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The recently discovered adipocytokine visfatin has insulin-like properties. It lowers blood glucose and improves insulin sensitivity; however, clinical data on visfatin are limited. To evaluate the role of visfatin in GDM (gestational diabetes mellitus), we determined visfatin levels in women with GDM and in healthy pregnant controls. Furthermore, visfatin concentrations were investigated longitudinally during pregnancy and after delivery in a subgroup of women with GDM. Blood for measurement of visfatin and metabolic parameters was obtained from 64 women with GDM [median week of gestation, 34 (interquartile range, 27-36) weeks] and 30 healthy pregnant controls [median week of gestation, 34 (interquartile range, 28-36) weeks]. In a subgroup of 24 women with GDM, visfatin, leptin and metabolic parameters were investigated twice during pregnancy (28-30 and 38-40 weeks of gestation) and 2 weeks after delivery. In the cross-sectional analysis, median visfatin levels were significantly elevated in women with GDM [64.0 (interquartile range, 50.9-74.8) ng/ml] compared with controls [46.0 (interquartile range, 36.9-54.6) ng/ml; P<0.0001]. In women with GDM, visfatin correlated with week of gestation at the time of blood draw (R=0.35, P=0.005). No association with fasting glucose, insulin, homoeostasis model assessment-insulin resistance or body mass index was observed. According to the longitudinal analysis, visfatin increased during pregnancy (P=0.002) and rose further after delivery (P=0.014), whereas leptin and insulin levels decreased after parturition (both P<0.001). In conclusion, visfatin is elevated in women with GDM and increases during the course of pregnancy as well as after delivery. Furthermore, visfatin shows no association with insulin and leptin in women with GDM.

Abstract-Impaired response to catecholamines contributes to the altered hemodynamics in sepsis, which has been attributed to excessive NO formation. We have studied the systemic hemodynamic and local forearm responses and inducible NO synthase (iNOS) expression during experimental endotoxemia in humans. Escherichia coli endotoxin (lipopolysaccharide [LPS]) was administered at doses of 1 or 2 ng/kg to healthy volunteers. In 10 subjects, the systemic pressor effect of phenylephrine was assessed before and after the administration of LPS. In 9 further subjects, forearm blood flow responses to intra-arterial noradrenaline, acetylcholine, glyceryl trinitrate, and N G -monomethyl-L-arginine (L-NMMA) were studied at baseline and after LPS administration. Peripheral blood was collected and analyzed for iNOS mRNA and protein. Four hours after LPS, the response of systolic blood pressure (PϽ0.0005) and heart rate (PϽ0.05) to phenylephrine was significantly reduced. In the forearm, noradrenaline-induced vasoconstriction was also reduced by Ϸ50% (PϽ0.01), but L-NMMA responsiveness was unchanged. iNOS mRNA or protein was not increased. Marked vascular adrenoceptor hyporeactivity is detectable in the absence of increased NO activity or iNOS expression in endotoxemia, arguing against major involvement of vascular iNOS activity in the acute systemic vasodilation to LPS. Key Words: inducible nitric oxide synthase Ⅲ nitric oxide Ⅲ sepsis Ⅲ lipopolysaccharide Ⅲ adrenoceptors S epsis is still associated with a high mortality rate and remains a major therapeutic challenge despite improved intensive care therapy. 1 One of the key clinical aspects of sepsis, which is responsible for the poor hemodynamic state of these patients, is inappropriate vasodilation and impaired response to catecholamines, 2 resulting in hemodynamic instability and shock.A variety of substances and mediators is released by activated blood cells and endothelial cells during sepsis. 2,3 Many in vitro and in vivo animal experiments have indicated that excess formation of nitric NO in the vasculature may play the key role in the systemic vasodilation in sepsis and endotoxemia. These data suggest that most of the NO produced is formed after the induction of an inducible form of NO synthase (iNOS), which is not expressed in the vasculature under normal conditions. 4 iNOS can be induced in a variety of cells, such as vascular endothelial cells, vascular smooth muscle cells, and white blood cells (WBCs) after in vitro stimulation with endotoxin 5 and remains present for several days. Inhibition of NO synthesis in animals by NO synthase inhibitors reduces Escherichia coli endotoxin (lipopolysaccharide [LPS])-induced hypotension and vascular leakage and improves mortality. 6 -8 Experiments with iNOS knockout animals 9 and animals treated with iNOS antisense oligonucleotides 10 corroborated these pharmacological studies.Data on iNOS expression in humans are limited. A recent study did not detect iNOS in cells or vessels of the systemic circulation in septic patients but...

OBJECTIVE -Circulating concentrations of an endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), are elevated in patients with increased cardiovascular risk. We hypothesized that ADMA predicts cardiovascular events and enhances risk prediction independent of established risk markers in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -This prospective cohort study included 125 patients with type 2 diabetes. ADMA, L-arginine, high-sensitivity C-reactive protein (CRP), and routine clinical parameters were determined at baseline. First occurrence of cardiovascular events (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke, carotid revascularization, or all-cause mortality) was defined as a composite end point. RESULTS-During a median follow-up of 21 (interquartile range 11-27) months, 84 events occurred in 48 patients. According to multivariate Cox regression analysis, patients with baseline ADMA or CRP in the highest tertile had a significantly increased hazard ratio for incident cardiovascular events compared with those with ADMA or CRP in tertile 1 (2.37 [95% CI 1.05-5.35], P ϭ 0.038, and 3.63 [1. 59 -8.28], P ϭ 0.002). Assessing the joint effect of ADMA and CRP revealed that patients with either ADMA or CRP or both in the highest tertile had increased hazard ratios for cardiovascular events compared with patients with neither ADMA nor CRP in the highest tertile before and after adjustment for possible confounders (hazard ratio 4.59 [95% CI 2.07-10.15], P Ͻ 0.001).CONCLUSIONS -ADMA predicted cardiovascular events and enhanced the predictive role of CRP in patients with type 2 diabetes. ADMA therefore could improve cardiovascular risk assessment in patients with type 2 diabetes. Diabetes Care 30:1834-1839, 2007T ype 2 diabetes is associated with a considerably increased risk for development of cardiovascular disease (1,2). Aggressive risk factor management is an important mean for reducing the cardiovascular morbidity in this patient group, which implies accurate risk stratification. Poorly controlled blood pressure and glycemia seem to be significantly involved in the development process of cardiovascular disease in patients with type 2 diabetes (3,4). Besides traditional risk markers, the acute-phase protein C-reactive protein (CRP) has turned out to be an important cardiovascular risk predictor in the general population and patients with type 2 diabetes (5,6). To further improve the identification of patients with type 2 diabetes, who are exposed to a particularly high cardiovascular risk, detection of additional independent risk markers might be useful.Nitric oxide (NO), which is synthesized by NO synthases, is an important antiatherogenic molecule (7). As initially described by Vallance et al. (8) an endogenous inhibitor of NO synthase, asymmetric dimethylarginine (ADMA), occurs in significant amounts in peripheral blood. Since this discovery, numerous clinical studies have been performed that found elevated circulating ADMA...

Objective-Circulating concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, are elevated in conditions associated with increased cardiovascular risk. We investigated whether elevated ADMA concentrations predict major adverse cardiovascular events (MACE) in patients with advanced peripheral artery disease (PAD). Methods and Results-We prospectively enrolled 496 of 533 consecutive patients with PAD (median age 70 years, 279 males). ADMA and L-arginine were assessed at baseline by high performance liquid chromatography. Key Words: asymmetric dimethylarginine Ⅲ major adverse cardiovascular events Ⅲ nitric oxide Ⅲ peripheral artery disease P eripheral artery disease (PAD) is a common condition with a prevalence of 3.6% in subjects older than 40 years in the Framingham Offspring Study. 1 Patients with advanced PAD are at increased risk for major adverse cardiovascular events (MACE). 2 Nitric oxide (NO) is produced from L-arginine by NO synthases 3 and is essential for physiological endothelial function. 4 NO has important antiatherogenic properties and reduced NO bioavailability might substantially contribute to the development of cardiovascular disease. 5 The endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is increased in conditions associated with high cardiovascular risk such as hyperlipidemia, 6,7 arterial hypertension, 8 renal impairment, 9 or PAD. 10 ADMA predicts cardiovascular events in patients with end-stage renal failure and in subjects with coronary artery disease. 11,12 ADMA has not only been shown to be associated with the presence of macrovascular disease 13,14 but also might be directly involved in the formation of vascular lesions. 15 This renders ADMA as cardiovascular risk marker or even contributor to cardiovascular disease. Only inconsistent and preliminary data on the role of the NO precursor L-arginine are available in patients with coronary heart disease and PAD. 16 -18 We hypothesized that ADMA is associated with future cardiovascular events in patients with advanced PAD and a pronounced adverse cardiovascular risk profile. Materials and Methods Study DesignPatients with advanced PAD, who were admitted to the Angiology department of a tertiary care university hospital from March 1, 2000 to March 1, 2001, were prospectively enrolled in a cohort study. Inclusion criteria were symptomatic PAD with intermittent claudication or critical limb ischemia and asymptomatic PAD with a history of surgical or endovascular lower limb revascularization. The