Nonsteroidal mineralcorticoid receptor antagonists: Novel therapeutic implication in the management of patients with type 2 diabetes.

Growing evidencehas described a correlation between aldosterone, obesity, and insulin resistance, suggesting that adipocyte-related factors and mineralocorticoid receptor (MR) overactivation may alter aldosterone secretion, potentially leading to obesity and glucose intolerance. Preclinical studies showed that pharmacological antagonism of MR prevents white adipose tissue dysfunction(s) and expansion, activates brown adipose tissue, and improves glucose tolerance. The clinical use of nonsteroidal MR antagonists has been shown to reduce the risk of diabetic kidney disease progression and cardiovascular events in patients with diabetes. This review aims to summarize the effects of pharmacological MR blockade on obesity and its associated metabolic comorbidities, with a particular focus on the therapeutic implications of nonsteroidal MR antagonists in the management of patients with diabetes.

Cadmium exposure alters steroid receptors and proinflammatory cytokine levels in endothelial cells in vitro: a potential mechanism of endocrine disruptor atherogenic effect.

BACKGROUND: Cadmium (Cd) is a widespread environmental pollutant that causes alterations in human health acting as endocrine disruptor. Recent data suggest that cardiovascular system might be a contamination target tissue, since Cd is found in atheromatic plaques. Thus, the purpose of this study was to evaluate the consequence of Cd exposure of endothelial cells in vitro to evaluate detrimental effect in vascular system by a potential sex-steroid hormone receptor-dependent mechanism(s). METHODS: To this aim, Human Umbilical Vein Endothelial Cells (HUVECs) were cultured and exposed to several concentrations of cadmium chloride (CdCl2) for different interval times. RESULTS: CdCl2 exposure of HUVECs induced a significant increase of ERß and Cyp19a1 at both mRNA and protein levels, while a drastic dose-dependent decrease of AR expression level was observed after 24 h of exposure. On the contrary, an increase of PhARser308 as well as a reduction of PhGSK-3ßser9 and PhAKTser473 was detected after 1 h treatment. This effect was consistently reduced by GSK inhibition. Furthermore, CdCl2 abolished DHT-induced cell proliferation in HUVECs suggesting an antagonist-like effect of Cd on AR-mediated signaling. Remarkable, after 6 h CdCl2-treatment, a relevant increase in TNF-α, IL-6 and IL-8 mRNA was observed and this effect was blocked by the presence of an ERß-selective antagonist. Moreover, Cd-induced TxR1 overexpression, likely, correlated with the activation of p38 MAPK/NF-κB pathway. CONCLUSION: In conclusion, our study demonstrates for the first time that Cd alters sex-steroid hormone receptors level and activity likely affecting intracellular signaling linked to a proinflammatory state in endothelial cells. This alteration might possibly lead to endothelial cell injury and vascular dysfunction and could be a mechanism of gender-specific atherogenic damages induced by endocrine disruptors and, thus, induce atherogenic events with increased risk of cardiovascular diseases in individuals exposed to this endocrine disruptor.

Correction to: Cadmium exposure alters steroid receptors and proinflammatory cytokine levels in endothelial cells in vitro: a potential mechanism of endocrine disruptor atherogenic effect.

Unfortunately, the figure captions 4 and 6 were incorrectly published in the original publication. The complete correct captions are given below.

Effects of an individualized home-based unsupervised aerobic training on body composition and physiological parameters in obese adults are independent of gender.

PURPOSE: Evaluation of the effects of an individualized home-based unsupervised aerobic training on body composition, physical and physiological parameters in female and male obese adults. METHODS: Two hundred and twenty obese adults (age 47.9 ± 12.4 years; BMI 38.0 ± 7.2 kg/m2) entered the 4-month training program. Body composition, physiological and functional capacities were assessed pre- and post-intervention. All subjects were requested to perform unsupervised aerobic training with the intensity based on heart rate, walking speed and OMNI-RPE score corresponding to the individual ventilatory threshold for at least 5 days/week. RESULTS: After 4-month study period, 40% of patients completed the protocol, 24% had high compliance (HC) (exercise ≥ 3 days/week), while 16% had low compliance (LC) to exercise prescription (exercise < than 3 days/week). In HC group, a significant improvement of body composition variables after training was performed. Moreover, oxygen uptake and metabolic equivalent at peak significantly increased after training. Six-minute walking test (6MWT) distance significantly increased while heart rate during 6MWT was significantly lower after training. No significant differences were found in LC group between pre- and post-intervention in all variables. Interestingly, gender does not influence the effects of training. CONCLUSIONS: Our results indicate that subjects, independent of gender, with high compliance to the aerobic training based on a new individualized method can achieve a significant reduction in weight loss and also an improvement in physical and physiological parameters. This innovative personalized prescription could be a valuable tool for exercise physiologist, endocrinologists, and nutritionists to approach and correct life style of obese subjects.

Persistence with denosumab therapy in women affected by osteoporosis with fragility fractures: a multicenter observational real practice study in Italy.

BACKGROUND: Persistence is commonly considered a key factor for the successful management of osteoporosis and fragility fractures. Denosumab is the first biologic agent developed for the treatment of osteoporosis with satisfying data regarding the persistence with this therapy. AIM: The purpose of this multicenter observational real practice study was to evaluate the persistence with denosumab treatment in post-menopausal women affected by osteoporosis. MATERIAL/SUBJECTS AND METHODS: Women were recruited in four specialized centers for the management of osteoporosis in North, Center and South of Italy. We included women with a diagnosis of post-menopausal osteoporosis, aged >50 years, able to obtain a prescription according to the Italian reimbursement criteria in force during the study period for anti-osteoporotic pharmacological treatment. They initiated a treatment with subcutaneous denosumab (Prolia®) 60 mg/every 6 months between November 2011 and May 2016. Women who had received aromatase inhibitors were excluded. Patients were assessed at baseline and every 6 months for all treatment length. Persistence data were evaluated for a total of 36 months. RESULTS: Eight hundred seventy women were enrolled; mean aged 70 years, with a mean body mass index of 24.8 ± 4.1 kg/m2. At the Dual-energy X-ray absorptiometry assessment, the mean lumbar spine T-score was -2.76 ± 1.14 standard deviations (SD) and the mean femoral neck T-score was -2.49 ± 0.80 SD. During the study, the total persistence was 91.4%. Total dropouts were 75 (8.6%), higher within the initial 6-month period of treatment. CONCLUSIONS: Persistence to denosumab treatment in our observational real practice study was very high. These results suggest that factors such as frequency of visits, pharmacological schedule, and opportunity to call the doctor might play an important role in the persistence and adherence to treatment to obtain maximum therapeutic effect and avoid further fragility fractures.

Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model.

PURPOSE: Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD). METHODS: Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression. RESULTS: Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation. CONCLUSIONS: Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

Effect of personalized dietary intervention on nutritional, metabolic and vascular indices in patients with chronic kidney disease.

OBJECTIVE: Patients with chronic kidney disease (CKD) present a markedly increased cardiovascular (CV) morbidity and mortality since the early stages of the disease and a high prevalence of malnutrition, inflammation, and accelerated atherosclerosis. Personalized nutritional intervention, with of a low-protein diet (LPD), since the early stages of CKD should be able to achieve significant metabolic improvements. In our study we have verified the effects of a personalized dietary intervention in patients in the CKD stages 3/4 KDOQI on nutritional, metabolic and vascular indices. PATIENTS AND METHODS: We have evaluated renal function, lipid profile, mineral metabolism, inflammatory indices, and acid-base balance of 16 patients with CKD (stages 3/4 KDOQI). Assessment of nutritional status, body composition, bone mineral density and muscle mass, using body mass index (BMI), handgrip strength, bioelectrical impedance analysis (BIA), and dual energy X-ray absorptiometry (DEXA) was performed. Vascular indices and endothelial dysfunction such as carotid intima-media thickness (cIMT) and the brachial artery flow-mediated dilation (baFMD) were also analyzed. RESULTS: After dietary interventions, we observed a significant increase in plasma bicarbonate (p = 0.004) and vitamin D levels (p = 0.03) and a concomitant significant reduction of phosphorus concentration (p = 0.001) and C-reactive protein (CRP) (p = 0.01). CONCLUSIONS: Nutritional intervention potentially plays a major role in reducing the progression of CKD and systemic complications of predialysis patients. A low-protein diet (LPD) ensuring vegetable protein intake and a reduced amount of specific micronutrients should be recommended to stage 3/4 CKD patients in order to ameliorate metabolic profile, renal outcome, and reduce cardiovascular risk factors.

Lean mass in obese adult subjects correlates with higher levels of vitamin D, insulin sensitivity and lower inflammation.

AIM: Several chronic metabolic alterations are present in obese subjects. While it is well known about the detrimental effect of abdominal adipose tissue on chronic metabolic clinical condition, less is known on the role of lean mass in obese subjects. Thus, the aim of our study was to evaluate the potential correlation of muscle mass, metabolic condition and inflammation status in obese individuals. METHODS: The study included 426 obese subjects (86 men and 340 female; mean age 44.8 ± 14 years; BMI: 34.9 ± 6.1 kg/m(2)). Exclusion criteria were chronic medical conditions or use of medications affecting bone metabolism, alterations of hormonal and nutritional status, vitamin D supplementation, recent weight loss and prior bariatric surgery. Patients underwent measurements of bone mineral density (lumbar and hip) and body composition (lean mass, total and trunk fat mass) by dual X-ray absorptiometry and were evaluated for hormonal and metabolic profile and inflammatory markers. RESULTS: Higher lean body mass (LM%) was inversely correlated with homeostasis model assessment of insulin resistance (p < 0.0091; r(2) 0.03938) and associated with lower fibrinogen levels (p < 0.0001; r(2) 0.1263). Interestingly, in obese subjects, LM% was associated with higher levels of vitamin D (p < 0.0001, r(2) 0.1140), osteocalcin (p < 0.0001, r(2) 0.2401) and insulin-like growth factor-1 (IGF-1) (p < 0.0002, r(2) 0.1367). CONCLUSION: Our results show for the first time that in obese patients, higher amounts of lean mass are directly linked to a lower inflammatory profile and to better insulin sensitivity, but also to the presence of higher level of vitamin D and IGF-1. Moreover, these data suggest that higher levels of lean mass in obese people correlate with a better metabolic profile and, thus, strongly suggest the need to develop programs to facilitate an increase in physical activity in obese people.

Is obesity protective for osteoporosis? Evaluation of bone mineral density in individuals with high body mass index.

BACKGROUND: Obese individuals often present comorbidities while they appear protected against the development of osteoporosis. However, few and contradictory data are now available on skeletal modifications in obese patients. The aim of this study was to characterise bone mineral density (BMD) in overweight (BMI > 25 < 29.9) and obese (BMI > 30) patients. METHODS: We selected 398 patients (291 women, 107 men, age 44.1 + 14.2 years, BMI 35.8 + 5.9 kg/m(2)) who underwent clinical examination, blood tests and examination of body composition. Subjects with chronic conditions or taking medications interfering with bone metabolism, hormonal and nutritional status and recent weight loss were excluded. RESULTS: Interestingly, 37% (n = 146) of this population showed a significantly lower than expected lumbar BMD: 33% (n = 98) of women showed a T-score -1.84 +/- 0.71, and 45% (n = 48) of men showed a T-score -1.88 +/- 0.64. When the population was divided into subgroups based on different BMI, it was noted that overweight (BMI > 25 < 29.9) was neutral or protective for BMD, whereas obesity (BMI > 30) was associated with a low bone mass, compatible with a diagnosis of osteoporosis. No differences were observed in hormones and lipid profiles among subgroups. CONCLUSIONS: Our results indicate that a subpopulation of obese patients has a significant low lumbar BMD than expected for age. Thus, a careful characterisation of skeletal metabolism might be useful in all obese individuals to avoid fragility fractures later in life.

Are subjects with erectile dysfunction aware of their condition? Results from a retrospective study based on an Italian free-call information service.

The aim of the study was to analyse the socio-demographic and epidemiological characteristics of the Italian male population affected by sexual disturbances. Men complaining of erectile dysfunction (ED) who called the Pfizer program "Man and Woman in Health" between April 18th 2001 and May 27th 2002 and asked for information about their medical condition, were interviewed by trained doctors using a computer-assisted questionnaire. 16007 out of 25018 calls were considered for statistical analysis. Mean age of callers was 48.8+/-14.2 yr, reporting ED in 83% of cases. In the majority of men ED was severe (58%) and lasting more than 3 yr (25%). Multivariate analysis revealed that diabetes, depression, prostate surgery, heart disease, neurological disorders, liver and renal diseases were all significant and independent contributors to the degree of erectile impairment adjusted for age (p<0.001). The principal concomitant medications were anti-hypertensive (23%), antidiabetic (9%) and cardiovascular agents (6%). Cigarette smoking was present in 24%. On directed questioning of the caller, anxiety and distress were perceived as the most frequent causes of ED (42%) across all age groups, followed by the presence of concomitant disease/s (26%) especially in aging men. Also, a large number of men (41 %) with severe ED waited for more than 3 yr before looking for medical referral. Interestingly, only 19% had ever tried any specific medication for ED. These data indicate that 5 yr after worldwide approval and release of sildenafil, ED is still largely undiagnosed and under-treated, possibly because it is still perceived as a condition mainly due to distress or advancing age and therefore not deserving medical referral. Effective prevention of ED commences with better awareness of the pathological causes by the population and modification of risk factors by the doctors.