Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance.

We examined the involvement of adipocyte cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2)-prostaglandin E receptor (EP)3-mediated signaling during hypertrophy and hypoxia in the development of obesity-associated adipose tissue (AT) inflammation and insulin resistance. The experiments were conducted with high-fat diet (HFD)-induced obese rats, db/db mice, human subjects, and 3T3-L1 and the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes; the groups were treated with selective inhibitors of COX-2 [celecoxib 30 mg/kg, half maximal inhibitory concentration (IC50) ≈ 0.04 µM] and EP3 (L-798106 100 µg/kg, IC50 ≈ 0.5 µM) or a short interfering RNA. There were strong, positive correlations between adipocyte COX-2 and EP3 gene expressions and the AT TNF-α and monocyte chemotactic protein-1 contents and the homeostatic model assessment for insulin resistance in HFD-induced obese rats, as well as body mass index in human subjects. Treatment with COX-2 and EP3 inhibitors significantly reversed AT inflammatory gene and protein expressions (-50%) and impaired glucose and insulin tolerance in db/db mice. COX-2 inhibition diminished the chemotaxis of adipocytes isolated from HFD rats to macrophages and T cells. Targeting inhibition of adipocyte COX-2 and EP3 during hypertrophy and hypoxia reversed the release of the augmented proinflammatory adipokines and the diminished adiponectin and also suppressed NF-κB and hypoxia-inducible factor-1α transcription activation. These findings suggest that adipocyte COX-2 PGE2-EP3-mediated signaling is crucially involved in the development of obesity-associated AT inflammation and insulin resistance.-Chan, P.-C., Hsiao, F.-C., Chang, H.-M., Wabitsch, M., Hsieh, P. S. Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance.

Platelet count can predict metabolic syndrome in older women.

Platelet count (PC) has been found to be related to the metabolic syndrome (MetS). However, the role of PC on MetS remained unclear. In order to evaluate the relationship between PC and MetS components cross-sectionally and determine the optimal cutoff PCs for predicting the subsequent risk of MetS development with sex specificity, two stages included cross-sectional (stage 1) and prospective (stage 2) cohort study were conducted. Stage 1 involved 10 579 subjects aged ≥60 years, of which 7718 subjects advanced to stage 2 with a mean 3.8 year follow-up were enrolled. The MetS components and PC were determined. The PC cutoffs for higher chances of developing MetS in stage 1 were calculated using receiver operating characteristic (ROC) curve analyses. In stage 2, non-MetS subjects were classified into high-PC (HPC) and low-PC (LPC) groups according to the cutoff values from stage 1. We examined the difference of future MetS incidence and calculated the odds ratio (OR) between these two groups. In stage 1, multiple regression showed that age and triglyceride (both sexes) and waist circumstance and high-density lipoprotein cholesterol (only women) were independently correlated with PC. There was significant difference in the area under the ROC curve (AUC) only of HPC women, which exceeded the standard curve (AUC = 0.542, p < 0.001), with a cutoff PC of 223 × 10(3)/µl. HPC women had an OR of 1.287 (95% confidence interval: 1.135-1.461) of developing MetS after 3.8 years. The Kaplan-Meier curve demonstrated a higher incidence of MetS development in HPC women. In conclusion, our results suggest that PC was associated with MetS with sex effects. Most of the MetS components were independent factors for increasing PC, and the risk for subsequent development of MetS was noted when PC >223 × 10(3)/µl in elderly women.

Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-κB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis.

AIMS/HYPOTHESIS: Chronic inflammatory processes have been increasingly shown to be involved in the pathogenesis of diabetes and diabetic nephropathy. Recently, we demonstrated that a lectin-like domain of thrombomodulin (THBD), which is known as THBD domain 1 (THBDD1) and which acts independently of protein C activation, neutralised an inflammatory response in a mouse model of sepsis. Here, therapeutic effects of gene therapy with adeno-associated virus (AAV)-carried THBDD1 (AAV-THBDD1) were tested in a mouse model of type 2 diabetic nephropathy. METHODS: To assess the therapeutic potential of THBDD1 and the mechanisms involved, we delivered AAV-THBDD1 (10(11) genome copies) into db/db mice and tested the effects of recombinant THBDD1 on conditionally immortalised podocytes. RESULTS: A single dose of AAV-THBDD1 improved albuminuria, renal interstitial inflammation and glomerular sclerosis, as well as renal function in db/db mice. These effects were closely associated with: (1) inhibited activation of the nuclear factor κB (NF-κB) pathway and the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome; (2) promotion of nuclear factor (erythroid-derived 2)-like 2 (NRF2) nuclear translocation; and (3) suppression of mitochondria-derived apoptosis in the kidney of treated mice. CONCLUSIONS/INTERPRETATION: AAV-THBDD1 gene therapy resulted in improvements in a model of diabetic nephropathy by suppressing the NF-κB-NLRP3 inflammasome-mediated inflammatory process, enhancing the NRF2 antioxidant pathway and inhibiting apoptosis in the kidney.

High glucose induces human endothelial dysfunction through an Axl-dependent mechanism.

BACKGROUND: The receptor tyrosine kinase Axl and its ligand growth arrest-specific protein 6 (Gas6) are involved in the diabetic vascular disease. The aim of this study was to explore the role of Gas6/Axl system in high glucose (HG)-induced endothelial dysfunction. METHODS: We investigated the effect of various glucose concentrations on Axl signaling in human microvascular endothelial cells (HMEC-1 s). RESULTS: Human plasma Gas6 value inversely correlated with glucose status, endothelial markers. HG decreased Gas6/Axl expression and increased intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in HMEC-1 s. HG significantly decreased HMEC-1 s cell viability and tube formation and promoted monocyte-EC adhesion. Down-regulation of Akt phosphorylation was found in HG culture. Axl transfection significantly reversed HG-induced Akt phosphorylation, VCAM-1 expression and endothelial dysfunction. We also found additive changes in Axl-shRNA-infected HMEC-1 cells in HG culture. Furthermore, Axl overexpression in HMEC-1 s significantly reversed HG-induced vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expression. In addition, significantly lower Axl and VEGFR2 expression in arteries were found in diabetic patients as compared with non-diabetic patients. CONCLUSIONS: This study demonstrates that HG can alter Gas6/Axl signaling and may through Akt and VEGF/VEGFR2 downstream molecules and suggests that Gas6/Axl may involve in HG-induced EC dysfunction.

Complexity analysis of beat-to-beat skin-surface laser-Doppler signals in diabetic subjects.

MOTIVATIONS: This study performed skin-surface laser-Doppler flowmetry (LDF) measurements with the aim of verifying if complexity analysis applied to the beat-to-beat LDF waveform index can be used to discriminate diabetic, prediabetic, and normoglycemic subjects. METHODS: Sixty-six subjects were assigned to three age-matched groups according to the results of oral glucose tolerance tests. Beat-to-beat analysis was performed on the pulsatile LDF waveform to obtain the pulse-to-mean ratio (AD) and pulse width (PW), and then approximate-entropy (ApEn) values for their 20-minute index sequences were calculated to evaluate the signal complexity. RESULTS: AD and PW did not differ significantly among the three study groups. ApEn values of AD and PW were significantly larger and marginally larger, respectively, in the diabetic group than in the prediabetic and normoglycemic groups. CONCLUSION: These results indicate the presence of significant differences in ApEn indexes among diabetic, prediabetic, and normoglycemic subjects. The presence of increased complexity in the LDF index sequence may be partly attributed to the adaptability of the microcirculatory regulatory activities or the impairment of the homeostasis mechanism of microcirculatory-blood-flow perfusion. The present findings may be pertinent to the early detection of the diabetes-induced impairment of this perfusion.

Thyrotropin as an independent factor of renal function and chronic kidney disease in normoglycemic euthyroid adults.

OBJECTIVES: The relationship between thyroid status and renal function has been well characterized. However, renal function is affected by various factors, including sex and dysglycemia. Because these studies have yet to be undertaken in a normoglycemic population, this study sought to explore the association between thyroid and renal function in large population of normoglycemic euthyroid adults. DESIGN: Population-based cross-sectional survey. PATIENTS: A total of 8,418 normoglycemic euthyroid participants were recruited after excluding individuals with thyroid dysfunction (thyrotropin, TSH < 0.47 mU/L, TSH ≥ 5.0 mU/L) or dysglycemia (fasting glucose ≥100 mg/dL). MEASUREMENTS: Anthropometric measurements were collected, and creatinine, TSH, and fasting glucose levels were evaluated. Renal function was determined by the estimated glomerular filtration rate (e-GFR) calculated using the simplified Modification of Diet in Renal Disease formula. RESULTS: TSH levels were inversely correlated with e-GFR. After adjustment for confounding factors, multivariate analysis revealed that TSH remained an independent factor of e-GFR in both genders (beta = -1.512 in males and -1.685 in females), and TSH was an independent factor of chronic kidney disease (OR = 1.28, 95% CI = 1.021-1.604). CONCLUSIONS: TSH is an independent factor for determining renal function and chronic kidney disease in normoglycemic euthyroid adults.

Chinese metabolic syndrome risk score.

BACKGROUND: The metabolic syndrome (MetS) was first proposed to predict the occurrence of cardiovascular disease and type 2 diabetes. However, it is difficult to identify subjects with MetS early. No previous studies designed to develop a predictive model for MetS in the Chinese population exists; this study was designed to fill that gap. METHODS: A middle-aged Chinese cohort of 198 men and 154 women were followed for two years. The binary logistic regression and receiver operation characteristic (ROC) curve were used to develop a predictive model for the future development of MetS. RESULTS: Over two years of follow up, 30 of the 352 subjects (8.52%) without MetS at baseline subsequently developed MetS. Triglycerides (TG) had the highest area under the curve (AUC), while diastolic blood pressure had the lowest. In order to increase the prediction power, MetS components were arranged in the ROC model according to their AUC. After adding waist circumference (WC) to TG (model 1), the AUC was significantly higher than for TG alone. Adding other components into the model did not increase the AUC significantly. A risk score cutoff (0.078) was selected for the best predictive power of model 1 (sensitivity of 76.7%, specificity of 63.4%, with AUC of 76.8%). CONCLUSIONS: These results imply that WC and TG are related to the pathophysiologies of MetS, and model 1 could also be used clinically for screening subjects at high risks for MetS.

Factor analysis of metabolic syndrome using direct measurement of insulin resistance in Chinese with different degrees of glucose tolerance.

BACKGROUND & OBJECTIVE: With the increasing prevalence of type 2 diabetes and cardiovascular disease in Taiwan, the understanding of metabolic syndrome (MetS) becomes more important. The purpose of this study was to investigate the clustering patterns of the risk variables of the MetS with factor analysis (FacAn). METHODS: A total of 564 Chinese individuals with normal glucose tolerance (N, n=345), impaired glucose tolerance (IGT, n=164) or diabetes mellitus (DM, n=55) were enrolled. Insulin resistance was measured by insulin suppression test (IST). The components of MetS such as waist hip ratio (WHR), fasting plasma glucose (FPG), systolic blood pressure (SBP), diastolic blood pressure (DBP), triglyceride (TG), high density lipoprotein cholesterol (HDLC) and steady state plasma glucose (SSPG) from IST were put into the model of exploratory FacAn. RESULTS: In spite of the minor different loading patterns, three dimensions were identified in the three subgroups; a "blood pressure" dimension, loading with mainly SBP and DBP, an "insulin resistance" dimension, loading mainly with SSPG, and an "adiposity/glucose" dimension loading with TG, WHR or FPG. INTERPRETATION & CONCLUSION: Our results were consistent with different ethnic groups in earlier reports that more than two dimensions were identified and that the MetS is not unified by a single underlying aetiology, i.e., insulin resistance. Longitudinal analysis in this and other populations will be required to validate our findings and to test their generalisability.

Umbilical myiasis in a healthy adult.

Myiasis occurs mainly on exposed skin-typically on the face, scalp, arms or legs. What may be the first recorded case of umbilical myiasis in a healthy adult is herein presented. The underlying entomology is briefly discussed to explain the clinical presentation.

Abdominal pain and multi-organ dysfunction syndrome in a young woman.

Thyroid storm is a rare but life-threatening condition caused by exaggerated thyrotoxic manifestations. Untreated thyroid storm is fatal, and the case fatality rate is 21% to 30%. The most important clinical management in thyroid storm is early recognition and treatment. We present the case of a previously healthy young woman in whom suspected gastrointestinal tract sepsis complicated by multi-organ dysfunction syndrome masked the major symptomatology of thyroid storm. This patient highlights the importance of a high clinical suspicion for potentially life-threatening conditions, such as thyroid storm, even in the absence of clinical clues (exophthalmos, lid lag, and goiter) or a history of thyrotoxicosis.

The Involvement of GAS6 Signaling in the Development of Obesity and Associated Inflammation.

Growth arrest-specific 6 (GAS6), a vitamin K-dependent protein, plays a role in the survival, proliferation, migration, differentiation, adhesion, and apoptosis of cells. GAS6 is highly expressed during growth arrest, followed by a sharp decrease during differentiation in adipocytes. The functions of GAS6 signaling are limited to TAM (Tyro3, Axl, and Mer) receptors and are dependent on the cell type. While many studies have focused on the role of GAS6 in inflammation and cancer, only few studies focused on its roles of GAS6 in obesity. Accordingly, the participation of GAS6 in the progression of obesity remains controversial. In this review, we summarize the results of current studies from clinical and basic research to elucidate the possible role of GAS6 signaling in obesity and associated disorders. In addition, this summary may offer a direction to develop clinical therapeutic strategies for the prevention and treatment of obesity and related complications.

Cilostazol attenuates the severity of peripheral arterial occlusive disease in patients with type 2 diabetes: the role of plasma soluble receptor for advanced glycation end-products.

Recent studies have demonstrated that the plasma soluble receptor for advanced glycation end-products (sRAGE) play a major role in developing macrovascular complications of type 2 diabetes, including peripheral arterial occlusion disease (PAOD). Cilostazol is an antiplatelet, antithrombotic agent, which has been used for the treatment of PAOD. We hypothesized that cilostazol attenuates the severity of PAOD in patients with type 2 diabetes through the augmentation of plasma sRAGE. Ninety type 2 diabetic patients with PAOD defined as intermittent claudication with ankle-brachial index (ABI) ≦0.9 were recruited for an open-labeled, placebo-controlled study for 52 weeks with oral cilostazol 100 mg twice daily (n = 45) or placebo (n = 45). Fasting plasma sRAGE, endothelial variables of E-selectin, soluble vascular cell adhesion molecule-1 (sVCAM-1), and inflammatory markers of high-sensitivity C-reactive protein (hsCRP) and tumor necrosis factor-α (TNF-α) were determined. After completely the 52-week treatment program, the ABI values were elevated in cilostazol group (P < 0.001). The plasma sRAGE was significantly increased (P = 0.007), and hsCRP, sVCAM, and E-selectin concentrations were significantly decreased (P = 0.028, <0.001 and <0.001, respectively) with cilostazol treatment. In a partial correlation analysis with adjustments for sex and age, the net change of sRAGE significantly correlated with the change of ABI in the cilostazol group (P = 0.043). In a stepwise multiple regression model, only the change with regards to sRAGE was significantly associated with the change of ABI (P = 0.046). Our results suggest that cilostazol may effectively attenuate the severity of PAOD in patients with type 2 diabetes. Plasma sRAGE plays a role as an independent predictor for improving the index of PAOD.

Gender differences in plasma growth arrest-specific protein 6 levels in adult subjects.

BACKGROUND: Growth-arrest-specific 6 (Gas6) is recognized as a secreted vitamin K-dependent protein, as it interacts with receptor tyrosine kinases of the TAM (Tyro-3, Axl, Mer) family. The plasma Gas6 are important to the inflammatory process, and are involved in diverse human diseases. Few studies have shown plasma Gas6 concentration varies with genders. We determined whether plasma Gas6 concentrations are associated with sex hormones in both genders. METHODS: A total of 589 adult subjects, including 361 male and 228 female were recruited. Plasma Gas6 concentration, biochemical, testosterone, estradiol (E2), and sex hormone-binding globulin were assayed. The indices of free androgen (FAI) and free E2 (FEI) were calculated. RESULTS: Significantly higher Gas6 concentrations were observed in adult male rather than female (P<0.05). In univariate regression analysis, plasma Gas6 concentrations were positively associated with FAI in male (ß=0.167, P=0.002) and both E2 and FEI in female (ß=0.384, P<0.001 andß=0.292, P<0.001, respectively). Otherwise, Gas6 concentrations were inversely associated with ages in both genders (ß=-0.234, P<0.001 in male and ß=-0.226, P=0.001 in female, respectively). In multivariate regression analysis, only age in male and E2 in female were independent variables to determine the plasma Gas6 concentrations (ß=-0.231, P=0.002 and ß=0.458, P=0.001). CONCLUSIONS: Plasma Gas6 is associated with sex hormones in female and ages in male, indicating a potential role of sex hormones and ages involving the Gas6/TAM system.

Characteristics in the beat-to-beat laser-Doppler waveform indices in subjects with diabetes.

MOTIVATIONS: The present study performed laser-Doppler flowmetry (LDF) measurements on the skin surface around the ankle with the aim of verifying if beat-to-beat analysis of the LDF waveform can help to discriminate the microcirculatory-blood-flow (MBF) characteristics between diabetic, prediabetic, and healthy subjects. METHODS: 84 subjects were assigned to three groups (diabetic, prediabetic, and normal) according to the results of oral glucose tolerance tests. Beat-to-beat analysis was performed on the pulsatile LDF waveform to obtain foot delay time (FDT), flow rise time (FRT), and the corresponding MBF-variability parameters (FDTCV and FRTCV). RESULTS: Relative to the control group, FDT and FRT were significantly shorter in prediabetic subjects, FDT was significantly shorter in diabetic subjects, and FRTCV and FDTCV were significantly larger in prediabetic and diabetic subjects. There were no significant associations for FRT after adjustment for age and gender. CONCLUSION: The present results indicate that FRT may help to discriminate differences in the elastic properties of local vascular beds during diabetes or even during prediabetic stages. The proposed blood-filling-volume model can help to explain the underlying mechanism. The present findings may aid the noninvasive early detection of diabetes-associated vascular damage, and could be used in the development of home-care and telemedicine applications.

Aggravation of hypertriglyceridemia and acute pancreatitis in a bipolar patient treated with quetiapine.

Pancreatitis is a very rare adverse effect of quetiapine treatment, with only 5 cases of quetiapine-associated pancreatitis reported in the English literature to date. Herein, we report one patient who developed severe hypertriglyceridemia (>1000 mg/dL) after quetiapine administration, resulting in acute pancreatitis. An analysis of the underlying pathogenic mechanisms and a review of relevant literature are also presented. Clinicians should be aware of the potentially life-threatening metabolic disturbances and/or pancreatitis associated with quetiapine therapy.

The levels of plasma growth arrest-specific protein 6 is associated with insulin sensitivity and inflammation in women.

AIMS: Vitamin K-dependent growth arrest-specific protein 6 (Gas6) and its receptors of the TAM (TYRO-3/Axl/Mer) family are ubiquitously expressed in immune, cardiovascular, and reproductive systems. They play pivotal roles of regulating tissue homeostasis via anti-inflammatory effects. Recent studies show that the Gas6/TAM system is involved in glucose tolerance-related metabolic disorders. Our aim was to investigate the link between Gas6 protein, insulin sensitivity and inflammatory cytokines in men and women. METHODS: A total of 278 adults (126 men and 152 women) were recruited in this study. Plasma Gas6 concentration and various biochemical, proinflammatory and endothelial markers were measured. Insulin sensitivity was estimated by homeostasis model assessment. RESULTS: Waist, fasting and 2h post-load glucose, and glycated hemoglobin (HbA1C) were significantly lower in women than in men. Age, high-density lipoprotein cholesterol, and highly-sensitive C-reactive protein levels were significantly higher in women than in men. Plasma Gas6 levels were negatively correlated with waist (r = -0.187, P = 0.022), HOMA-IR (r = -0.171, P=0.035), interleukin 6 (r = -0.362, P < 0.001), and E-selectin (r = -0.216, P = 0.008), while they were positively correlated with insulin sensitivity (QUICKI) (r = 0.168, P = 0.039) in women, but not in men. Stepwise multiple regression analysis showed that TNF-α was independently correlated with plasma Gas6 levels in both the sexes (P < 0.001). CONCLUSION: Plasma Gas6 is associated with obesity, insulin sensitivity, inflammation, and endothelial dysfunction in women and may be a general marker of inflammatory conditions in women.

Soluble form of receptor for advanced glycation end products is associated with obesity and metabolic syndrome in adolescents.

The aim of this cross-sectional study was to investigate the relationship between soluble form of receptor for advanced glycation end products (sRAGE), obesity, and metabolic syndrome (MetS) in adolescents. A total of 522 male and 561 female adolescents were enrolled into the final analyses. Anthropometric parameters, blood pressure, blood biochemistry, fasting insulin, and plasma sRAGE levels were measured. In males, sRAGE was significantly and inversely correlated with waist circumference (WC), body mass index (BMI), systolic blood pressure, triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and homeostasis model assessment-insulin resistance (HOMA-IR). Only WC and BMI were significantly and inversely correlated with sRAGE in females. Using linear regression analysis adjusting for age and gender, significant association was found between sRAGE and WC, BMI, TG, LDL-C, and HOMA-IR in adolescents of either gender (P < 0.05). This association was abolished when further adjusting BMI. In addition, sRAGE was significantly and inversely correlated with the increasing number of components of MetS in males (P for trend = 0.006) but not in females (P for trend = 0.422). In conclusion, plasma sRAGE is associated with obesity and MetS among adolescents. BMI may be the most important determinant of sRAGE levels in adolescents.

Plasma growth arrest-specific protein 6 levels in premenopausal and postmenopausal women: the role of endogenous estrogen.

Growth arrest-specific 6 (Gas6) is a vitamin K-dependent protein that interacts with receptor tyrosine kinases of the Tyro-3, AXL, Mer (TAM) family. The Gas6/TAM system contributes to the regulation of cell survival and proliferation, cell adhesion and migration, and inflammatory cytokines release. Plasma Gas6 plays an important role in the inflammatory process, and is involved in diverse human diseases. Few studies have investigated gender-specific variations in plasma Gas6 concentration. Hence, the aim of this study was to determine whether plasma Gas6 levels are associated with sex hormones in premenopausal and postmenopausal women. A total of 103 premenopausal and 135 postmenopausal women were recruited. Plasma Gas6 concentration, estradiol (E2), and sex hormone-binding globulin were assayed. The free estrogen index (FEI) was calculated. The results showed significantly lower Gas6 levels in the postmenopausal compared to the premenopausal women (P < 0.005). Plasma Gas6 levels were positively correlated with E2 levels in the pre- and postmenopausal women (r = 0.359, P < 0.001 and r = 0.261, P = 0.002, respectively). Gas6 levels were also correlated with FEI in the pre- and postmenopausal women (r = 0.234, P = 0.017 and r = 0.188, P = 0.029, respectively). After adjusting for confounders, the correlations still remained significant. In multiple stepwise regression analysis, only E2 in premenopausal and both age and E2 in postmenopausal women were independently correlated with the plasma Gas6 levels (all P < 0.001). These results suggest that plasma Gas6 is associated with sex hormones in both pre- and postmenopausal women, indicating a potential role of sex hormones in the Gas6/TAM system.

Cilostazol effectively attenuates deterioration of albuminuria in patients with type 2 diabetes: a randomized, placebo-controlled trial.

Cilostazol is an antiplatelet, antithrombotic agent with anti-inflammatory properties. To date, no clinical study has specifically evaluated the efficacy of cilostazol in patients with diabetic nephropathy (DN). We hypothesized that cilostazol might delay renal deterioration in DN patients at high risk of progression. Between April 2008 and April 2010, we screened 156 consecutive patients aged 35-80 years who were first diagnosed with type 2 diabetes after the age of 30 years. Of these, 90 patients with DN, as defined by morning spot urine microalbuminuria (MAU) >20 mg/L or an albumin-to-creatinine ratio (ACR) >30 µg/mg on at least two consecutive occasions within the prior 3 months, were enrolled into a 52-week randomized, single-blinded, placebo-controlled trial of oral cilostazol 100 mg twice daily or placebo (45 subjects in each group). Morning spot urine samples were collected to determine MAU and ACR. Fasting plasma levels of metabolic, endothelial variables, and inflammatory markers were examined. Following 52 weeks of treatment, urinary MAU and ACR were significantly reduced in the cilostazol group compared with the placebo group (P = 0.024 and P = 0.02, respectively). In regression analyses, changes in monocyte chemotactic protein-1, E-selectin, and soluble vascular cell adhesion molecule-1 (sVCAM-1) were significantly associated with changes in MAU and ACR. Net changes of E-selectin (P < 0.001) and sVCAM-1 (P < 0.05) were independent predictors of change in MAU and ACR, respectively. Our results suggest that cilostazol may effectively attenuate deterioration of albuminuria in patients with type 2 diabetes. This effect is likely mediated by an improvement of adhesion molecules.