肥胖、胰岛素抵抗等病理生理过程. 目前许多研究发现,它们与糖尿病肾病关系密切,直接或间接参与了糖尿病肾病的病理生理过程.对这几种因子的深入研究将为糖尿病肾病的防治提供新的预测指标及治疗靶点.     

视黄醇结合蛋白4：一种新的脂肪细胞因子

视黄醇结合蛋白（RBP）4是近年来新发现的一种脂肪细胞因子,在动物与人类的研究中均发现其与肥胖、胰岛素抵抗及糖、脂代谢密切相关。本文介绍了有关RBP4的结构和功能、RBP4血清水平及基因多态性与肥胖、胰岛素抵抗和糖、脂代谢关系等方面的研究进展。     

Glypican-4与肥胖及胰岛素抵抗

Glypican-4是一种新的脂肪细胞因子,其在皮下和内脏脂肪组织中差异表达,并与体重指数、腰臀比密切相关.Glypican-4通过直接与胰岛素受体结合,发挥类似胰岛素的作用,促进葡萄糖的摄取和前脂肪细胞的分化.在肥胖和糖尿病等具有胰岛素抵抗的患者中,glypican-4可通过代偿性分泌增加,维持机体血糖水平正常.Glypican-4是第一个被发现能直接与胰岛素受体结合,发挥增强胰岛素信号转导作用的脂肪细胞因子.研究其在胰岛素信号转导方面的功能将可能为肥胖和糖尿病的诊治带来新的契机.     

visfatin与2型糖尿病

visfatin是在人和小鼠的内脏脂肪中提取出的一种新的脂肪细胞因子,它可以结合并激活胰岛素受体,模拟胰岛素的作用,降低血糖水平,改善胰岛素抵抗。糖尿病的患病人数逐年增加,糖尿病已经成为一个新的流行性疾病。现发现visfatin与糖尿病关系密切,本文将visfatin的结构及在体内的分布以及visfatin与胰岛素受体、血糖水平和胰岛素抵抗和脂代谢紊乱的关系作一综述。     

视黄醇结合蛋白4在非酒精性脂肪肝发病机制中的作用

非酒精性脂肪肝(NAFLD)是一种与血脂异常、高胰岛素血症、2型糖尿病以及遗传-环境-代谢应激密切相关的临床病理综合征,胰岛素抵抗(IR)与其发病关系密切.视黄醇结合蛋白(RBP)4是新近发现的一种调节肝脏和肌肉组织中胰岛素作用的脂肪因子,与IR发病相关.目前RBP4与NAFLD的关系正逐渐受到人们的重视,现就RBP4在NAFLD发病机制中的作用作一综述.     

脂肪因子与妊娠糖尿病

人体脂肪细胞可分泌多种具有生物活性的脂肪因子,且在妊娠糖尿病(GDM)患者中存在分泌失调的现象.研究发现,妊娠早期瘦素的增加和脂联素的下降可能预示着GDM的发生;脂联素通过影响胰岛素信号转导改变胰岛素敏感性,调节血糖和胰岛素水平;视黄醇结合蛋白4(RBP4)可能通过调节血脂间接调节血糖;内脂素和vaspin的表达受多种因素影响,可能是发生胰岛素抵抗的中心环节;抵抗素基因多态性亦在不同方面对人体产生影响.综上,脂肪因子作用机制复杂,其分泌失调与GDM患者胰岛素抵抗及糖、脂代谢密切相关,并影响其病理生理学变化及预后.     

Visfatin研究进展

Visfatin是新发现的由内脏脂肪细胞分泌的一种脂肪细胞因子,可结合并激活胰岛素受体,模拟胰岛素作用,从而降低血糖;还能够促进脂肪组织的分化、合成及积聚。而对于visfatin与胰岛素抵抗之间的关系目前仍不清楚。现有研究表明visfatin可能是联系肥胖和糖尿病之间的未知环节,它的发现为研究肥胖和糖尿病的发病机制增加了新内容,可能为糖尿病治疗提供一个新的靶点。     

视黄醇结合蛋白4与多囊卵巢综合征及妊娠糖尿病

视黄醇结合蛋白4主要由肝脏合成,是血液中一种运送视黄醇的结合蚩白,亦是脂肪组织分泌的一种脂肪细胞因子.小鼠实验发现,其在组织中的过度表达可使磷脂酰肌醇3激酶活性下降,胰岛素受体底物1酪氨酸磷酸化降低.可能与胰岛素抵抗的发生有关.肥胖、糖耐量减低、胰岛素抵抗、多囊卵巢综合征、妊娠糖尿病患者血清中视黄醇结合蛋白4含量与正常者相比升高,其可能与此类疾病的发病机制有关.     

Serum concentrations of retinol-binding protein 4 in women with and without gestational diabetes

AIMS/HYPOTHESIS: Pregnancy is characterised by temporarily increased insulin resistance. Gestational diabetes occurs when pancreatic beta cell function is unable to compensate for this insulin resistance. Retinol-binding protein 4 (RBP4) could be related to insulin resistance. We hypothesised that RBP4 is elevated in gestational diabetes. METHODS: Serum RBP4, transthyretin and retinol were cross-sectionally measured in 42 women with gestational diabetes and 45 pregnant controls. Of these, 20 women with and 22 without gestational diabetes were included in an additional longitudinal study. RBP4 was determined by enzyme immunometric assay (EIA) and western blot. RESULTS: Women with gestational diabetes had lower RBP4 EIA and western blot levels than controls (median 6.8 [interquartile range, 3.9-14.3] vs 11.3 [7.8-19.9] microg/ml, p < 0.001 and 25.1 [21.7-29.6] vs 26.6 [23.5-32.2] microg/ml, p = 0.026). Transthyretin and the RBP4:transthyretin molar ratio were comparable between the groups. Serum retinol was lower (p < 0.001) and the RBP4 Western blot level: retinol molar ratio was higher in women with gestational diabetes (p = 0.044). RBP4 was not associated with the glucose or homeostasis model assessment of insulin resistance (HOMA-IR), but in gestational diabetes the RBP4:retinol molar ratio correlated with blood glucose and negatively with 2 h post-load insulin. The RBP4:transthyretin ratio correlated with HOMA-IR and fasting insulin in controls. In women with gestational diabetes RBP4 EIA and western blot levels increased after delivery. Retinol increased in both groups, while transthyretin and the RBP4:transthyretin ratio were not altered after parturition. CONCLUSIONS/INTERPRETATION: RBP4 measured by two different techniques is not elevated, but the RBP4:retinol molar ratio is higher and correlates with fasting blood glucose in women with gestational diabetes. Thus, the RBP4:retinol ratio and the RBP4:transthyretin ratio are more informative than RBP4 levels alone when assessing insulin-glucose homeostasis during pregnancy.     

Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease

Aims/hypothesis Retinol-binding protein 4 (RBP4) has recently been reported to be associated with insulin resistance and the metabolic syndrome. This study tested the hypothesis that RBP4 is a marker of insulin resistance and the metabolic syndrome in patients with type 2 diabetes or coronary artery disease (CAD) or in non-diabetic control subjects without CAD. Methods Serum RBP4 was measured in 365 men (126 with type 2 diabetes, 143 with CAD and 96 control subjects) and correlated with the homeostasis model assessment of insulin resistance index (HOMA-IR), components of the metabolic syndrome and lipoprotein metabolism. RBP4 was detected by ELISA and validated by quantitative Western blotting. Results RBP4 concentrations detected by ELISA were shown to be strongly associated with the results gained in quantitative Western blots. There were no associations of RBP4 with HOMA-IR or HbA_1c in any of the groups studied. In patients with type 2 diabetes there were significant positive correlations of RBP4 with total cholesterol, LDL-cholesterol, VLDL-cholesterol, plasma triacylglycerol and hepatic lipase activity. In patients with CAD, there were significant associations of RBP4 with VLDL-cholesterol, plasma triacylglycerol and hepatic lipase activity, while non-diabetic control subjects without CAD showed positive correlations of RBP4 with VLDL-cholesterol and plasma triacylglycerol. Conclusions/interpretation RBP4 does not seem to be a valuable marker for identification of the metabolic syndrome or insulin resistance in male patients with type 2 diabetes or CAD. Independent associations of RBP4 with pro-atherogenic lipoproteins and enzymes of lipoprotein metabolism indicate a possible role of RBP4 in lipid metabolism.     

Retinol-binding protein 4 is associated with insulin resistance and body fat distribution in nonobese subjects without type 2 diabetes

BACKGROUND: Adipose tissue is responsible for releasing various adipokines that have been related to insulin resistance. Understanding the relationship of these adipokines to insulin resistance may foster the development of new treatments for diabetes. OBJECTIVES: The primary objective of this study was to determine whether an association between retinol-binding protein 4 (RBP4) and insulin resistance exists in nonobese individuals without a family history or diagnosis of diabetes. The secondary objective was to determine by a dual energy x-ray absorptiometry scan which adipose tissue depot most closely relates to RBP4 levels. DESIGN: Cross-sectional analysis of 92 study participants ranging in age from 20 to 83 yr was performed. The range of body mass index (BMI) was from 18 to 30 kg/m(2). Exclusion criteria were a BMI greater than 30 kg/m(2), family history of diabetes, or a diagnosis of diabetes. Insulin sensitivity was determined by a hyperinsulinemic euglycemic clamp. Body fat was measured by dual energy x-ray absorptiometry scan. RESULTS: RBP4 values were lower in females (35.8 +/- 1.7 microg/ml) compared with males (39.9 +/- 1.4 microg/ml; P = 0.06). RBP4 levels were found to correlate negatively with insulin sensitivity (r = -0.32; P = 0.002) and positively with age (r = 0.38; P < 0.001). RBP4 levels did not correlate with BMI (r = -0.13; P = 0.22), trunk fat (r = 0.16; P = 0.22), or percent body fat (r = 0.07; P = 0.65). However, RBP4 levels did correlate with percent trunk fat (r = 0.36; P = 0.001). CONCLUSION: These findings indicate a relationship between RBP4, insulin sensitivity, and percent trunk fat in individuals who may not have features of insulin resistance.     

RBP4: a controversial adipokine

Adipose tissue is an endocrine organ secreting biologically active factors called adipokines that act on both local and distant tissues. Adipokines have an important role in the development of obesity-related comorbidities not only in adults but also in children and adolescents. Retinol binding protein 4 (RBP4) is a recently identified adipokine suggested to link obesity with its comorbidities, especially insulin resistance, type 2 diabetes (T2D), and certain components of the metabolic syndrome. However, data, especially resulting from the clinical studies, are conflicting. In this review, we summarize up-to-date knowledge on RBP4's role in obesity, development of insulin resistance, and T2D. Special attention is given to studies on children and adolescents. We also discuss the role of possible confounding factors that should be taken into account when critically evaluating published studies or planning new studies on this exciting adipokine.     

Association of serum retinol-binding protein 4 and visceral adiposity in Chinese subjects with and without type 2 diabetes

OBJECTIVE: Previous studies have shown that adipose-derived serum retinol-binding protein 4 (RBP4) levels are increased in insulin-resistant mouse models and in subjects with insulin resistance or type 2 diabetes. However, the association of visceral fat and serum RBP4 has not been studied. The purpose of this study was to investigate the relationship between serum RBP4 and regional fat distribution in Chinese subjects with and without type 2 diabetes. DESIGN: We measured serum RBP4 concentrations from 1033 Chinese subjects with various degrees of obesity and tested the association between visceral adiposity and serum RBP4. In a subgroup of this study, euglycemic-hyperinsulinemic clamp was performed to measure insulin sensitivity. The association between visceral adiposity and serum RBP4 was also determined in response to rosiglitazone treatment in a subgroup of patients with diabetes. RESULTS: Serum RBP4 level was positively correlated with visceral adipose area in male (r = 0.171; P < 0.001) and female (r = 0.215; P < 0.001) subjects. However, there was no correlation between serum RBP4 and body mass index. Subjects with visceral obesity had higher serum RBP4 concentrations than those without visceral obesity in both men and women. Rosiglitazone treatment in patients with diabetes resulted in a lower serum RBP4 level (35.2 +/- 10.2 vs. 24.9 +/- 5.6 microg/ml, before vs. after treatment). These changes were accompanied by improved insulin sensitivity and reductions in visceral fat area. The latter was found to be highly correlated with the decline of serum RBP4 levels (r = 0.471; P = 0.027). CONCLUSIONS: Serum RBP4 level is positively associated with visceral adiposity in both men and women. Our data suggest that RBP4 may contribute to the development of insulin resistance along with other adipokines.     

Elevated serum retinol-binding protein 4 is associated with insulin resistance in older women

Retinol-binding protein 4 (RBP4), a molecule secreted from adipocytes and hepatocytes, may contribute to insulin resistance and is a potential predictor for type 2 diabetes mellitus. We investigated the association between serum RBP4 concentrations and insulin resistance in perimenopausal women. In addition, we examined associations of serum RBP4 concentrations with age, risk factors of cardiovascular disease, and metabolic syndrome. A total of 73 healthy women were included in this study. Subjects' anthropometric measurements were taken, and body mass index and waist-hip ratio were calculated. Fasting glucose, fasting insulin, serum RBP4, and lipid parameters were examined. These various parameters were compared in subjects younger than and older than 50 years. Serum RBP4 concentrations in women at least 50 years of age were significantly higher than those in women younger than 50 years. In all subjects, serum RBP4 concentrations positively correlated with age, diastolic blood pressure, fasting glucose, and homeostatic assessment model of insulin resistance. After subgroup analysis, serum RBP4 concentrations positively correlated with age, fasting glucose, and homeostatic assessment model of insulin resistance in women at least 50 years of age. In women younger than 50 years, serum RBP4 concentrations positively correlated only with fasting glucose. Serum RBP4 appears to identify age-induced insulin resistance by physiologic changes due to aging or menopause and by increasing hepatic glucose production. However, the clinical implication of RBP4 for detecting cardiovascular disease and metabolic syndrome is not clear.     

视黄醇结合蛋白4、核因子κB的表达与糖尿病大鼠动脉粥样硬化的相关性

目的探讨视黄醇结合蛋白4（RBP4）、主动脉壁核因子κB（NF-κB）与糖尿病大血管病变的关系。方法Wistar大鼠分为：对照组（NC组）、单纯糖尿病组（（DM组）、糖尿病合并动脉粥样硬化组（DM＋AS组）。测大鼠主动脉NF-κB活性、血清和附睾RBP4水平、FBG、FIns、TG、HDL-C、LDL-C、尾动脉SBP,计算血浆致动脉粥样硬化指数（AIP）及胰岛素抵抗指数（HOMAIR）。结果DM组和DM＋AS组的RBP4、NF-κB、TG、LDL-C、FBG、FIns、SBP、AIP、HOMA-IR高于NC组;DM＋AS组上述指标高于DM组;RBP4与TG、LDL-C、HOMA-IR、AIP、NF-κB、SBP、体脂比成正相关,与HDL-C成负相关。RBP4、TG是糖尿病大血管病变发生的独立危险因素。结论NF-κB与RBP4与糖尿病大血管病变发生相关,RBP4可能通过胰岛素抵抗、炎症机制及脂代谢紊乱参与糖尿病大血管病变的发生。     

Shortcomings in methodology complicate measurements of serum retinol binding protein (RBP4) in insulin-resistant human subjects

Aims/hypothesis Levels of retinol binding protein (RBP4) are increased in the serum of insulin-resistant human subjects even before overt diabetes develops. RBP4 levels correlate with insulin resistance, BMI, WHR, dyslipidaemia and hypertension. Improvement of insulin sensitivity with exercise training is associated with reduction in serum RBP4 levels. Therefore serum RBP4 may be useful for early diagnosis of insulin resistance and for monitoring improvements in insulin sensitivity. We sought to determine the performance of assays for this application. Subjects and methods We compared quantitative western blotting and three commercially available multiwell immunoassays in parallel measurements of RBP4 concentrations in serum from insulin-sensitive subjects and from insulin-resistant subjects with impaired glucose tolerance or type 2 diabetes. Results The assays yielded different absolute values and magnitudes of elevation of serum RBP4. Western blotting and a sandwich ELISA reported RBP4 concentrations that highly inversely correlated with insulin sensitivity measured by euglycaemic–hyperinsulinaemic clamp. However, western blotting yielded concentrations with a greater dynamic range and less overlap between control and insulin-resistant subjects. Two competitive enzyme-linked immunoassays undervalued serum RBP4 concentrations in insulin-resistant subjects, possibly due to assay saturation. Poor linearity of dilution also limited assay utility. All assays tested exhibited greater immunoreactivity with urinary (C-terminal proteolysed) RBP4 than with full-length RBP4, the predominant form in serum. Conclusions/interpretations These findings support the use of quantitative western blotting standardised to full-length RBP4 protein as a ‘gold standard’ method for measuring serum RBP4 in insulin-resistant states. Other assays should use full-length RBP4 and be extensively cross-validated using other methods.     

视黄醇结合蛋白4与胰岛素抵抗

视黄醇结合蛋白4（RBP4）是一种主要来源于肝脏和脂肪细胞的转运蛋白。过去认为其作用是转运血液中的视黄醇（维生素A）。而近期的研究发现,RBP4作为一种脂质因子,可能具有引起胰岛素抵抗（IR）的作用,参与一系列与IR相关疾病,包括糖尿病、代谢综合征、非酒精性脂肪肝的发生发展。除外受到IR的影响,不同个体RBP4血清水平的影响因素各不相同。