Search

Objective: Follistatin binds and inactivates activins, which are potent inhibitors of muscle growth and metabolism and are currently being developed for the treatment of obesity and type 2 diabetes (T2D). We have recently reported that follistatin is regulated by glucose (and not lipids) and can prospectively predict the metabolic improvements observed after bariatric surgery. We utilized novel assays herein to investigate whether activins are regulated by glucose or lipids, whether their circulating levels change after bariatric surgery and whether these changes are predictors of metabolic outcomes up to 12 months later.Design and Methods: Activin A, B, AB and their ratios to follistatin were measured in (a) healthy humans (n = 32) undergoing oral or intravenous lipid or glucose intake over 6 h, (b) morbidly obese individuals with or without type 2 diabetes undergoing three different types of bariatric surgery (gastric banding, Roux-en-Y bypass or sleeve gastrectomy) in two clinical studies (n = 14 for the first and n = 27 for the second study).Results: Glucose intake downregulates circulating activin A, B and AB, indicating the presence of a feedback loop. Activin A decreases (~30%), activin AB increases (~25%) and activin B does not change after bariatric surgery. The changes in activin AB and its ratio to follistatin 3 months after bariatric surgery can predict the BMI reduction and the improvement in insulin and HOMA-IR observed 6 months postoperatively.Conclusion: Activins are implicated in glucose regulation in humans as part of a feedback loop with glucose or insulin and predict metabolic outcomes prospectively after bariatric surgery. [ABSTRACT FROM AUTHOR]

Aims: It has been suggested recently that follistatin (FST) and its homologous protein, follistatin‐like 3 (FSTL3), may be a therapeutic target in the treatment of type 2 diabetes because of their glucose‐regulatory effects in rodents. Materials and Methods: We investigated this hypothesis in humans by studying the physiology of a possible glycaemia–follistatin feedback loop, that is, whether glucose, but not lipid intake (oral or intravenous), can regulate circulating FST and FSTL3 in healthy humans (n = 32), whether the levels of follistatins change in response to various types of bariatric operation in morbidly obese individuals, with or without type 2 diabetes (n = 41), and whether such changes are associated prospectively with improvement of glucose homeostasis/insulin sensitivity. Results: In healthy individuals, circulating FST decreases after intravenous or oral glucose intake compared to controls, indicating the presence of a negative feedback mechanism. In morbid obesity, insulin resistance, glycaemia, circulating FST and FSTL3 are all reduced (by 22%‐33%) after Roux‐en‐Y gastric bypass (RYGB) and sleeve gastrectomy. Importantly, the changes in circulating FST 3 months after bariatric surgery are associated prospectively with the changes in glucose, insulin, HOMA‐IR and HbA1c observed 6 months postoperatively in individuals with and without type 2 diabetes. Conclusions: Our findings provide evidence of an important role of FST in glucose homeostasis in healthy individuals as well as in severely obese individuals with insulin resistance and type 2 diabetes. Our data extend recent results from animal studies to humans and support the need for further evaluation of FST inactivation strategies for targeting hyperglycaemia and insulin resistance. [ABSTRACT FROM AUTHOR]

Aim: The purpose of our study was to investigate the possible effect of BsmI vitamin D receptor (VDR's) polymorphism on changes in bone mineral density (BMD) and bone turnover markers in postmenopausal women receiving different treatments. Material and Methods: This pilot study included 42 postmenopausal women with elevated fracture risk, randomized into 1-year treatment with weekly oral alendronate or daily subcutaneous teriparatide. Both groups received daily supplements of 1000 mg calcium and 800 IU vitamin D. Blood samples were obtained for biochemical evaluation and genotyping. BMD at the lumbar spine and femoral neck were assessed with dual energy X-ray absorptiometry. Baseline, follow-up BMD and markers of bone turnover were assessed according to the BsmI genotype. Results: BMD at the lumbar spine increased in patients carrying at least one b allele, while it decreased in patients with the BB genotype ( P = 0.041). Whereas no gene-treatment interaction was observed in teriparatide-receiving patients, women with the BB genotype receiving alendronate resulted in negative BMD (−0.056 ± 0.032 g/m2) and T-score (−0.295 ± 0.190) gradient, compared to carriers of the b allele (BMD: +0.020 ± 0.017 g/m2, P = 0.054; T-score: +0.217 ± 0.100, P = 0.030). No effect of genotype was apparent with respect to gradients of biochemical bone markers. Conclusions: These preliminary results indicate that alendronate has a differential effect on BMD, depending on the VDR genotype. Carriers of the b allele may be more responsive to treatment compared to patients with the BB genotype. The interaction of VDR's BsmI polymorphism with the efficacy of the anti-osteoporotic treatment needs further investigation by larger prospective studies. [ABSTRACT FROM AUTHOR]

The aim of our study was to evaluate the effect of BMI on the change in circulating sex hormone in postmenopausal women during 6 months of oral continuous combined low-dose hormone therapy (HT). Fifty postmenopausal women were allocated to receive daily one tablet containing combination of 17β-estradiol (1 mg)/norethindrone acetate (0.5 mg) for 6 months. Serum levels of follicle-stimulating hormone (FSH), estradiol, total testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), free estrogen index (FEI), Δ4-androstendione (Δ4A), and dehydroepiandrosterone sulfate were assessed at baseline and at the end of 6 months. Mean absolute values and percent changes from baseline were compared between lean and overweight women. Mean FSH decreased and mean 17β-estradiol increased significantly in both groups (FSH lean: 82.3 ± 26.7 decreased to 45.0 ± 17.0 mIU/ml, P = 0.0001; FSH overweight: 85.5 ± 22.1 decreased to 52.3 ± 23.8 mIU/ml, P = 0.003; P between groups = 0.661; E2 lean: 23.24 ± 12.55 increased to 53.62 ± 28.29 pg/ml, P = 0.006; E2 overweight: 24.17 ± 10.88 increased to 68.36 ± 53.99 pg/ml, P = 0.0001; P between groups = 0.619). Lean individuals had statistically significant higher increments of FAI and specifically FEI compared to overweight (FEI lean; 0.14 ± 0.09 increased to 0.29 ± 0.14, P = 0.009; overweight 0.23 ± 0.18 increased to 0.52 ± 0.40, P = 0.126; P between groups = 0.034). Although BMI does not affect total 17β-estradiol changes, free sex steroid concentrations increase more steeply in lean compared to overweight women receiving oral low-dose HT. [ABSTRACT FROM AUTHOR]

Background: Inherited thrombophilia is associated with both poor obstetrical outcomes and increased cardiovascular risk later in life. In fact, a personal history of spontaneous miscarriage is reported to increase the risk of subsequent ischaemic heart disease . Aims: This pilot study aims to evaluate the association between genetic polymorphism-related increased risk of arterial thrombosis and the history of spontaneous miscarriage early in pregnancy, among healthy postmenopausal women. Methods: The following polymorphisms were assessed in 84 healthy post-menopausal women: Glycoprotein IIIa leu33pro, Apolipoprotein E2/E3/E4, Methylenetetrahydrofolate reductase, Apolipoprotein B arg3500gln, Paraoxonase 1 gln182arg, Plasminogen activator inhibitor 1 4G/5G, Cholesterol-7α-hydroxylase and Cholesterol ester transfer protein (ΤaqIB) B1/B2. The association between the polymorphisms and history of spontaneous pregnancy loss was evaluated. Results: The frequency of the PLA2 allele of glycoprotein IIIa was significantly higher in women who experienced spontaneous miscarriage when compared with controls ( P = 0.033). Glycoprotein IIIa leu33pro polymorphism correlated positively with the frequency of spontaneous miscarriage ( P = 0.027). Among women reporting miscarriage, 55.6% were heterozygous compared with 44.4% who were wild type. We found no significant association between any of the other polymorphisms and spontaneous pregnancy loss. Conclusions: Our findings indicate that Glycoprotein IIIa leu33pro polymorphism is associated with early, spontaneous miscarriage. The causative role of this polymorphism as a risk factor of pregnancy loss needs further investigation by prospective studies. [ABSTRACT FROM AUTHOR]

Objective Autoimmune thyroiditis and overt or subclinical hypothyroidism have been associated with increased prevalence of cardiovascular disease (CVD). Design Cross-sectional investigation of the association between gene polymorphisms related to CVD with thyroid function and autoimmunity. Patients In total 84 healthy postmenopausal women aged 49–69 years. Measurements FT3, FT4, anti-TPO and anti-TG were assessed in the sera of participants. The following polymorphisms were assessed from peripheral lymphocyte DNA: Apolipoprotein E E2/E3/E4, paraoxonase 1 A/B, Glycoprotein IIIa leu33pro, MTHFR ala222val, ApoBarg3500gln, plasminogen activator inhibitor 1 4G/5G, cholesterol 7-α hydroxylase A204C and cholesterol ester transfer protein B1/B2. Results A statistically significant correlation was found between Apolipoprotein E and paraoxonase1 polymorphisms and serum thyroid hormones: carriers of the E2 or E4 allele of the ApoE gene had lower levels of FT4 ( P = 0·0005) than women with the E3/E3 genotype. Carriers of the B allele of paraoxonase 1 gene had lower levels of FT3 compared to women with the wild-type genotype ( P = 0·047). A statistically significant positive association ( P = 0·049) was also observed between anti-TG antibodies and the presence of the E2 allele of the Apolipoprotein E gene. Conclusions Polymorphisms of apolipoprotein E and paraoxonase 1 are associated with different levels of thyroid hormone and anti-Tg antibody levels in the study population in this pilot study. The mechanism underlying this association remains to be elucidated. [ABSTRACT FROM AUTHOR]