Plasma Retinol-binding Protein 4 Research Articles

Associations of retinol-binding protein 4 with oxidative stress, inflammatory markers, and metabolic syndrome in a middle-aged and elderly Chinese population

BackgroundRetinol-binding protein 4 (RBP4), a novel adipokine secreted by adipocytes and the liver, has elevated levels in type 2 diabetes mellitus (T2DM). However, its association with human metabolic diseases remains controversial. The present study was designed to investigate the associations of plasma RBP4 levels with oxidative stress, inflammatory markers, and metabolic syndrome (MetS) in a Chinese population.MethodWe evaluated plasma RBP4 levels in a cross-sectional sample of 1748 Chinese men and women aged 50 to 70 years in Guangzhou using an in-house developed and validated sandwich ELISA. Plasma glucose, insulin, lipid profile, serum adiponectin, adipocyte fatty acid-binding protein (A-FABP), 8-iso-prostaglandin F2α (8-iso PGF2α), 13-(S)-hydroxyoctadecadienoic acid (13-HODE), high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL6), monocyte chemotactic protein 1 (MCP1) and tumor necrosis factor α (TNFα) were all measured. MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans.ResultsCirculating RBP4 levels were positively correlated with A-FABP (r = 0.104, P < 0.001), 8-iso PGF2α (0.236, P < 0.001), and 13-HODE (0.204, P < 0.001) and were inversely correlated with HDL cholesterol (r = −0.072, P = 0.004). After multivariable adjustment, the RBP4 levels were strongly associated with MetS and its components. The ORs (95% CIs) for the comparisons of the extreme quartiles of RBP4 were 3.46 (2.87, 4.42) for MetS, 5.92 (4.47, 8.02) for hypertriglyceridemia, 1.42 (1.11, 1.68) for reduced HDL cholesterol, 1.87 (1.48, 2.36) for central obesity and 2.74 (2.15, 3.36) for hyperglycemia (all P < 0.001). When we further controlled for adipokines, markers of oxidative stress and proinflammatory response, the association of RBP4 with central obesity was abolished but not the association with other MetS components.ConclusionsPlasma RBP4 levels are associated with an adverse profile of oxidative stress and inflammatory markers and an increased risk of MetS in this Chinese population. These associations are independent of conventional risk factors.

A Comparison of the Effects of Aerobic and Intense Exercise on the Type 2 Diabetes Mellitus Risk Marker Adipokines, Adiponectin and Retinol Binding Protein-4.

With a more sedentary population comes growing rates of obesity and increased type 2 diabetes mellitus (T2DM) risk. Exercise generally induces positive changes in traditional T2DM risk markers such as lipids, glucose tolerance, and insulin sensitivity; however alterations in concentrations of many circulating cytokines and their respective receptors are also becoming apparent. These cytokines may be early-response health risk factors otherwise overlooked in traditional T2DM risk marker analysis. Plasma levels of two adipocyte-originating cytokines, adiponectin and retinol binding protein 4 (RBP-4), alter following exercise. Adiponectin has anti-inflammatory, anti-atherosclerotic, and anti-insulin resistance roles and its secretion increases with physical activity, whilst elevated RBP-4 leads to increased insulin resistance, and secretion decreases with increasing physical activity; thus these plasma adipokine levels alter favourably following exercise. Although current data are limited, they do suggest that the more intense the exercise, the greater the positive effect on plasma RBP-4 levels, whilst lower intensity aerobic exercise may positively improve adiponectin concentrations. Therefore short-duration, high intensity training may provide a time-efficient alternative to the recommended 150 min moderate aerobic exercise per week in providing positive changes in RBP-4 and other traditional T2DM risk markers and due to increased compliance give greater health benefits over the longer term.

Relation between Elevated Plasma Retinol Binding Protein-4 &amp; Glucose Dysregulation in Type 2 Diabetes

DOI: http://dx.doi.org/10.3329/ibmcj.v2i1.17312 IBMC J 2011; 2(1): 17-20

High Plasma Retinol-Binding Protein 4 Levels as Risk Factor of Type 2 Diabetes Mellitus in Abdominal Obesity

Background. Abdominal obesity is a risk factor for cardiovascular disease and type 2 diabetes mellitus (T2DM). Plasma retinol-binding protein 4 (RBP4) levels have been reported to increase in the abdominally obese subjects and it has been hypothesized that high plasma protein levels were considered to play an important role in the occurrence of T2DM. Objective. We assessed the value of high plasma RBP4 levels as risk factor of T2DM in abdominally obese subjects. Methodology. A case-control study, nested within a cross-sectional study, on 81 abdominally obese subjects was performed. We studied 33 patients with T2DM, compared with 33 matched controls. The plasma RBP4 levels were measured by ELISA. Insulin resistance (IR) status of the patients were determined using HOMA-IR; β-cell function was determined using HOMA-B. Analysis of variance (ANOVA) was used to test the equality of continuous variables. Forward conditional logistic regression analyses were performed to examine the odds ratios (OR) between high plasma RBP4 levels and consequent T2DM. Path analyses models were performed to assess the influence of risk factors on occurrence of T2DM. Result. Plasma RBP4 levels were significantly increased, while HOMA-B was significantly lower in cases with respect to controls. In analyses adjusted for multiple T2DM risk factors, we observed positive association with high plasma RBP4 levels 9.74 (CI 95%; 2.03 – 46.67) (p = 0.004). It has been proven that high RBP4 level was a dominant risk factor (66.9%, p = < 0.001) influencing incidence of T2DM in the abdominally obese subjects. Conclusion. The present study confirmed that high plasma RBP4 level is associated with increased incident T2DM in the abdominally obese subjects, and suggested that RBP4 has a major effect in the development of T2DM.

GW24-e2993 Relationship between plasma retinol binding protein-4 and vascular smooth muscle proliferation in hyperinsulinemic rats

ObjectivesRetinol binding protein 4 (RBP4)-a newly discovered adipocytokines, has been found to be associated closely with obesity, insulin resistance, cardiac vascular disease (CVD), metabolic syndrome. Recent researches show that RBP4...

Associations of RBP4 with lipid metabolism and renal function in diabetes mellitus

AbstractTo investigate the plasma retinol‐binding protein 4 (RBP4), small dense low‐density lipoprotein cholesterol (sdLDL‐C), oxidized low‐density lipoprotein (ox‐LDL) levels and to evaluate the associations of RBP4 with abnormal lipid metabolism and renal dysfunction in type 2 diabetes mellitus (T2DM) patients, we determined RBP4, sdLDL‐C, ox‐LDL levels and renal parameters in 120 T2DM patients with or without nephropathy and 70 controls. The correlation analysis and multiple linear regression analysis were performed. Compared with controls, the RBP4 and sdLDL‐C levels were found significantly increased only in diabetic nephropathy (DN) patients and ox‐LDL levels were elevated in both groups of T2DM patients. The RBP4 levels were positively correlated with sdLDL‐C, ox‐LDL, and negatively with estimated glomerular filtration rate (eGFR) in all the T2DM patients. Multiple linear regression analysis showed that sdLDL‐C and eGFR were the independent predictors of RBP4 levels, and RBP4 were one of the independent determinants for sdLDL‐C and ox‐LDL levels in T2DM patients, respectively. In conclusion, plasma RBP4, sdLDL‐C, ox‐LDL levels were significantly increased in DN patients. Circulating RBP4 may be associated with abnormal lipid metabolism and renal dysfunction, and considered as a biomarker of cardiovascular disease and renal function in T2DM patients.Practical applications: The findings in the present study support the hypothesis that circulating RBP4 not only plays an important role in lipid metabolism abnormalities of atherosclerosis, contributing to the increased risk of CVD, but also could reflect renal dysfunction and be associated with the severity of nephropathy in T2DM patients. Therefore, the clinical monitoring of plasma RBP4 level as well as its dynamic changes may possess distinctly clinical value for assessments of renal function and CVD risk in T2DM patients. These findings may contribute to the further understanding of the pathogenic role of circulating RBP4 in proatherogenic dyslipidemia and nephropathy in T2DM.

Association of Plasma Retinol Binding Protein-4 (RBP4) and Sonographic Grading of Fatty Liver in Obese Iranian Children

BackgroundThe prevalence of obesity and its related comorbidities, such as fatty liver, in children is increasing worldwide mostly due to changes in diet and life-style. Many serological markers have been suggested for screening of fatty liver but investigations for finding more reliable factors are still in progress.ObjectivesThis study aimed to investigate the correlation between the level of retinol binding protein-4 (RBP4) in the serum and sonographic grading of fatty-liver severity in obese Iranian children.Patients and MethodsThis case-control, double-blind study involved 51 obese children aged between five and 17 years as the case group. In addition, 35 healthy lean children with no liver problems were selected as the control group. Plasma RBP4 (using an ELISA), serum triglycerides (TG), low-density-lipoproteins (LDL), high-density-lipoproteins (HDL), total-cholesterol (Chol), and body mass index (BMI) were measured. Grading the severity of the fatty liver condition was done by an expert radiologist in the case group.ResultsRBP4 levels in obese children (19 482.9 ± 3 302.2 pg/ml) were higher than those found in the lean control group (14 295.68 ± 2 381.3 pg/ml) (P < 0.05). In the obese patients, RBP4 levels showed a significant correlation with the grade of fatty liver and BMI (P < 0.05).ConclusionsIt was found that the level of RBP4 had a strong correlation with the severity of fatty liver. Therefore, RBP4 may be considered as a useful, noninvasive predictive biomarker of intrahepatic lipid content in obese children prior to using radiological investigations. In particular, abdominal sonography, for the evaluation of intrahepatic lipid content in obese patients, as the sensitivity of a sonography is decreased due to the increased thickness of the abdominal wall as a result of fat deposits.

Contrasting effects of type 2 and type 1 diabetes on plasma RBP4 levels: The significance of transthyretin

Retinol-binding protein 4 (RBP4) is the principle carrier of retinol in the human plasma, which circulates as a complex with transthyretin (TTR), a homotetrameric thyroxine transport protein. Although this complex formation is thought to prevent glomerular filtration of RBP4, it also stabilizes the quaternary structure of TTR. Recent studies indicate elevated plasma levels of RBP4 in type 2 diabetes (T2D). In contrast, reduced RBP4 levels were observed in type 1 diabetes (T1D). Herein, we critically examine the probable mechanisms involved in the regulation of RBP4 and TTR levels during T2D and T1D. The available evidences point to the involvement of pancreatic factors in regulating the expression of both RBP4 and TTR. It appears that during T1D, TTR levels are reduced and it exists predominantly as a monomer that may interfere its interaction with RBP4 resulting in its loss through glomerular filtration. However, plasma TTR levels remain high under T2D conditions and thus reducing glomerular filtration of RBP4. Therefore, the plasma TTR levels appear to be an important determinant of plasma RBP4 levels in these two diabetic conditions.

Effect of weight loss, independent of change in diet composition, on apolipoprotein AI kinetic in men with metabolic syndrome

We investigated the effect of weight loss, independent of change in diet composition, on HDL and apoAI metabolism in men with metabolic syndrome (MetS). Subjects (19 men with MetS [NCEP-ATPIII]) were fed an isoenergetic Mediterranean-style diet for 5 weeks (all foods provided). Participants then underwent a 20-week free-living period during which they were counseled to restrict energy intake, after which they were again fed an isoenergetic Mediterranean-style diet for 5 weeks. At the end of the two controlled diets, participants received a single bolus of [5,5,5-(2)H(3)] (L)-leucine, and fasting blood samples were collected over a 96 h period. ApoAI kinetic was assessed using multicompartmental modeling of the tracer enrichment data. Participants achieved a 9.1 ± 2.8% reduction in body weight (P < 0.001). Weight loss resulted in an increase in plasma HDL-cholesterol (HDL-C) concentrations of 6.0% (P = 0.059) and HDL(3)-C of 7.9% (P = 0.045), attributable to a reduction in apoAI fractional catabolic rate (-7.8%; P = 0.046) with no change in apoAI production rate (2.2%; P = 0.58). These data indicate that weight loss, independent of variation in diet composition, increases plasma HDL primarily by delaying the catabolism of apoAI.

Plasma level of RBP4 in patients with coronary heart disease and the effect of hyperinsulinemia

To evaluate the change of plasma level of retinol binding protein 4 (RBP4) in patients with coronary heart disease, and to explore the effect of hyperinsulinemia. This study was carried out at Xiangya Hospital of Central South University, China, from September 2009 to May 2010. Thirty patients with coronary artery disease (the CAD group) were confirmed by coronary angiography, 29 patients with CAD plus hyperinsulinemia (the CAD+HIns group), and 30 healthy subjects were enrolled as controls (the control group). The peripheral blood sample from the anticubital vein was collected aseptically in all the subjects to measure the RBP4 by enzyme linked immunosorbent-assay (ELISA). The height, weight, body mass index (BMI) the waist-to-hip ratio (WHR), the blood pressure, the fasting plasma glucose (FPG), the fasting insulin (Fins), the 2-hour postprandial inslulin (2hPIns), and the homeostasis model assessment-insulin resistance index (HOMA-IR) was measured. The lipids, high sensitivity C reactive protein (hsCRP), uric acid(UA), free fatty acids (FFA) were all examined. The level of plasma RBP4 in the CAD+HIns group was higher than that in the CAD group and the control group (both P<0.01), with no significant difference of plasma RBP4 between the CAD group and the control group (P>0.05). Correlation analysis showed that the plasma RBP4 level was significantly correlated with BMI, FPG, FIns, 2hPIns, HOMA-IR, TG, HDL-C, UA, and hsCRP (r=0.259, 0.331, 0.582, 0.452, 0.600, 0.236, -0.290, 0.243, 0.231, respectively; all P>0.05). Multiple regression analysis showed that BMI, 2hPIns, and HOMA-IR were the independent factors related to RBP4. The plasma level of RBP4 does not increase in the CAD group, but it is high in the CAD +HIns group. RBP4 level is related to BMI, lipids, UA, and other cardiovascular risk factors. BMI, 2hPIns, and HOMA-IR are the independent factors associated with RBP4.

The Association of Retinol-Binding Protein 4 With Metabolic Syndrome and Obesity in Adolescents

Retinol-binding protein 4 (RBP4) has a role in the development of insulin resistance (IR), type 2 diabetes, obesity, and metabolic syndrome among adults. However, data among adolescents are limited, and the effects of gender and sex hormones on RBP4 are not well defined. A total of 1082 adolescents were enrolled and categorized based on their body mass index. Blood samples were collected, and biochemical characteristics, sex hormones, RBP4 concentrations, and IR were determined. Testosterone and estradiol were not directly correlated with RBP4 concentrations in both genders. Multivariate regression analysis revealed that fasting plasma glucose (FPG), triglyceride (TG), and testosterone levels were independently associated with RBP4 concentrations in boys; also, there was a trend of increasing RBP4 levels with the severity of obesity. Plasma RBP4 concentrations correlated with obesity and cardiovascular risk factors, predominantly evident in boys. Testosterone, FPG, and TG levels were independent predictors of RBP4 concentrations.

Abstract 241: Influence of Dietary Salt and Renin-angiotensin System activity on plasma Retinol-binding Protein 4 in Healthy Human Subjects

Introduction: Retinol-binding protein 4 (RBP-4) is a circulating adipokine associated with insulin resistance, obesity and cardiovascular risk. Previous evidence suggests a negative impact on insulin sensitivity via an interaction with the insulin-stimulated glucose transporter (GLUT-4), specifically in adipocytes. Since angiotensin-2 (ANG-2) impairs GLUT-4 presentation and insulin sensitivity, we hypothesized that renin-angiotensin system (RAS) activity might affect RBP-4 expression as well. Furthermore, both RAS activity and insulin sensitivity are affected by dietary salt, but the relationship between these factors and RBP-4 expression is unknown. We hypothesized that liberal salt diet, via suppression of RAS activity, would be associated with reduced RBP-4 levels compared to salt restriction. METHODS: Healthy subjects (7 men, 7 women, mean age 24 yr, BMI 22.6) were studied on low salt (LS 10 mmol Na/day) diet and then liberal salt (HS 200 mmol Na/day) diet for 1 week each. Samples were drawn after overnight rest in the supine position for plasma renin activity (PRA), serum Aldosterone (Aldo) and plasma RBP-4 and again after ANG-2 infusion (3ng/kg/min x 45 mins). Results: Salt manipulation predictably modified RAS activity (HS v. LS Aldo, 4.5 ± 3.8 v. 19.5 ± 8.5 ng/dl [p&lt;0.01]; HS v. LS PRA, 0.5 ± 0.4 v. 2.7 ± 1.4 ng/ml/hr [p&lt;0.01]). RBP-4 was significantly lower on a HS compared to LS diet (35.4 ± 6.6 v. 38.6 ± 7.9 mg/L, p= 0.017). No significant change was observed in RBP-4 level after ANG-2 infusion on either diet. Fasting insulin levels trended lower on HS compared to LS (3.9 ± 6.8 v. 4.4 ± 1.2 μIU/ml, p=0.09), but there was no difference in fasting glucose (81.9 ± 6.8 v. 82.1 ± 4.7 mg/dl, p=0.92). Conclusion: RBP-4 levels are modified by dietary salt intake. RBP-4 levels were lower under HS conditions (suppressed RAS) as compared to LS conditions. Acute administration of ANG-2 does not increase RBP-4 levels in this healthy population. Insulin response was similar to prior reports suggesting that the connection between RAS activity, dietary salt and insulin sensitivity may include RBP-4. Future work exploring the relationship between RBP-4, GLUT-4 and insulin sensitivity should take into consideration the effect of dietary salt intake.

Circulating retinol-binding protein 4 concentrations in patients with coronary artery disease and patients with type 2 diabetes mellitus

Circulating Retinol-Binding Protein 4 (RBP4) has recently been identified as a marker of insulin resistance. We tested this hypothesis in patients with coronary artery disease (CAD), patients with type 2 diabetes mellitus (T2DM), and in non-diabetic control subjects. We studied plasma RBP4 levels and RBP4-to-transthyrethin (TTR) ratio, estimating the excess circulating RBP4 in proportion to TTR, in 45 individuals divided into three groups (15 CAD, 15 T2DM, and 15 controls). Plasma RBP4 levels were significantly lower in patients with T2DM than in non-diabetic control subjects (P = 0.05). The RBP4/TTR ratio was not statistically different between the groups. There was no difference in plasma RBP4 levels and RBP4/TTR ratio between non-diabetic CAD patients and control subjects or those with and without metabolic syndrome. No significant associations were found between RBP4 and RBP4/TTR ratio, as dependent parameters, with markers of the metabolic syndrome and lipid metabolism. RBP4 does not seem to be a valuable marker for identification of the metabolic syndrome or insulin resistance in patients with T2DM or CAD.

Fenretinide Ameliorates Insulin Resistance and Fatty Liver in Obese Mice

Fenretinide (FEN), a ligand of retinol binding protein 4 (RBP4), has been suggested as a measure to reduce insulin resistance and its associated disorders such as obesity, and fatty liver by reducing serum RBP4. We investigated whether there is another possible mechanism by which fenretinide reduces insulin resistance and fatty liver in genetically obese (ob/ob) mice. Male obese mice fed a high-fat diet (45% of calories from fat) were divided into two groups (n=13 each). One (FEN) received fenretinide (20 mg/kg body weight, intraperitoneally) and the other (O) received vehicle three times weekly for 24 d. C57BL/6J mice fed a normal-fat diet (16% of calories from fat) were used as a control (C; n=13). No changes in fat weight and serum leptin level could be observed in FEN mice. Lower plasma RBP4 was observed in FEN mice compared with O mice. Fenretinide improved whole-body insulin sensitivity based on glucose and insulin tolerance tests and the homeostasis model assessment of insulin resistance. Fenretinide decreased the plasma lipid (triglyceride, cholesterol, and free-fatty acid) levels, hepatic TG level, and histological steatosis score. The mechanism by which fenretinide prevents fatty liver may be explained by an increased plasma adiponectin level, increased activation of hepatic AMP-activated protein kinase, and the expression of peroxisome proliferator-activated protein-α and peroxisomal acyl-CoA oxidase, which promote fat oxidation. FEN alleviated insulin resistance and fatty liver in obese mice and thus may act as an anti-lipidemic and anti-diabetic drug.

Toll-like receptors 1–9 are elevated in livers with fructose-induced hepatic steatosis

Studies in animals and human subjects indicate that gut-derived bacterial endotoxins may play a critical role in the development of non-alcoholic fatty liver disease (NAFLD). In the present study, we investigated if the liver is also sensitised by other microbial components during the onset of fructose-induced steatosis in a mouse model. C57BL/6 mice were either fed with 30 % fructose solution or tap water (control) with or without antibiotics for 8 weeks. Expression of toll-like receptors (TLR)1-9, TNF-α, inducible NO synthase (iNOS), myeloid differentiation factor 88 (MyD88) and number of F4/80 positive cells in the liver were assessed. Occludin protein, DNA of microbiota in the small and large intestine and retinol binding protein 4 (RBP4) in plasma were analysed using Western blot, DNA fingerprinting and ELISA, respectively. F4/80 positive cells were determined by immunohistochemistry. The accumulation of TAG found in the livers of fructose-fed mice was associated with a significant induction of TLR 1-4 and 6-8. Plasma RBP4 concentration and hepatic mRNA expression levels of TNF-α, iNOS, MyD88 and number of F4/80 positive cells of fructose-fed animals were significantly higher than those of controls; however, these effects of fructose were attenuated in antibiotic-treated mice. Whereas protein concentration of occludin was lower in the duodenum of fructose-treated mice, no systematic alterations of microbiota were found in this part of the intestine. Taken together, these data support the hypothesis that (1) an increased intestinal translocation of microbial components and (2) an increased number of F4/80 positive cells and induction of several TLR and dependent pathways (e.g. MyD88 and iNOS) may be involved in the onset of fructose-induced NAFLD.

Association of plasma retinol-binding protein-4, adiponectin, and high molecular weight adiponectin with metabolic adversities in patients with schizophrenia

Metabolic adversities are prevalent in patients with schizophrenia. Retinol-binding protein 4 (RBP4) and high molecular weight (HMW) adiponectin have been recently found to be associated with metabolic features in non-psychiatric population. The study aimed to evaluate the associations between metabolic features and RBP4, total adiponectin, and HMW adiponectin in patients with schizophrenia. We recruited 109 patients with schizophrenia treated with clozapine or haloperidol and evaluated their body mass index (BMI), waist circumference, blood pressure, and fasting triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose, insulin, RBP4, total adiponectin, and HMW adiponectin levels. We found that patients with metabolic syndrome (MS) had higher RBP4 level, and lower total adiponectin and HMW adiponectin levels than those without MS. There were no significant differences in metabolic features and adipocytokine levels between patients treated with clozapine and haloperidol. Most of the metabolic indexes were significantly correlated with the levels of adipocytokines. After adjusting the effects of age, gender, and BMI, marginal significant correlations existed between TG and RBP4 levels; HDL-C and total adiponectin and HMW adiponectin; insulin and HOMA-IR and HMW adiponectin. Receiver operating curve analysis showed that all of the three adipocytokines could differentiate patients with MS from those without MS. Meanwhile, total adiponectin and HMW adiponectin, but not RBP4, had the differentiating power for insulin resistance. Higher RBP4 and lower total adiponectin and HMW adiponectin levels were observed in schizophrenic patients with MS. Only HMW adiponectin is marginally correlated with insulin sensitivity. The finding that metabolic profiles, but not the antipsychotic types, are associated with adipocytokine levels should be confirmed in longitudinal studies.

Retinol-Binding Protein 4 Is Associated With Prediabetes in Adults From the General Population

OBJECTIVEWe examined the association between retinol-binding protein 4 (RBP4), a novel adipokine, and prediabetes (isolated impaired fasting glucose [i-IFG], isolated impaired glucose tolerance [i-IGT], and combined IFG and IGT) in men and women aged 32–81 years.RESEARCH DESIGN AND METHODSThe analysis was based on 2,614 participants without previously diagnosed diabetes and those with newly diagnosed diabetes of the Cooperative Health Research in the Region of Augsburg (KORA) F4 Study, conducted from 2006 to 2008 in southern Germany. Plasma RBP4 was analyzed by immunonephelometry.RESULTSIn logistic regression analysis, RBP4 levels in the fourth quartile versus the first quartile were significantly associated with prediabetes (i-IGT, i-IFG, and IFG/IGT; reference normal glucose tolerance) independent of known metabolic risk factors and lifestyle variables (odds ratio 1.63 [95% CI 1.17–2.27] after multivariable adjustment). Stratification by sex showed generally similar results.CONCLUSIONSRBP4 levels were associated with prediabetes in individuals from the general population. Prospective studies investigating the impact of RBP4 on the development of glucose intolerance are needed.

High plasma retinol binding protein 4 (RBP4) is associated with systemic inflammation independently of low RBP4 adipose expression and is normalized by transplantation in nonobese, nondiabetic patients with chronic kidney disease

Adipose-secreted retinol binding protein 4 (RBP4) circulates in free (active) and transthyretin (TTR)-bound forms and may be associated with obesity-related inflammation. Potential involvement of plasma and adipose RBP4 in systemic inflammation in the absence of obesity and diabetes is unknown. Inflammation reduces survival in chronic kidney disease (CKD) [particularly in maintenance haemodialysis (MHD)], and plasma RBP4 may increase with renal dysfunction. We investigated (i) potential associations between RBP4 and inflammation in CKD and (ii) the role of adipose tissue in this putative interaction. Cross-sectional. Nonobese, nondiabetic patients with CKD undergoing conservative (CT: n = 10) or MHD treatment (n = 25) and healthy control subjects (C: n = 11). Renal transplant recipients (n = 5) were studied to further assess the impact of restored near-normal renal function. Plasma RBP4, TTR and C-reactive protein (CRP), adipose RBP4 expression. Plasma RBP4, TTR and CRP were highest in MHD (P < 0·05). Adipose RBP4 mRNA was, however, comparably low in CT and MHD (P < 0·05 vs C), and all parameters were normalized in transplant recipients (P < 0·05 vs MHD). In all subjects (n = 51), creatinine and TTR (P < 0·05) but not adipose RBP4 mRNA were associated with plasma RBP4. Plasma RBP4 but not its adipose expression was in turn associated positively (P < 0·05) with CRP independently of creatinine-TTR. High plasma RBP4 and inflammation are clustered in CKD in the absence of obesity and diabetes and are normalized by transplantation. Adipose RBP4 expression is not involved in plasma RBP4 elevation, which appears to be mainly because of passive accumulation, or in CKD-associated inflammation.

Retinol‐Binding Protein 4 in Young Men With Low Versus Normal Birth Weight: Physiological Response to Short‐Term Overfeeding

Retinol-binding protein 4 (RBP4) is a plasma protein which is elevated in obesity and type 2 diabetes. We aimed to investigate whether RBP4 represents a mechanism underlying the associations between low birth weight (LBW), high-fat diet, and insulin resistance. Forty-six young, lean men with low (n = 20) or normal (n = 26) birth weight underwent a 5-day high-fat high-calorie (HFHC) dietary intervention. In vivo glucose metabolism was assessed by euglycemic-hyperinsulinemic clamp, glucose tracer and intravenous glucose tolerance test techniques. Body composition was measured by a dual-energy x-ray absorptiometry scan, and plasma RBP4 by an enzyme-linked immunosorbent assay. RBP4 was not associated with birth weight, but with BMI (β = 0.9 µg/ml (0.08; 1.8) (95% confidence interval), P = 0.03) and plasma levels of low-density lipoprotein cholesterol (β = 5.3 µg/ml (1.9; 8.7), P = 0.03) and triglycerides (β = 15.4 µg/ml (9.5; 21.3), P < 0.001). Under baseline diet conditions, RBP4 was associated with decreased disposition index (D(i)) (β = -2.4% (-4.5%; -0.2%), P = 0.04) and increased basal hepatic glucose production rate (HGP) (β = 0.02 mg kg(-1) min(-1) (0.002; 0.04), P = 0.03), but not associated with peripheral glucose disposal rate or hepatic insulin resistance index. RBP4 levels were not influenced by overfeeding or related to peripheral and hepatic insulin resistance provoked by the dietary intervention. In conclusion, plasma RBP4 in young men associates with components of the metabolic syndrome, but is not determined by birth weight and seems not to be involved in short-term high-fat diet-induced insulin resistance.

Elevated Retinol Binding Protein 4 Contributes to Insulin Resistance in Spontaneously Hypertensive Rats

Retinol binding protein 4 (RBP4) is an adipokine secreted by adipose tissue and liver and contributes to insulin resistance (IR) in animals. Although several human studies indicated that RBP4 is positively correlated with blood pressure and is elevated in untreated hypertensive subjects, the role of RBP4 in IR of hypertensive animals still remains obscure. In this study, spontaneously hypertensive rats (SHR) were used to investigate the relationship between RBP4 levels and IR. We found that at 7 weeks old, SHR had significantly increased plasma RBP4 levels and RBP4 expression in liver and epididymal adipose tissue accompanied by worsening of IR as compared with Wistar-Kyoto (WKY) control rats. Administration of fenretinide in SHR to increase urinary RBP4 excretion significantly decreased plasma RBP4 levels and improved IR. Moreover, treatment with valsartan markedly reduced blood pressure, circulating RBP4 and adiponectin levels, and IR in SHR. Valsartan also reversed the increase of hepatic gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and the decrease of type 4 glucose transporter (GLUT4) in adipose tissue. In conclusion, these results suggest that RBP4 contributes, at least partly, to the pathogenesis of IR in SHR. Furthermore, the decrease of blood pressure caused by valsartan not only decreased RBP4 levels, but also improved IR in SHR.