Christian Bieglmayer

Leptin Induces Endothelin-1 in Endothelial Cells In Vitro

Leptin, a protein encoded by the obese gene, is produced by adipocytes and released into the bloodstream. In obese humans, serum leptin levels are increased and correlate with the individual’s body mass index and blood pressure. Elevated serum concentrations of endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, were also observed in obese subjects. The pathomechanisms underlying this ET-1 increase in obesity are poorly understood. In the present study, we investigated the influence of the ob gene product leptin on the expression of ET-1 in human umbilical vein endothelial cells (HUVECs). Binding studies using 125I-radiolabeled leptin revealed high- and low-affinity leptin binding sites on HUVECs (Kd1=13.1±3.1 nmol/L and Kd2=1390±198 nmol/L, respectively), mediating a time- and dose-dependent increase of ET-1 mRNA expression and protein secretion after incubation of HUVECs with leptin. This leptin-induced ET-1 expression was inhibited by preincubation of HUVECs with 0.75 &mgr;mol/L antisense phosphorothioate oligonucleotides directed against the leptin receptor Ob-Rb. Furthermore, after incubation with leptin, increased nuclear staining of c-fos and c-jun, the major components of the transcription factor AP-1, and increased AP-1 DNA binding were observed. Transient transfection studies with ET-1 promoter constructs showed that leptin-induced promoter activity was abolished in the absence of AP-1 binding sites or by cotransfection with a plasmid overexpressing a mutated jun, which is able to bind c-fos but not DNA. Thus, leptin upregulates ET-1 production in HUVECs via a mechanism potentially involving jun binding members of the bZIP family.

Increased plasma leptin in gestational diabetes

Aims/hypothesis. Insulin resistance as well as marked changes in body weight and energy metabolism are associated with pregnancy. Its impact on plasma leptin is not known and was determined in this longitudinal study in both diabetic and normal pregnancy. Methods. At 28 gestational weeks plasma concentrations of leptin and B-cell hormones were measured at fasting and after an oral glucose load (OGTT:75 g) in women with gestational diabetes and pregnant women with normal glucose tolerance and compared with women who were not pregnant (C). Results. Plasma leptin (ng/ml) was higher (p < 0.001) in women with gestational diabetes (24.9 ± 1.6) than in women with normal glucose tolerance (18.2 ± 1.5) and increased in both groups when compared with the non-pregnant women (8.2 ± 1.3; p < 0.0005). No change in plasma leptin concentrations was induced by OGTT in any group. Basal insulin release was higher (p < 0.05) in women with gestational diabetes compared with the pregnant women with normal glucose tolerance. Marked insulin resistance was confirmed by a 20 % lower (p < 0.05) insulin sensitivity in subgroup analysis and a decrease of almost 40 % in fasting glucose/insulin ratio (p < 0.005) in women with gestational diabetes. Leptin correlated in women with gestational diabetes with basal plasma concentrations of glucose (p < 0.02), insulin (p < 0.004) and proinsulin (p < 0.01) as well as with BMI (p < 0.001) and overall pregnancy induced maternal weight gain (p < 0.009). With normalisation of blood glucose 8 weeks after delivery in women with gestational diabetes their plasma leptin decreased (p < 0.0005) to 17.3 ± 1.9 ng/ml but did not completely normalize (p < 0.05 vs non-pregnant women). Conclusion/interpretation. Our data show that women with gestational diabetes without any change in plasma leptin upon oral glucose loading have increased plasma leptin concentrations during and after pregnancy, a clear association of plasma leptin with the respective concentration of glucose and insulin resistance as well as with changes in body weight, and a failure to normalize spontaneously BMI to the same extent as pregnant women with normal glucose tolerance when compared with matched control subjects. [Diabetologia (2001) 44: 164–172]

The Role of Oxytocin in Relation to Female Sexual Arousal

Oxytocin is clearly involved in human reproduction and serves an important role in sexual arousal. Oxytocin serum levels were measured before and after sexual stimulation in 12 healthy women. Values of oxytocin 1 min after orgasm were significantly higher (p < 0.05) than baseline levels. This finding supports the hypothesis that oxytocin plays a major part in human sexual response both in neuroendocrine function and postcoital behavior.

TREATMENT OF SKIN AGING WITH TOPICAL ESTROGENS

Background. The coincidence of climacteric symptoms and the beginning of skin aging suggests that estrogen deficiency may be a common and important factor in the perimenopausal woman. Often hormones have been considered important in endogenous aging of the skin, but their role has not been clearly defined. Therefore, we investigated, whether topical treatment of the skin with estrogen could reverse some of the changes in the aging skin.

Mode of delivery is associated with maternal and fetal endocrine stress response

Objective  To determine whether mode of delivery is associated with the endocrine stress response in mother and child.

Sclerostin serum levels correlate positively with bone mineral density and microarchitecture in haemodialysis patients

BACKGROUND Sclerostin is a soluble inhibitor of osteoblast function. Sclerostin is downregulated by the parathyroid hormone (PTH). Here, it was investigated whether sclerostin levels are influenced by intact (i) PTH and whether sclerostin is associated with bone turnover, microarchitecture and mass in dialysis patients. METHODS Seventy-six haemodialysis patients and 45 healthy controls were included in this cross-sectional study. Sclerostin, Dickkopf-1 (DKK-1), intact parathyroid hormone (iPTH), vitamin D and markers of bone turnover were analysed. A subset of 37 dialysis patients had measurements of bone mineral density (BMD) using dual-energy X-ray absorptiometry and bone microarchitecture using high-resolution peripheral quantitative computed tomography. RESULTS Dialysis patients had significantly higher sclerostin levels than controls (1257 pg/mL versus 415 pg/mL, P < 0.001). Significant correlations were found between sclerostin and gender (R = 0.41), iPTH (R = -0.28), 25-hydroxy-cholecalciferol (R = 0.27) and calcium (R = 0.25). Gender and iPTH remained significantly associated with sclerostin in a multivariate analysis. Sclerostin serum levels were positively associated with BMD at the lumbar spine (R = 0.46), femoral neck (R = 0.36) and distal radius (R = 0.42) and correlated positively mainly with trabecular structures such as trabecular density and number at the radius and tibia in dialysis patients. DKK-1 was related neither to bone measures nor to serologic parameters. CONCLUSIONS Considering that sclerostin is an inhibitor of bone formation, the observed positive correlations of serum sclerostin with BMD and bone volume were unexpected. Whether its increase in dialysis patients has direct pathogenetic relevance or is only a secondary phenomenon remains to be seen.

Low Total Vitamin C Plasma Level Is a Risk Factor for Cardiovascular Morbidity and Mortality in Hemodialysis Patients

Hemodialysis patients are prone to deficiency of vitamin C, which constitutes the most abundant nonenzymatic antioxidant in blood. Because antioxidants are involved in the pathogenesis of atherosclerosis, the authors examined the association of total vitamin C plasma level with cardiovascular outcomes in such patients. One hundred thirty-eight consecutive maintenance hemodialysis patients (median age 61 yr, 90 males) were enrolled in a single-center study. At baseline, routine laboratory parameters were recorded, and predialysis total vitamin C plasma levels were measured by high-pressure liquid chromatography. Patients were prospectively followed-up for the occurrence of a primary composite endpoint consisting of fatal and nonfatal major adverse cardiovascular events (MACE) and for all-cause and cardiovascular mortality. MACE occurred in 35 patients (25%) over a period of median 30 mo, and 42 patients (30%) died [29 cardiovascular deaths (21% of total)]. Using Cox proportional hazards modeling, adjusted hazard ratios for the occurrence of MACE were 3.90 (95% confidence interval [CI]: 1.42 to 10.67; P = 0.008) and 3.03 (95% CI: 1.03 to 8.92; P = 0.044) for patients in the lower (<32 micromol/L) and middle (32 to 60 micromol/L) tertile of total vitamin C levels, compared with patients in the upper tertile (>60 micromol/L). Hazard ratios for cardiovascular death were 3.79 (95% CI: 1.23 to 11.66; P = 0.020) and 2.89 (95% CI: 0.89 to 9.37; P = 0.076). Total vitamin C levels were not independently associated with all-cause mortality. This study concludes that low total vitamin C plasma levels predict adverse cardiovascular outcomes among maintenance hemodialysis patients. Future studies should address the potential protective effect of an adequate vitamin C supplementation.

Concentrations of various arachidonic acid metabolites in menstrual fluid are associated with menstrual pain and are influenced by hormonal contraceptives

In a pilot study we investigated the association between concentrations of various eicosanoids in menstrual blood with pain and oral contraceptive use. Menstrual fluid was collected on tampons by 12 women who did not use an oral contraceptive but suffered from slight primary dysmenorrhea and by three pain-free women who used an oral contraceptive. Eicosanoids (cyclooxygenase products: 6-ketoprostaglandin F1 alpha, thromboxane B2, prostaglandin E2, prostaglandin F2 alpha, 13,14-dihydro-15-ketoprostaglandin F2 alpha, 12-hydroxy-heptadecatrienoic acid; lipoxygenase products: 5-, 12-, 15-hydroxy-eicosatetraenoic acid (HETE), leukotriene B4, leukotriene C4, leukotriene D4, leukotriene E4) and female sex steroids (17 beta-estradiol and progesterone) were analyzed by the combined use of high-performance liquid chromatography and radioimmunoassay. 12-HETE was the main arachidonic acid metabolite. An increased metabolism of arachidonic acid was associated with pain, especially when synthesis of 12-HETE was elevated. Oral contraceptive use decreased the synthesis of prostaglandins as well as leukotrienes. The concordant changes of cyclooxygenase and lipoxygenase products in dysmenorrhea or in oral contraceptive use may be explained by an increased or decreased phospholipid metabolism, respectively.

Acetaminophen has greater antipyretic efficacy than aspirin in endotoxemia: a randomized, double-blind, placebo-controlled trial.

To compare the antipyretic efficacy of aspirin and acetaminophen (INN, paracetamol) in 30 male volunteers with the use of endotoxin (lipopolysaccharide) to elicit a standardized febrile response.

Osteocalcin Is Related to Enhanced Insulin Secretion in Gestational Diabetes Mellitus

OBJECTIVE There is growing evidence that osteocalcin, an osteoblast-derived protein locally acting on bone formation, can increase insulin secretion as well as insulin sensitivity and thus prevent the development of obesity and diabetes in experimental animals. In humans, osteocalcin has been reported to be decreased in patients with type 2 diabetes. Because gestational diabetes mellitus (GDM) can serve as a model of pre–type 2 diabetes, the aim of this study was to investigate osteocalcin in GDM. RESEARCH DESIGN AND METHODS Osteocalcin measurement and an oral glucose tolerance test were performed in 78 pregnant women (26 women had GDM and 52 women had normal glucose tolerance [NGT] during pregnancy; women were matched for age and BMI) and in 34 women postpartum. RESULTS During pregnancy osteocalcin was significantly higher in the women with GDM than in the women with NGT (15.6 ± 6.4 vs. 12.6 ± 4.0 ng/ml; P < 0.015), whereas no difference was observed between the two groups at 12 weeks postpartum (36.2 ± 10.2 vs. 36.2 ± 13.0 ng/ml), when osteocalcin was found to be increased compared with the level in the pregnant state in all women (+145 ± 102% in GDM vs. +187 ± 119% in NGT; P < 0.0001). Moreover, osteocalcin showed a significant correlation with basal and total insulin secretion in the whole study group (R = 0.3, P < 0.01). CONCLUSIONS In GDM osteocalcin was higher and thus less restrained than in women with NGT during pregnancy and furthermore correlated with insulin secretion parameters. Therefore, it could be hypothesized that osteocalcin can enhance insulin secretion in insulin-resistant states; alternatively an effect of hyperinsulinemia on osteocalcin secretion cannot be excluded.