Open-label, multicenter, dose-titration study to determine the efficacy and safety of tolvaptan in Japanese patients with hyponatremia secondary to syndrome of inappropriate secretion of antidiuretic hormone.

The purpose of this study was to determine the efficacy and safety of tolvaptan in Japanese patients with hyponatremia secondary to syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This multicenter, open-label, dose-escalation, phase III study enrolled Japanese patients (20-85 years old) with hyponatremia secondary to SIADH who were unresponsive to fluid restriction. Oral tolvaptan was administered for up to 30 days, initially at 7.5 mg/day, but escalated daily as necessary, based on the serum sodium concentration and safety, over the first 10 days until the optimal maintenance dose was determined for each patient (maximum 60 mg/day). The primary endpoint was the proportion of patients with normalized serum sodium concentration on the day after the final tolvaptan dose. Secondary endpoints included the mean change in serum sodium concentration from baseline on the day after the final dose. Sixteen patients (male, 81.3%; mean ± standard deviation age 71.9 ± 6.1 years) received tolvaptan treatment and 11 patients completed the study with one patient re-administered tolvaptan in the treatment period. Serum sodium concentrations normalized in 13 of 16 (81.3%) patients on the day after the final tolvaptan dose. The mean change in serum sodium concentration from baseline on the day after the final dose was 11.0 ± 4.3 mEq/L. Adverse events considered related to tolvaptan (10 [62.5%] patients) were generally of mild to moderate severity. Oral tolvaptan corrects hyponatremia in Japanese patients with SIADH with a similar efficacy and safety profile as that noted in non-Japanese patients.

Daily variability in serum levels of calciprotein particles and their association with mineral metabolism parameters: A cross-sectional pilot study.

AIM: Calciprotein particles (CPPs), colloidal protein-mineral nanoparticles composed of solid-phase calcium phosphate and serum protein fetuin-A found in blood, are emerging as a novel component of chronic kidney disease-mineral and bone disorder (CKD-MBD). The relationship of CPPs with factors known to underlie the CKD-MBD pathophysiology is not well known.The aim of this study is to examine daily variations in CPPs as well as their association with mineral metabolism parameters in normal individuals and early-stage CKD patients. METHODS: Twenty subjects (10 healthy adults, 10 diabetic patients) were enrolled. Serum CPP Fetuin-A was measured and analyzed in relation to clinical parameters. RESULTS: Estimated glomerular filtration rates (eGFR) were 103 ± 11 and 75 ± 24 mL/min per 1.73 m2 in healthy adults and diabetic patients, respectively. Serum CPP Fetuin-A (g/L) were elevated at postprandial 2 h in diabetic patients. Furthermore, serum CPP Fetuin-A were inversely correlated with eGFR and serum 1,25-dihydroxyvitamin D3 and magnesium levels and were positively correlated with serum fibroblast growth factor-23. CONCLUSIONS: These findings indicated that serum CPP Fetuin-A were affected by food intake and may contribute to the pathophysiology of mineral metabolism in subjects with normal and moderately impaired renal function.

High-density lipoprotein and apolipoprotein A-I inhibit palmitate-induced translocation of toll-like receptor 4 into lipid rafts and inflammatory cytokines in 3T3-L1 adipocytes.

Saturated fatty acids (SFAs) activate toll-like receptor 4 (TLR4) signal transduction in macrophages and are involved in the chronic inflammation accompanying obesity. High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) produce anti-inflammatory effects via reverse cholesterol transport. However, the underlying mechanisms by which HDL and apoA-I inhibit inflammatory responses in adipocytes remain to be determined. Here we examined whether palmitate increases the translocation of TLR4 into lipid rafts and whether HDL and apoA-I inhibit inflammation in adipocytes. Palmitate exposure (250 µM, 24 h) increased interleukin-6 and tumor necrosis factor-α gene expressions and translocation of TLR4 into lipid rafts in 3T3-L1 adipocytes. Pretreatment with HDL and apoA-I (50 µg/mL, 6 h) suppressed palmitate-induced inflammatory cytokine expression and TLR4 translocation into lipid rafts. Moreover, HDL and apoA-I inhibited palmitate-induced phosphorylation of nuclear factor-kappa B. HDL showed an anti-inflammatory effect via ATP-binding cassette transporter G1 and scavenger receptor class B, member 1, whereas apoA-I showed an effect via ATP-binding cassette transporter A1. These results demonstrated that HDL and apoA-I reduced palmitate-potentiated TLR4 trafficking into lipid rafts and its related inflammation in adipocytes via these specific transporters.

Factors affecting the progression of renal dysfunction and the importance of salt restriction in patients with type 2 diabetic kidney disease.

BACKGROUND: Type 2 diabetic kidney disease (DKD) is the most common cause of end-stage renal failure, and the prevention of its progression has been a topic of discussion. METHODS: Sixty type 2 DKD patients were retrospectively evaluated for 1 year. Factors independently affecting the annual Ccr decline were examined by multivariable linear regression analysis. Patients were further divided into 2 groups based on their degree of renal function, and between-group differences at study initiation were evaluated. RESULTS: Ccr values were 21.0 ± 11.8 mL/min/1.73 m(2) at study initiation, and 15.7 ± 10.9 mL/min/1.73 m(2) after 1 year of observation. The multivariable linear regression analysis indicated salt intake (standardized coefficient: -0.34, P = 0.010) and urinary protein excretion (standardized coefficient: -0.33, P = 0.011) to be factors independently affecting the annual Ccr decline. Although decliners (-9.8 ± 4.7 mL/min/1.73 m(2)/year) had a significantly higher salt intake than non-decliners (-1.1 ± 3.8 mL/min/1.73 m(2)/year) at study initiation, this difference disappeared at the end of the study as a result of intensive dietary education. In 21 decliners with an additional year of follow-up, the annual Ccr decline significantly improved from -10.1 ± 5.3 to -5.3 ± 7.4 mL/min/1.73 m(2)/year (P = 0.02). CONCLUSION: Salt intake and urinary protein excretion were associated with annual Ccr decline in type 2 DKD patients. Furthermore, dietary education covering salt intake may have positively affected the change in Ccr.

Circulating betatrophin is elevated in patients with type 1 and type 2 diabetes.

There is evidence that betatrophin, a hormone derived from adipose tissue and liver, affects the proliferation of pancreatic beta cells in mice. The aim of this study was to examine circulating betatrophin concentrations in Japanese healthy controls and patients with type 1 and type 2 diabetes. A total of 76 subjects (12 healthy controls, 34 type 1 diabetes, 30 type 2 diabetes) were enrolled in the study. Circulating betatrophin was measured with an ELISA kit and clinical parameters related to betatrophin were analyzed statistically. Circulating betatrophin (Log transformed) was significantly increased in patients with diabetes compared with healthy subjects (healthy controls, 2.29 ± 0.51; type 1 diabetes, 2.94 ± 0.44; type 2 diabetes, 3.17 ± 0.18; p<0.001, 4.1 to 5.4 times in pg/mL order). Age, HbA1c, fasting plasma glucose and Log triglyceride were strongly associated with Log betatrophin in all subjects (n=76) in correlation analysis. In type 1 diabetes, there was a correlation between Log betatrophin and Log CPR. These results provide the first evidence that circulating betatrophin is significantly elevated in Japanese patients with diabetes. The findings of this pilot study also suggest a possibility of association between the level of betatrophin and the levels of glucose and triglycerides.

Association of serum osteoprotegerin with vascular calcification in patients with type 2 diabetes.

BACKGROUND: Osteoprotegerin is a member of the tumor necrosis factor-related family and inhibits RANK stimulation of osteoclast formation as a soluble decoy receptor. The goal of this study was to determine the relationship of serum osteoprotegerin with vascular calcification in patients with type 2 diabetes. METHODS: The subjects were 124 patients with type 2 diabetes mellitus, including 88 males and 36 females with a mean (± SD) age of 65.6 ± 8.2 years old. Serum levels of osteoprotegerin, osteocalcin, fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D3 and adiponectin were measured by ELISA. Vascular calcification in the cervical artery was examined by ultrasound sonography. The subjects were divided into 4 quartiles depending on serum osteoprotegerin levels. RESULTS: Vascular calcification was significantly higher in the 4th quartile and significantly lower in the 1st quartile of serum osteoprotegerin levels, compared to other quartiles. There were no differences in serum osteoprotegerin and vascular calcification among patients with different stages of diabetic nephropathy, but serum FGF23 levels were elevated in those with stage 4 diabetic nephropathy. Simple regression analysis showed that serum osteoprotegerin levels had significant positive correlations with age, systolic blood pressure and serum adiponectin levels, and significant negative correlations with BMI and serum 25-hydroxyvitamin D3. CONCLUSIONS: These findings suggest that elevated serum osteoprotegerin may be involved in vascular calcification independently of progression of diabetic nephropathy in patients with type 2 diabetes.

Hyponatremia as a predictor for worsening heart failure in patients receiving cardiac resynchronization therapy.

BACKGROUND: Various factors associated with worsening heart failure (HF) events have been investigated in HF subjects. The purpose of this study was to identify the predictive factor(s) for worsening HF events after cardiac resynchronization therapy (CRT) among baseline parameters, as well as baseline factors associated with responsiveness or non-responsiveness to CRT. METHODS AND RESULTS: Seventy-seven HF patients with an indication for CRT were enrolled. Baseline parameters of blood chemistry, electrocardiogram, echocardiogram and cardiac catheterization before device implantation were measured, and subsequent clinical HF events after CRT were investigated. During the follow-up period (median 601 days), 22 of 77 (29%) recipients had HF events (unscheduled HF hospitalization: 16; use of left ventricular assist system: 1; heart transplantation: 1; cardiac death: 4). In the multivariate Cox proportional hazards model, low serum sodium concentration was associated with the occurrence of HF events after CRT (hazard ratio 0.82, 95% confidence interval 0.68-0.99, P=0.034). At baseline, serum sodium concentration negatively correlated with pulmonary capillary wedge pressure (r=-0.71, P<0.001) and with plasma arginine vasopressin level (r=-0.68, P=0.008). CONCLUSIONS: Hyponatremia is an independent predictor for worsening HF events after CRT implantation, which may be partly explained by elevated level of plasma arginine vasopressin.

Hyponatremia Associated with Congestive Heart Failure: Involvement of Vasopressin and Efficacy of Vasopressin Receptor Antagonists.

Hyponatremia is frequently found in patients with congestive heart failure. A reduction in effective circulatory blood volume in a volume-expanded patient with decreased cardiac output is linked to a baroreceptor-mediated non-osmotic release of arginine vasopressin (AVP). The increased production of AVP and salt and water retention in the proximal and distal tubules of the kidney by humoral, hemodynamic, and neural mechanisms increase circulatory blood volume and contribute to hyponatremia. Recent studies have indicated that hyponatremia predicts the short-term and long-term prognosis of heart failure by increasing cardiac death and rehospitalization. In addition, the early development of hyponatremia in acute myocardial infarction also predicts the long-term prognosis of worsening heart failure. AVP V2 receptor antagonism may relieve water retention, but it is unknown whether the V2 receptor inhibitor, tolvaptan, improves the long-term prognosis of congestive heart failure. The newly identified natriuretic factor in renal salt wasting has the potential of improving clinical outcomes when combined with a distal diuretic.

Transit analysis of thyroid antibodies in graves' disease following painless thyroiditis: a case report.

Graves' disease and painless thyroiditis induce hyperthyroidism and are manifestations of an immunological disorder; however, their clinical entities differ. This case report illustrates a possible interrelation between the pathogenesis of these two disorders. A 34-year-old woman presented with palpitations, fatigue, and shortness of breath and was initially diagnosed with painless thyroiditis, which spontaneously normalized within 2 months. Within the euthyroid state, there were atypical alterations in thyroid autoantibodies, namely, activation of the thyroid stimulating hormone receptor antibody and inactivation of thyroid peroxidase and thyroglobulin antibodies. Ten months later, her hyperthyroidism recurred, with this second incidence deemed to be related to Graves' disease. Our patient had two types of painless thyroiditis with no successive hyperthyroidism, followed by Graves' disease, with her clinical manifestation transitioning from painless thyroiditis to Graves' disease over a 20-month period. Future studies are needed to elucidate the mechanisms and relationship between painless thyroiditis and Graves' disease.

Latent associations of low serum amylase with decreased plasma insulin levels and insulin resistance in asymptomatic middle-aged adults.

BACKGROUND: Low serum amylase is likely to be associated with obesity and metabolic abnormalities, which are often accompanied by impaired insulin action. However, it is unclear whether low serum amylase is associated with impaired insulin action in clinical settings. Therefore, we investigated the associations of low serum amylase with plasma insulin levels, and obesity-related parameters, including leptin. RESEARCH DESIGN AND METHODS: We measured serum amylase, plasma insulin, obesity-related parameters such as leptin, cardiometabolic risk factors, and anthropometric parameters in a cross-sectional study of 54 asymptomatic subjects (mean age 48.6 ± 7.6 years) who were not being treated for diabetes. RESULTS: Body mass index (BMI) and plasma glucose at 120 min after a 75-g oral glucose tolerance test (OGTT) were significantly higher in subjects with low serum amylase (< 60 IU/l, n = 21) than in those with normal-to-high serum amylase (n = 33) (P = 0.04 and P = 0.004, respectively). In univariate correlation analysis, serum amylase was significantly correlated with BMI alone (r = -0.39, P = 0.004). By contrast, multivariate logistic analysis showed that each 1-SD increase in quantitative insulin sensitivity check index, and each 1-SD decrease in plasma insulin OGTT at 0 and 60 min, homeostasis model assessment of insulin resistance (HOMA)-R, and HOMA-ß were significantly associated with low serum amylase, particularly after adjusting for BMI. When subjects were divided into three groups according to HOMA-R, serum amylase levels were significantly lower in subjects with HOMA-R > 2.5 (n = 23) compared with subjects with HOMA-R 1.6-2.5 (n = 10) (61.1 ± 13.6 U/ml versus 76.9 ± 20.5 U/ml, Bonferroni test, P = 0.02), but not compared with subjects with HOMA-R<1.6 (n = 21; 62.7 ± 17.6 U/ml). Similar trends were observed when subjects were divided according to plasma leptin and fasting plasma insulin levels. CONCLUSIONS: These results suggest that after adjusting for BMI, low serum amylase is associated with decreased basal insulin levels and insulin secretion, as well as high insulin resistance. The nature of these associations remains to be elucidated in further studies.

Association of subcutaneous and visceral fat mass with serum concentrations of adipokines in subjects with type 2 diabetes mellitus.

The goal of the study was to examine the association of subcutaneous and visceral fat mass with serum concentrations of adipokines in 130 subjects with type 2 diabetes mellitus. The levels of serum high sensitivity C-reactive protein (HS-CRP), adiponectin, high-molecular-weight (HMW) adiponectin, interleukin-18, and retinol-binding protein 4 were measured. Percentage body fat was determined by dual energy X-ray absorptiometry, and subcutaneous and visceral fat areas were measured by abdominal CT. HS-CRP had significant positive correlations with percentage body fat and subcutaneous fat area, and a particularly significant positive correlation with visceral fat area. Serum adiponectin had a negative correlation with the subcutaneous and visceral fat areas, with the strongest correlation with the visceral fat area. Similar results were obtained for HMW adiponectin. Serum adiponectin had a negative correlation with visceral fat area in subjects with a visceral fat area < 100 cm², but not in those with a visceral fat area ≥ 100 cm². In contrast, serum HS-CRP showed a positive correlation with visceral fat area in subjects with visceral fat area ≥ 100 cm², but not in those with a visceral fat area < 100 cm². These findings indicate that an increased visceral fat area is associated with inflammatory changes, and that inflammatory reactions may alter the functional properties of visceral fat in type 2 diabetes mellitus.

Hyponatremia is the valuable manifestation for initiating diagnosis of hypopituitarism in elderly.

The present study was undertaken to determine clinical features of hypopituitarism in elderly subjects. Thirty-one elderly patients with hypopituitarism were enrolled. They were 19 males and 12 females, with the ages of 70.7±5.4 years ranging from 62 to 80 years. High prevalence of hyponatremia (80.6%) and hypoglycemia (29.0%) was found, and it was totally different from that in hypopituitarism from general population. There were two groups of hyponatremia derived from their clinical courses, namely, acute deterioration of hyponatremia and chronically persistent hyponatremia. Analysis for deficient hormones clearly showed that ACTH deficiency was highly found in 30 of 31 patients. There was no difference in serum cortisol levels between the hyponatremic and normonatremic patients. Despite hypoosmolality, plasma arginine vasopressin (AVP) was apparently high in the hyponatremic patients compared with in the normonatremic ones. The present study indicates that hyponatremia is the valuable finding for initiating diagnosis of hypopituitarism, and that augmented release of AVP may be involved in developing hyponatremia in elderly patients with hypopituitarism.

Prompt increases in retinol-binding protein 4 and endothelial progenitor cells during acute exercise load in diabetic subjects.

The present study was undertaken to determine whether acute exercise load alters serum retinol-binding protein 4 (RBP4) and numbers of endothelial progenitor cells (EPC) in diabetic subjects. Sixty-two subjects with type 2 diabetes mellitus were enrolled in the present study. They were 50 males and 12 females with the ages of 65.1±8.1 (mean ± SD) years. Cardio-pulmonary exercise stress test (CPX) was carried out, and the numbers of EPC and serum RBP4 levels before and after the CPX were measured. RBP4 is a cytokine synthesized in hepatocytes, white adipose tissues and skeletal muscles, and serum RBP4 was determined by ELISA. EPC was determined as CD34(+)/133(+) cells by FACS. The subjects were subgrouped into two groups with or without nephropathy. Serum RBP4 levels promptly increased from 48.2±4.3 (mean±SEM) to 54.3±4.2 µg/mL after the CPX (mean exercise time of 8 min) in the diabetic subjects without nephropathy (p=0.0006), but did not in those with nephropathy. There was a positive correlation between changes in serum RBP4 during the exercise and estimated glomerular filtration rate (r=0.30, p=0.018). Also, an acute exercise load promptly increased the number of EPCs in the diabetic subjects with and without nephropathy. These findings suggest that a prompt increase in exercise-induced RBP4 is retarded by progression of nephropathy, and that an exercise-induced mobilization of EPCs could maintain endothelial cells in diabetic subjects.

Early development of hyponatremia implicates short- and long-term outcomes in ST-elevation acute myocardial infarction.

BACKGROUND: Clinical importance of hyponatremia in ST-elevation acute myocardial infarction (STEMI) in the era of primary intervention has not been fully understood. The aim of this study was to investigate the impact of hyponatremia on outcomes in patients with STEMI and secondarily to investigate the contribution of arginine vasopressin (AVP) to hyponatremia in STEMI. METHODS AND RESULTS: Hyponatremia was defined as a sodium concentration <136 mmol/L at 72h after hospitalization. First, the short-term (in-hospital mortality or congestive heart failure (CHF)) and long-term prognosis (cardiac death, re-admission for CHF) in STEMI patients was conducted. Second, the relationship between serum sodium level and plasma AVP was investigated. In hyponatremic patients the incidence of in-hospital heart failure was significantly greater (P=0.0018), long-term cardiac death was a higher trend (17.2% vs. 6.3%, P=0.19) and re-admission due to CHF was significantly more frequent (20.7% vs. 4.5%, P=0.0024). Plasma AVP level was higher in the hyponatremia group (4.5 vs. 2.7 pg/ml, P=0.003), and it had a negative correlation with serum sodium level (r=-0.28, P=0.02). CONCLUSIONS: Hyponatremia was frequently found in the early phase of STEMI, and associated with heart failure in both short- and long-term outcomes. Non-osmotic secretion of AVP could be involved in hyponatremia in STEMI patients.

Close Association of Matrix Metalloproteinase-9 Levels With the Presence of Thin-Cap Fibroatheroma in Acute Coronary Syndrome Patients: Assessment by Optical Coherence Tomography and Intravascular Ultrasonography.

BACKGROUND: Thin-cap fibroatheroma (TCFA) has been suggested as a precursor lesion of coronary plaque rupture. As elevated plasma matrix metalloproteinase-9 (MMP-9) levels have been documented in patients with acute coronary syndrome (ACS), we sought to determine whether the presence of TCFA is linked to MMP-9 levels in these patients. METHODS: We evaluated 51 ACS patients with de novo culprit lesions who were examined via optical coherence tomography and intravascular ultrasound. Blood samples were obtained from the peripheral vein (PV) and the ostium and culprit lesion of the infarct-related coronary artery (CA) in the acute phase of ACS and from the PV in the chronic phase (8 months after ACS). RESULTS: The plasma MMP-9 level in the acute phase was significantly higher than that in the chronic phase. Plasma MMP-9 levels at the culprit lesion of the infarct-related CA were significantly higher than, but positively correlated with those in the PV (10.9 (5.9-16.1) ng/mL and 8.9 (5.6-13.0) ng/mL, p < 0.0001, respectively; Spearman ρ = 0.84, p < 0.0001). Significantly higher PV plasma MMP-9 levels were observed in patients with TCFA than in patients without TCFA (12.1 (7.0-13.5) and 5.7 (4.0-8.2) ng/ml, p<0.0001, respectively). Further, plasma MMP-9 levels in the PV were positively correlated with the remodeling index (Spearman ρ = 0.29, p = 0.039) and negatively correlated with fibrous cap thickness (Spearman ρ = -0.42, p = 0.0021). Receiver operating characteristic curve analysis showed that the plasma MMP-9 levels in the PV could predict the presence of TCFA at a cut-off value of 9.9 ng/mL. CONCLUSIONS: Plasma MMP-9 levels were closely associated with MMP-9 levels in the CA and were further linked with TCFA in patients with ACS.

Voltage-dependent metabolic regulation of Kv2.1 channels in pancreatic beta-cells.

Voltage-gated potassium channels (Kv channels) play a crucial role in formation of action potentials in response to glucose stimulation in pancreatic beta-ells. We previously reported that the Kv channel is regulated by glucose metabolism, particularly by MgATP. We examined whether the regulation of Kv channels is voltage-dependent and mechanistically related with phosphorylation of the channels. In rat pancreatic beta-cells, suppression of glucose metabolism with low glucose concentrations of 2.8mM or less or by metabolic inhibitors decreased the Kv2.1-channel activity at positive membrane potentials, while increased it at potentials negative to -10 mV, suggesting that modulation of Kv channels by glucose metabolism is voltage-dependent. Similarly, in HEK293 cells expressing the recombinant Kv2.1 channels, 0mM but not 10mM MgATP modulated the channel activity in a manner similar to that in beta-cells. Both steady-state activation and inactivation kinetics of the channel were shifted toward the negative potential in association with the voltage-dependent modulation of the channels by cytosolic dialysis of alkaline phosphatase in beta-cells. The modulation of Kv-channel current-voltage relations were also observed during and after glucose-stimulated electrical excitation. These results suggest that the cellular metabolism including MgATP production and/or channel phosphorylation/dephosphorylation underlie the physiological modulation of Kv2.1 channels during glucose-induced insulin secretion.

Circulating CD34+/133+ progenitor cells in patients with stable angina pectoris undergoing percutaneous coronary intervention.

BACKGROUND: This study explored the clinical significance of CD34(+)/133(+) circulating progenitor cell (CPC) counts in patients with stable angina pectoris (AP) who underwent percutaneous coronary intervention (PCI). METHODS AND RESULTS: Subjects comprised 52 patients with stable AP requiring PCI and 50 control patients without AP. In the AP group, blood samples were taken before and 20 min and 24 h after PCI to measure CPC counts by fluorescence-activated cell sorter analysis. The baseline number of CPCs was smaller in the AP group than in controls. In the AP group, body mass index (BMI) correlated positively with the baseline number of CPCs and was an independent predictor of CPC count in multivariate regression analysis. Other conventional risk factors, daily exercise activity and statin administration showed no association with CPC count. CPC counts remained unchanged within 24 h after PCI. CONCLUSIONS: CPC counts in patients with AP are influenced by BMI, but not by other coronary risk factors. CPC counts remain unchanged within 24 h after PCI.

An increase in serum retinol-binding protein 4 in the type 2 diabetic subjects with nephropathy.

UNLABELLED: The present study was undertaken to determine retinol-binding protein 4 (RBP4) levels in subjects with diabetic nephropathy. A total of 149 type 2 diabetic subjects and 19 control subjects were enrolled. Serum levels of RBP4 were measured by a method of ELISA. Serum RBP4 levels were significantly greater in the subjects with type 2 diabetes mellitus than the controls (70.5 +/- 35.3 vs. 40.1 +/- 13.0 microg/ml, mean +/- SD, p<0.01). Serum RBP4 levels were gradually increased according to the progression of diabetic nephropathy (p value in trend test: <0.001). Its elevation was significantly greater in the diabetic subjects with stages 1, 3B and 4 than the control subjects (Stage 1: 64.6 +/- 29.7, Stage 3B: 123.3 +/- 71.8, Stage 4: 91.4 +/- 33.8 vs. CONTROL: 40.1 +/- 13.0 microg/ml, p<0.01). Similar results were obtained in the subjects based on the amount of albuminuria (Normo-: 64.6 +/- 29.7, Micro-: 63.7 +/- 29.4, and Marcoalbuminuria: 90.3 +/- 44.6 microg/ml, p <0.001). Serum RBP4 levels had a positive correlation with serum creatinine levels(r = 0.377, p<0.001), and a negative correlation with 1/creatinine (r = -0.420, p<0.001). Also, there was a negative correlation between serum RBP4 and the estimated glomerular filtration rate(r = -0.436, p<0.001). Multiple regression analysis showed that estimated glomerular filtration rate was an independent determinant for increased serum RBP4 levels. There was no difference in serum RBP4 levels between the advanced nephropathy with and without macrovascular diseases. These results indicate an increase in serum RBP4 levels in the type 2 diabetic subjects, particularly complicated with advanced renal impairment.