Friedrich Mittermayer

Increased visfatin concentrations in women with gestational diabetes mellitus

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.

Simvastatin Prevents Vascular Hyporeactivity During Inflammation

Background—There is growing evidence that statins exert anti-inflammatory and antioxidative vascular actions that are independent of lipid lowering. We tested whether hyporeactivity to the endothelium-dependent vasodilator acetylcholine (ACh) and the vasoconstrictor norepinephrine (NE) during acute experimental inflammation could be prevented by simvastatin. Methods and Results—In a randomized, placebo-controlled, parallel group study, forearm blood flow (FBF) responses to NE, ACh, and the endothelium-independent vasodilator nitroglycerin (NTG) were assessed at baseline, after 4 days of simvastatin 80 mg PO or placebo treatment, and during Escherichia coli endotoxin (lipopolysaccharide [LPS])–induced inflammation in 20 healthy volunteers. Additionally, markers of inflammation and neutrophil oxidative burst were assessed. Simvastatin and placebo had no effect on FBF or oxidative/inflammatory markers. LPS administration decreased the responses of FBF to NE by 43% (P<0.05) and decreased responses to ACh by 48% (P<0.05) but did not decrease FBF responses to NTG. Simvastatin completely preserved responses to NE and to ACh. The LPS-induced increases in neutrophil oxidative burst and plasma tumor necrosis factor-α concentrations were mitigated by simvastatin (P<0.05 versus placebo). Conclusions—This study demonstrates potent vasoprotective properties of high-dose simvastatin during endotoxemia that may be useful for patients with acute systemic inflammation and associated vascular hyporeactivity.

Asymmetric Dimethylarginine Enhances Cardiovascular Risk Prediction in Patients With Chronic Heart Failure

Objective—The purpose of this study was to investigate whether elevated asymmetrical dimethylorginine (ADMA) concentrations are associated with increased cardiovascular risk in chronic heart failure (HF) patients. Methods and Results—253 patients with symptomatic chronic HF and impaired left ventricular function (median age 70 years, 202 males) were followed for a median of 14.2 months (interquartile range 6.8 to 21.2). ADMA and N-terminal pro-brain natriuretic peptide (NT-proBNP) were assessed by high performance liquid chromatography and by an enzyme-linked immunosorbent assay, respectively. Subjects with ADMA concentrations in the highest tertile had a significantly higher adjusted hazard ratio (HR; 2.00; 95% confidence interval [CI] 1.01 to 3.97) for occurrence of an end point (cardiac decompensation, major adverse cardiovascular events or all-cause mortality) compared with patients in the lowest tertile (P=0.046) during the first 6 months of follow-up. NT-proBNP also identified subjects at risk before adjustment for confounders at 6 and 12 months of follow-up. HR for patients with ADMA and NT-proBNP in the highest tertile was significantly increased (3.68, CI 1.67 to 8.14; at 6 months follow-up) compared with patients without ADMA and NT-proBNP in the highest tertile (P<0.001). Conclusions—Elevated ADMA plasma concentrations are associated with adverse cardiovascular outcome in patients with chronic HF. Quantification of ADMA with NT-proBNP improves risk stratification in this cohort.

Increase in Visfatin after Weight Loss Induced by Gastroplastic Surgery

Objective: The recently described adipokine visfatin is produced in visceral fat and has been suggested to influence insulin resistance. To investigate whether visfatin concentrations are related to changes in body weight, this adipokine was measured in insulin‐resistant severely obese patients before and after gastroplastic surgery.

Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: a placebo-controlled randomized trial

Eur J Clin Invest 2010; 40 (2): 148–154

Asymmetrical Dimethylarginine Plasma Concentrations Are Related to Basal Nitric Oxide Release but Not Endothelium-Dependent Vasodilation of Resistance Arteries in Peritoneal Dialysis Patients

Vascular dysfunction in chronic renal failure may be linked to reduced nitric oxide (NO) bioactivity and increased circulating concentrations of the endogenous NO synthase inhibitor asymmetrical dimethyl L-arginine (ADMA). The association between ADMA and basal endothelial NO release and endothelium-dependent vasodilation in resistance arteries of chronic renal failure patients is unknown. Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine, the endothelium-independent vasodilator nitroglycerine, and the endothelium-dependent vasoconstrictor N(G)-monomethyl-L-arginine (L-NMMA) were assessed in 37 peritoneal dialysis patients. L-arginine and ADMA plasma concentrations were measured by HPLC. ADMA (mean +/- SEM: 0.68 +/- 0.02 micromol/L) was associated with basal forearm blood flow (r = -0.33; P < 0.05) and L-NMMA induced vasoconstriction (r = -0.55; P < 0.0005), but not with dilator effects of acetylcholine or nitroglycerine. L-arginine (68 +/- 3 micromol/L) tended to correlate with acetylcholine-induced vasodilation (r = 0.32; P = 0.05) but was not associated with other parameters. ADMA is related to basal but not to acetylcholine-stimulated NO bioactivity in patients on peritoneal dialysis. Impaired endothelium-dependent vasodilation found in chronic renal failure is not explained by elevated circulating NO synthase inhibitors in renal failure.

ADMA, cardiovascular disease and diabetes

The endogenous competitive nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is an emerging risk marker for future cardiovascular events. Elevated ADMA concentrations have been described in patients with an adverse cardiovascular risk profile. Recently, various studies investigated the independent role of ADMA as a cardiovascular risk predictor in several patient cohorts. In addition, ADMA might not only be a risk marker but also a causative factor for cardiovascular disease. This review summarizes the literature on the relationship between ADMA, cardiovascular disease and diabetes.

Elevated concentrations of asymmetric dimethylarginine are associated with deterioration of glucose tolerance in women with previous gestational diabetes mellitus.

Objective.  Women with previous gestational diabetes mellitus (GDM) have a high risk for development of type 2 diabetes mellitus. The endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) could be related to disorders of the glucose metabolism. To evaluate if ADMA predicts deterioration of glucose tolerance in women with previous GDM and to assess concentration changes we analysed ADMA in women with previous GDM after delivery and after a median follow‐up of 2.75 years (interquartile range: 1.47–4.60).

Circulating ADMA concentrations are elevated in hypopituitary adults with and without growth hormone deficiency.

Background  Cardiovascular mortality is increased in patients with hypopituitarism. Elevated concentrations of the endogenous NO synthase antagonist asymmetrical dimethylarginine (ADMA) may be related to the development of atherosclerosis and are associated with cardiovascular risk. We studied the concentrations of ADMA in hypopituitary patients with and without growth hormone deficiency (GHD) and in healthy subjects.

Impaired vascular nitric oxide bioactivity in women with previous gestational diabetes

ZusammenfassungHINTERGRUND: Eine Dysfunktion des Gefäß-Endothels, die vaskulären Erkrankungen und Typ 2 Diabetes vorausgehen kann, zeigt sich bei Patientinnen nach Gestationsdiabetes. Es ist allerdings nicht geklärt ob Adipositas, asymetrisches Dimethylarginin (ADMA), ein endogener Stickstoffmonoxid (NO) Synthese Inhibitor oder Insulin-Resistenz die beobachteten Gefäß-Veränderungen bei diesen Patientinnen zusätzlich verstärken. Ziel dieser Studie war es daher, Faktoren zu finden, die die Gefäß-Dysfunktion zusätzlich zum Gestationsdiabetes beeinträchtigen. METHODEN: 7 übergewichtige und 5 normalgewichtigen Patientinnen nach Gestationsdiabetes wurden in diese Studie eingeschlossen. Die Gefäß-Funktion wurde durch Änderungen des Unterarm-Blutflusses auf den Endothel-abhängigen Vasodilatator Acetylcholin (ACh), den Endothel-unabhängigen Vasodilatator Nitroglycerin (GTN), den Vasokonstriktor Norepinephrin (NE) und den NO-Synthase Inhibitor N(G)-monomethyl-L-arginine (L-NMMA) gemessen. ADMA wurde aus venösen Blutproben bestimmt und die Insulin-Resistenz wurde mittels eines modifizierten intravenösen Glukose-Toleranz Tests abgeschätzt. 20 gesunde, männliche Probanden dienten als historische Kontroll-Gruppe. RESULTATE: Verglichen mit Normalgewichtigen war die Reaktion des Unterarm-Blutflusses auf ACh bei übergewichtigen Frauen gestört (p < 0.05); ebenso war die Antwort auf den Vasokonstriktor NE tendenziell bei dieser Gruppe verringert. Weiters gab es signifikante Korrelationen zwischen der vaskulären Antwort auf ACh beziehungsweise L-NMMA und Body Mass Index, Serum ADMA Konzentrationen und stimulierten Glukose Werten (alle p < 0.05). Normalgewichtigen Patientinnen hatten mit der gesunden Kontrollgruppe vergleichbares Ansprechen auf ACh und ADMA Konzentrationen. SCHLUSSFOLGERUNG: Faktoren wie Übergewicht, erhöhte ADMA Werte und Insulin-Resistenz dürften starken Einfluss auf die Endotheliale Dysfunktion bei Patientinnen nach Gestationsdiabetes haben.SummaryBACKGROUND: Dysfunction of the vascular endothelium, preceding vascular morbidity and type 2 diabetes, is present in women with previous gestational diabetes (GDM). However, it is unknown whether excess weight, insulin resistance, and asymmetric dimethylarginine (ADMA) – an endogenous nitric oxide (NO) synthase inhibitor – also contribute to the vascular changes observed in these patients. The aim of this study was therefore to identify factors other than GDM that impair vascular function. METHODS: Seven overweight and five non-overweight women with previous GDM were included in this study. Vascular function was assessed from forearm blood-flow responses to the endothelium-dependent vasodilator acetylcholine (ACh), the endothelium-independent vasodilator glyceryltrinitrate, the vasoconstrictor norepinephrine and the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA). ADMA was measured in venous blood, and insulin resistance was estimated from a modified intravenous glucose tolerance test. Twenty healthy male volunteers served as a historical control group. RESULTS: Vasodilation of forearm resistance vessels in response to ACh was impaired in overweight women when compared with non-overweight women (P < 0.05); similarly, vasoconstrictor reactivity tended to be smaller in the overweight group. In addition, there was a significant relationship between vascular responsiveness to ACh and L-NMMA, body-mass index, serum ADMA concentrations and stimulated glucose levels (all P < 0.05). ACh responses and ADMA levels in non-overweight women were similar to those of healthy controls. CONCLUSION: Factors such as obesity, increased ADMA levels and insulin resistance appear to be strong contributors to endothelial dysfunction observed in women with GDM.