The evaluation study for social cognition measures in Japan: Psychometric properties, relationships with social function, and recommendations.

AIM: Patients with schizophrenia can have significant subjective difficulties in social cognition, but few undergo testing or treatment for social cognition. The Social Cognition Psychometric Evaluation (SCOPE) study recommends six social cognitive measures; however, the reliability and validity of these measures in different cultural and linguistic areas has not been adequately examined. We examined the psychometric properties of nine social cognitive measures and the relationship to social function, with the aim of determining the level of recommendation for social cognitive measures in clinical practice in Japan. METHODS: For our test battery, an expert panel previously selected nine measures: the Bell Lysaker Emotion Recognition Task (BLERT); Facial Emotion Selection Test (FEST); Hinting Task (Hinting); Metaphor and Sarcasm Scenario Test (MSST); Intentionality Bias Task (IBT); Ambiguous Intentions and Hostility Questionnaire (AIHQ); Social Attribution Task-Multiple Choice (SAT-MC); SAT-MCII; and Biological Motion (BM) task. In total, 121 outpatients with schizophrenia and 70 healthy controls were included in the analysis, and the results were provided to an expert panel to determine the recommendations for each measure. The quantitative psychological indices of each measure were evaluated for practicality, tolerability, test-retest reliability, correlation with social function, and the incremental validity of social function. RESULTS: Hinting and FEST received the highest recommendations for use in screening, severity assessment, and longitudinal assessment, followed by BLERT, MSST AIHQ, SAT-MC, and SAT-MCII, with IBT and BM receiving the lowest recommendations. CONCLUSION: This study provides a uniform assessment tool that can be used in future international clinical trials for social cognitive impairment.

Ten-year follow-up of sitagliptin treatment in patients with type 2 diabetes mellitus.

BACKGROUND: Early and effective intervention with a dipeptidyl peptidase 4 inhibitor (DPP4i) before the development of advanced atherosclerosis in type 2 diabetes mellitus (T2DM) patients without a history of cardiovascular disease (CVD) is reported to increase the chance of significant reductions in not only microvascular disease, but also CVD. METHOD: This study aimed to investigate whether sitagliptin is effective and tolerated for glycemic control and whether renoprotective effects and ß-cell function are preserved for as long as ten years in Japanese patients with T2DM without a history of CVD. RESULTS: The situation is equivalent to improving glycemic control as assessed by hemoglobin A1c both in a sitagliptin group [sitagliptin 50 mg as either monotherapy or combination therapy with other oral glucose-lowering drugs (n = 17)] or a control group [placebo as either monotherapy or combination therapy with other glucose-lowering drugs (n = 9)], while anti-inflammatory effects as assessed by high-sensitivity C-reactive peptide in the sitagliptin group were superior to those in the control group. In the sitagliptin group, mean urinary albumin excretion (measured as urinary albumin-to-creatinine ratio) was markedly decreased, but no changes in estimated glomerular filtration rate were seen throughout the study. Beta-cell function as evaluated by homeostatic model assessment of ß-cell function values was reduced at baseline in both groups, improved significantly in the sitagliptin group, and continued unchanged in the control group during the study. CONCLUSION: These observations suggest that early intervention with sitagliptin in patients with T2DM may have long-lasting renoprotective and islet-protective effects. TRIAL REGISTRATION: UMIN Clinical Registry (UMIN000038459). Registered 01 November (retrospectively registered): https://upload.umin.ac.jp/UMIN000038459.

Beneficial effect of omarigliptin on diabetic patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis.

BACKGROUND: Dipeptidyl peptidase 4 (DPP4) is a serine exopeptidase able to inactivate various oligopeptides, and also a hepatokine. Hepatocyte-specific overexpression of DPP4 is associated with hepatic insulin resistance and liver steatosis. METHOD: We examined whether weekly DPP4 inhibitor omarigliptin (OMG) can improve liver function as well as levels of inflammation and insulin resistance in type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD). Further, we investigated the effects of OMG in a diabetic patient with biopsy-confirmed nonalcoholic steatohepatitis (NASH). RESULTS: In NAFLD patients, OMG significantly decreased levels of aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP), while no significant change was seen in hemoglobin A1c or body mass index. In the NASH patient, liver function improved markedly, and levels of the hepatic fibrosis marker FIB-4 decreased in parallel with HOMA-IR and hsCRP. Slight but clear improvements in intrahepatic fat deposition and fibrosis appeared to be seen on diagnostic ultrasonography. CONCLUSION: Weekly administration of the DPP4 inhibitor OMG in ameliorating hepatic insulin resistance may cause beneficial effects in liver with NAFLD/NASH.

Omarigliptin decreases inflammation and insulin resistance in a pleiotropic manner in patients with type 2 diabetes.

BACKGROUND: Omarigliptin is a potent, selective, oral dipeptidyl peptidase 4 (DPP4) inhibitor with a half-life that allows weekly dosing. Inflammation or insulin resistance might be pathological mediators of cardiovascular events in patients with type 2 diabetes. METHODS: Whether omarigliptin has anti-inflammatory effects that result in decreased levels of high-sensitivity C-reactive protein (hsCRP) and anti-insulin resistance effects that decrease levels of homeostatic model assessment of insulin resistance (HOMA-IR) were investigated. Patients were allocated to continue with daily DPP4 inhibitors (control, n = 28) or to switch from daily DPP4 inhibitors to weekly omarigliptin (omarigliptin, n = 56). Fasting blood and urine samples were collected before, and every 3 months after intervention for 1 year. RESULTS: Omarigliptin tended to elicit reductions in fasting blood glucose (FBG), LDL-cholesterol, triglyceride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), the urinary albumin-to-creatinine ratio (ACR) with logarithmic transformation (log ACR), and systolic and diastolic blood pressure, but the differences did not reach statistical significance compared with control. Values for HDL-cholesterol tended to increase, but also did not reach statistical significance compared with control. Omarigliptin significantly decreased HOMA-IR, remnant-like particle cholesterol (RLP-C), and hsCRP with logarithmic transformation (log hsCRP) compared with control. However, omarigliptin did not affect hemoglobin A1c (HbA1c), body mass index (BMI), and estimated glomerular filtration rates (eGFR). CONCLUSION: Omarigliptin decreased inflammation and insulin resistance without affecting HbA1c or BMI. Although how DPP4 inhibitors affect cardiovascular (CV) outcomes remains uncertain, omarigliptin might confer CV benefits at least in part, via pleiotropic anti-inflammatory or anti-insulin resistance effects.Trial registration UMIN Clinical Registry (UMIN000029288). Registered 22 September, 2017, https://upload.umin.ac.jp/UMIN000029288.

Anti-inflammatory effects of empagliflozin in patients with type 2 diabetes and insulin resistance.

BACKGROUND: Inflammation might be a pathological mediator of cardiovascular events in patients with type 2 diabetes and high cardiovascular risk. METHODS: We investigated whether empagliflozin (EMPA) exerts anti-inflammatory effects that are reflected in decreased high-sensitivity C-reactive protein (hsCRP) values. Patients were allocated to receive a placebo (n = 51) or EMPA (n = 51) as an add-on treatment. Fasting blood samples were collected before and every 3 months after this intervention for 1 year. RESULTS: Empagliflozin tended to elicit reductions in BMI, HbA1c, aspartate aminotransferase, alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase compared with the placebo, but the differences did not reach statistical significance. Levels of LDL-cholesterol, HDL-cholesterol, and triglycerides were unaltered, significantly increased, and decreased, respectively, by EMPA, but the differences were not statistically significant compared with the placebo. Empagliflozin for 12 months notably reduced the homeostatic model assessment of insulin resistance (HOMA-IR), remnant-like particle cholesterol (RLP-C), and hsCRP by 43%, 52% and 54%, respectively. The time courses of these reductions significantly differed from those of the placebo. Systolic and diastolic blood pressure were also significantly reduced by EMPA compared with the placebo. We applied multiple linear regression analysis to determine which factors were associated with changes in hsCRP induced by EMPA. The results revealed that alterations in hsCRP values (log [hsCRP at 12 months] minus log [hsCRP at month 0]) were significantly associated with changes in HOMA-IR, RLP-C, systolic blood pressure, HDL-C and ALT. CONCLUSION: Empagliflozin decreased hs-CRP and lowered levels of remnant related lipoproteins probably via ameliorating insulin resistance. The cardiovascular benefits conferred by EMPA might be driven at least partly by anti-inflammatory effects, and this mechanism might cooperate with other EMPA-induced changes including reduced blood pressure, to achieve the degree of cardioprotection revealed by the EMPA-REG OUTCOME trial.Trial registration UMIN Clinical Registry (UMIN000021552). Registered 21 March 2016, https://upload.umin.ac.jp/UMIN000021552.

Empagliflozin decreases remnant-like particle cholesterol in type 2 diabetes patients with insulin resistance.

AIMS/INTRODUCTION: Remnant lipoproteins are thought to be atherogenic. Remnant-like particle cholesterol (RLP-C), which reflects the levels of various kinds of remnant lipoproteins in the blood, has a significant correlation with insulin resistance. MATERIALS AND METHODS: In the present study, we measured the effect of empagliflozin (EMPA) on the levels of RLP-C, and investigated whether EMPA-mediated change in RLP-C is associated with a change in insulin resistance in type 2 diabetes patients who have insulin resistance. RESULTS: Patients were allocated to receive a placebo (n = 51) or EMPA (n = 58) as an add-on treatment. Fasting blood samples were collected before and 12 weeks after this intervention. EMPA significantly decreased glycated hemoglobin, bodyweight, systolic blood pressure, plasma triglycerides, liver transaminases and estimated glomerular filtration rate, and increased high-density lipoprotein cholesterol. Furthermore, EMPA decreased RLP-C and homeostatic model assessment of insulin resistance. In the placebo group, there were no significant changes in these factors except for slight increases in liver transaminases. Multiple regression analysis showed that the change in homeostatic model assessment of insulin resistance (P = 0.0102) and the change in alanine aminotransferase (P = 0.0301) were significantly associated with the change in RLP-C in the EMPA group. The change in RLP-C significantly correlated with the change in homeostatic model assessment of insulin resistance (Pearson correlation coefficient 0.503, 95% confidence interval 0.199-0.719; P = 0.00241). CONCLUSION: EMPA decreases RLP-C levels, which is closely associated with amelioration of insulin sensitivity in diabetes patients who have insulin resistance.

Sitagliptin reduces albuminuria in patients with type 2 diabetes.

We investigated the inhibitory effect of sitagliptin on albuminuria in patients with type 2 diabetes. Thirty-six patients (19 men and 17 women) whose HbA1c was higher than 6.5% (NGSP) despite receiving education on diet and exercise and medical treatment for at least 6 months at our clinic were enrolled into this study and were successfully followed over 6 months of sitagliptin treatment. Sitagliptin (50 mg/day) treatment significantly lowered both systolic and diastolic blood pressures, fasting blood glucose and postprandial blood glucose, HbA1c, and glycated albumin at 3 months and 6 months. Significant reductions in highly sensitive C-reactive protein and soluble vascular cell adhesion molecule 1 were also observed at 6 months. Urinary albumin excretion (measured as urinary albumin-to-creatinine ratio (ACR: mg/g Cr)) did not change in the 6 months before sitagliptin treatment (ΔACR: 2.3 ± 19.9) and decreased in the 6 months after sitagliptin treatment (ΔACR: -20.6 ± 24.6); these differences were statistically significant. At 6 months, the ACR decreased from 11.6 ± 8.4 to 4.5 ± 5.0 in 13 patients with normoalbuminuria (ACR < 30), from 98.4 ± 79 to 24.9 ± 20 in 15 patients with microalbuminuria (30 < ACR < 300), and from 1263 ± 492 to 561 ± 89 in 8 patients with macroalbuminuria (ACR > 300). Thus, the present findings strongly suggest that sitagliptin reduces albuminuria without lowering the estimated glomerular filtration rate, most likely depending on known factors such as blood sugar reduction, blood pressure reduction, and inflammation reduction, as well as yet undetermined factors caused by an increase in active glucagon-like peptide-1.

Fenofibrate suppresses microvascular inflammation and apoptosis through adenosine monophosphate-activated protein kinase activation.

The Fenofibrate Intervention and Event Lowering in Diabetes study demonstrated that treatment with fenofibrate in individuals with type 2 diabetes mellitus not only reduced nonfatal coronary events but also diminished the need for laser treatment of diabetic retinopathy and delayed the progression of diabetic nephropathy. However, the mechanism by which fenofibrate may have altered the microvasculature remains unclear. We thus investigated the effect of fenofibrate on human glomerular microvascular endothelial cells (HGMEC). Treatment of HGMEC with fenofibrate resulted in transient activation of adenosine monophosphate-activated protein kinase (AMPK), thereby inducing the phosphorylation of Akt and endothelial nitric oxide synthase, leading to nitric oxide production. We compared AMPK activation induced by bezafibrate and WY14643 with that induced by fenofibrate in HGMEC as well as HepG2 cells. Only fenofibrate activated AMPK in HGMEC. Fenofibrate also inhibited nuclear factor-κB activation by advanced glycation end-products, thereby suppressing the expression of various adhesion molecule genes in HGMEC. Suppression of fenofibrate-induced inhibition of nuclear factor-κB activation was observed in cells treated with AMPK small interfering RNA or compound C. Furthermore, fenofibrate was observed to significantly suppress apoptosis of HGMEC in hyperglycemic culture medium. Treatment with compound C or Nw-nitro-L-arginine methyl ester (L-NAME) abolished the suppressive effect of fenofibrate on HGMEC apoptosis. Our findings suggest that fenofibrate might exert a protective effect on the microvasculature by suppressing inflammation and apoptosis through AMPK activation beyond its lipid-lowering actions.

Efficacy and safety of ezetimibe in patients undergoing hemodialysis.

Patients with dyslipidemia and advanced renal failure are at markedly increased risk of cardiovascular morbidity and mortality. We evaluated the efficacy and safety of ezetimibe administration to patients with endstage renal failure (ESRF) who are undergoing hemodialysis. Ezetimibe at 10 mg/day was given to 20 patients for 12 weeks. Efficacy was determined by monitoring lipids, and safety was determined by monitoring clinical and laboratory parameters. We also evaluated the effects of ezetimibe on surrogate markers of cholesterol absorption and synthesis. Compared to baseline values, LDL-cholesterol (LDL-C) was reduced by 24.9% (p<0.005) after 12 weeks of ezetimibe administration. Treatment with ezetimibe did not change HDL-cholesterol, triglyceride and HbA1c values but caused a significant reduction in remnant like particles-cholesterol (RLP-C, p<0.05) and high-sensitive C-reactive protein (hsCRP, p<0.05). Ezetimibe therapy decreased cholesterol absorption markers (campesterol and sitosterol) and increased a marker of cholesterol synthesis (lathosterol). A highly significant correlation was observed between alterations in LDL-C and campesterol levels in response to ezetimibe therapy. No patients reported musculoskeletal symptoms. None of the patients experienced elevations in their creatine kinase or liver transaminase levels. Ezetimibe not only reduced serum LDL-C, but also RLP-C and hsCRP, in ESRF patients. Inhibition of cholesterol absorption by ezetimibe is an important therapeutic option in these patients due to its efficacy and safety.

Cilostazol inhibits cytokine-induced nuclear factor-kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells.

AIMS: Cilostazol is a selective inhibitor of phosphodiesterase 3 that increases intracellular cyclic AMP (cAMP) levels and activates protein kinase A, thereby inhibiting platelet aggregation and inducing peripheral vasodilation. We hypothesized that cilostazol may prevent inflammatory cytokine induced-nuclear factor (NF)-kappaB activation by activating AMP-activated protein kinase (AMPK) in vascular endothelial cells. METHODS AND RESULTS: Cilostazol was observed to activate AMPK and its downstream target, acetyl-CoA carboxylase, in human umbilical vein endothelial cells (HUVEC). Phosphorylation of AMPK with cilostazol was not affected by co-treatment with an adenylate cyclase inhibitor, SQ 22536, and a cell-permeable cAMP analogue, pCTP-cAMP, did not induce AMPK phosphorylation and had no effect on cilostazol-induced AMPK phosphorylation, suggesting that cilostazol-induced AMPK activation occurs through a signalling pathway independent of cyclic AMP. Cilostazol also dose-dependently inhibited tumour necrosis factor alpha (TNFalpha)-induced NF-kappaB activation and TNFalpha-induced I kappa B kinase activity. Furthermore, cilostazol attenuated the TNFalpha-induced gene expression of various pro-inflammatory and cell adhesion molecules, such as vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, monocyte chemoattractant protein-1 (MCP-1), and PECAM-1 in HUVEC. RNA interference of AMPK alpha 1 or the AMPK inhibitor compound C attenuated cilostazol-induced inhibition of NF-kappaB activation by TNFalpha. CONCLUSION: In the light of these findings, we suggest that cilostazol might attenuate the cytokine-induced expression of adhesion molecule genes by inhibiting NF-kappaB following AMPK activation.

High molecular weight adiponectin activates AMPK and suppresses cytokine-induced NF-kappaB activation in vascular endothelial cells.

Various isoforms of adiponectin circulate in the plasma. We purified high molecular weight (HMW) adiponectin from human plasma. HMW adiponectin was observed to activate AMP-activated protein kinase (AMPK), thereby increasing the phosphorylation of eNOS and NO production in endothelial cells. On the other hand, cells preincubated with HMW adiponectin had reduced TNFalpha-induced NF-kappaB activation. HMW adiponectin by itself was found to modestly activate NF-kappaB, which was significantly enhanced by inhibition of AMPK/eNOS activation. Thus, HMW adiponectin might have dual action, both pro and anti-inflammatory. An initial period of NF-kappaB activation by HMW adiponectin might be proinflammatory, but it could be counteracted by activation of AMPK/eNOS, which lead to a potential reduction in a second activation of NF-kappaB against inflammatory stimuli.

Decreased maternal protein S activity is associated with fetal growth restriction.

INTRODUCTION: Protein S (PS) activity has been shown to decrease during normal pregnancy. The aim of this study was to determine any correlation between decreased maternal PS activity and fetal growth restriction (FGR). METHODS: We carried out a retrospective study of maternal PS activity and complement 4b-binding protein (C4BP) concentration in 102 patients with FGR and 58 patients with fetuses that had normal growth. Among pregnancies affected by FGR, 14 diagnoses were made in the second trimester and 88 in the third trimester. Patients whose fetuses had normal growth were matched with FGR subjects for maternal age and gestational age at sampling (29 cases each in the second and third trimester). RESULTS: Mean PS activity of the control group in the third trimester was significantly lower than in the second trimester (56.5+/-16.5% vs 35.8+/-13.8%). PS activity in women with FGR was significantly decreased in both the second trimester (36.6+/-13.2%) and third trimester (30.2+/-12.2%) compared with control group levels. Plasma concentrations of C4BP for the control group were significantly higher in the third trimester than in the second trimester (90.5+/-17.5% vs 81.1+/-13.6%). However, in women with FGR, plasma C4BP concentrations in both the second trimester (84.0+/-14.8%) and the third trimester (86.0+/-17.7%) were comparable with concentrations of the control group. CONCLUSIONS: Maternal PS activity decreased as normal pregnancies progressed but decreased over time in cases with FGR. Excessive decreases in PS activity during pregnancy could contribute to development of FGR.

Globular adiponectin activates nuclear factor-kappaB and activating protein-1 and enhances angiotensin II-induced proliferation in cardiac fibroblasts.

Adiponectin is present in the serum as a trimer, hexamer, or high-molecular weight form. A proteolytic cleavage product of adiponectin, known as globular adiponectin (gAd), also circulates in human plasma. The biological activities of these isoforms are not well characterized. Pressure overload in adiponectin-deficient mice results in enhanced concentric cardiac hypertrophy and increased mortality, suggesting that adiponectin inhibits hypertrophic signaling in the myocardium. Therefore, we examined whether gAd exerts the same effects on myocardium signaling. Nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) activation were examined using cardiac fibroblasts prepared from the ventricles of 1- to 2-day-old Wistar rats and grown in culture. gAd activated NF-kappaB and enhanced tumor necrosis factor-alpha (TNF-alpha)-induced NF-kappaB activity. gAd also activated AP-1 and enhanced angiotensin II (Ang II)-induced AP-1 activity. gAd induced mRNA expression of c-fos and c-jun and activated extracellular signal-regulated kinase. Thus, gAd enhanced Ang II-induced DNA and collagen synthesis. Antibodies against adiponectin receptor (AdipoR)1 and AdipoR2 elicit activation of NF-kappaB or AP-1, two redox-sensitive transcription factors. Thus, rather than having an antihypertrophic effect, gAd might contribute to the activation of myocardium signaling, leading to myocardial hypertrophy.

Oral administration of tetrahydrobiopterin slows the progression of atherosclerosis in apolipoprotein E-knockout mice.

OBJECTIVE: Although it has been reported that oral administration of tetrahydrobiopterin (BH4) prevents endothelial dysfunction and vascular oxidative stress in various rat models, the effect of treatment with BH4 on atherogenesis remains unclear. METHODS AND RESULTS: In this study, we investigated whether oral BH4 treatment might slow the progression of atherosclerosis using hypercholesterolemic apolipoprotein E-knockout mice. We report that ingesting BH4 in drinking water is sufficient to inhibit atherogenesis in mice. Furthermore, we report that BH4 treatment improves endothelial dysfunction and attenuates increased mRNA expression of NADPH oxidase components, as well as a number of inflammatory factors, such as LOX-1 and MCP-1, in the aortas of apolipoprotein E- knockout mice. CONCLUSION: Strategies such as oral administration of BH4 to ensure continuous BH4 availability may be effective in restoring nitric oxide-mediated endothelial function and limiting vascular disease and the progression of atherosclerosis.

Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells.

AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in regulation of energy homeostasis and metabolic stress. Metformin has been shown to activate AMPK. We hypothesized that metformin may prevent nuclear factor kappaB (NF-kappaB) activation in endothelial cells exposed to inflammatory cytokines. Metformin was observed to activate AMPK, as well as its downstream target, phosphoacetyl coenzyme A carboxylase, in human umbilical vein endothelial cells (HUVECs). Metformin also dose-dependently inhibited tumor necrosis factor (TNF)-alpha-induced NF-kappaB activation and TNF-alpha-induced IkappaB kinase activity. Furthermore, metformin attenuated the TNF-alpha-induced gene expression of various proinflammatory and cell adhesion molecules, such as vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1, in HUVECs. A pharmacological activator of AMPK, 5-amino-4-imidazole carboxamide riboside (AICAR), dose-dependently inhibited TNF-alpha- and interleukin-1beta-induced NF-kappaB reporter gene expression. AICAR also suppressed the TNF-alpha- and interleukin-1beta-induced gene expression of vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 in HUVECs. The small interfering RNA for AMPKalpha1 attenuated metformin or AICAR-induced inhibition of NF-kappaB activation by TNF-alpha, suggesting a possible role of AMPK in the regulation of cell inflammation. In light of these findings, we suggest that metformin attenuates the cytokine-induced expression of proinflammatory and adhesion molecule genes by inhibiting NF-kappaB activation via AMPK activation. Thus, it might be useful to target AMPK signaling in future efforts to prevent atherogenic and inflammatory vascular disease.

Hypoadiponectinemia is caused by chronic blockade of nitric oxide synthesis in rats.

Adiponectin is an adipocyte-derived anti-atherogenic protein. Adiponectin levels are decreased in patients and animal models with obesity, diabetes, and coronary artery disease. However, the mechanism by which adiponectin levels are reduced remains unknown. Since hypoadiponectinemia is closely linked to endothelial dysfunction, we examined the regulation of adiponectin in a rat model of chronic blockade of nitric oxide (NO) synthesis by N omega-nitro-L-arginine methyl ester (L-NAME). Decreased production of NO and increased production of O2- were observed in aorta from L-NAME-treated rats. Plasma adiponectin levels and adiponectin mRNA levels of adipose tissue were markedly decreased in L-NAME-treated rats. Cotreatment of pioglitazone (PIO) or allopurinol (ALL) with L-NAME restored plasma adiponectin concentration and fat adiponectin mRNA levels to control levels. Thus, adiponectin levels were decreased in L-NAME-treated rats, however, they returned to normal following administration of PIO due to transcriptional activation of the adiponectin gene, as well as administration of ALL, likely due to elimination of oxidative stress. Oxidative stress appears to be an important cause of hypoadiponectinemia.