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Open access

Xue-Lian Zhang, Xinyi Zhao, Yong Wu, Wen-qing Huang, Jun-jiang Chen, Peijie Hu, Wei Liu, Yi-Wen Chen, Jin Hao, Rong-Rong Xie, Hsiao Chang Chan, Ye Chun Ruan, Hui Chen, and Jinghui Guo


The beneficial effect of angiotensin(1–7) (Ang(1–7)), via the activation of its receptor, MAS-1, has been noted in diabetes treatment; however, how Ang(1–7) or MAS-1 affects insulin secretion remains elusive and whether the endogenous level of Ang(1–7) or MAS-1 is altered in diabetic individuals remains unexplored. We recently identified an important role of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl channel, in the regulation of insulin secretion. Here, we tested the possible involvement of CFTR in mediating Ang(1–7)’s effect on insulin secretion and measured the level of Ang(1–7), MAS-1 as well as CFTR in the blood of individuals with or without type 2 diabetes.


Ang(1–7)/MAS-1/CFTR pathway was determined by specific inhibitors, gene manipulation, Western blotting as well as insulin ELISA in a pancreatic β-cell line, RINm5F. Human blood samples were collected from 333 individuals with (n  = 197) and without (n  = 136) type 2 diabetes. Ang(1–7), MAS-1 and CFTR levels in the human blood were determined by ELISA.


In RINm5F cells, Ang(1–7) induced intracellular cAMP increase, cAMP-response element binding protein (CREB) activation, enhanced CFTR expression and potentiated glucose-stimulated insulin secretion, which were abolished by a selective CFTR inhibitor, RNAi-knockdown of CFTR, or inhibition of MAS-1. In human subjects, the blood levels of MAS-1 and CFTR, but not Ang(1–7), were significantly higher in individuals with type 2 diabetes as compared to those in non-diabetic healthy subjects. In addition, blood levels of MAS-1 and CFTR were in significant positive correlation in type-2 diabetic but not non-diabetic subjects.


These results suggested that MAS-1 and CFTR as key players in mediating Ang(1–7)-promoted insulin secretion in pancreatic β-cells; MAS-1 and CFTR are positively correlated and both upregulated in type 2 diabetes.

Open access

Xiying Zeng, Yinxiang Huang, Mulin Zhang, Yun Chen, Jiawen Ye, Yan Han, Danyan Ma, Xin Zheng, Xiaohong Yan, and Changqin Liu


Anti-Müllerian hormone (AMH) is recognized as the most important biomarker for ovarian reserve. In this cross-sectional study, we aimed to explore the potential association of AMH with central obesity or general obesity in women with polycystic ovary syndrome (PCOS).


In this cross-sectional study, 179 patients with PCOS were enrolled and underwent anthropometric measurements (BMI and waist circumference (WC)) and serum AMH level detection. Pearson’s correlation and multivariable logistic regression analyses were performed to determine the associations of AMH with central obesity and general obesity.


Subjects with increasing BMI showed significantly lower values of AMH (median (interquartile range (IQR)) 8.95 (6.03–13.60) ng/mL in normal weight group, 6.57 (4.18–8.77) ng/mL in overweight group, and 6.03 (4.34–9.44) ng/mL in obesity group, P = 0.001), but higher levels of systolic blood pressure, fasting insulin, total cholesterol, triglycerides, LDL-c, obesity indices (WC, hip circumferences, waist-to-hip ratio, waist-to-height ratio (WHtR), and Chinese visceral adiposity index (CVAI)). Compared with the group of PCOS women without central obesity, the group with central obesity had significantly lower value of AMH (median (IQR) 8.56 (5.29–12.96) ng/mL vs 6.22 (4.33–8.82) ng/mL; P = 0.003). Pearson’s correlation analysis showed that AMH was significantly and negatively correlated with BMI (r = −0.280; P < 0.001), WC (r = −0.263; P < 0.001), WHtR (r = −0.273; P < 0.001), and CVAI (r = −0.211; P = 0.006). Multivariate logistic regression analysis with adjustment for potential confounding factors showed that AMH was independently and negatively associated with central obesity but was not significantly associated with general obesity.


AMH was independently and negatively associated with central obesity. Closely monitoring the WC and AMH should be addressed in terms of assessing ovarian reserve in women with PCOS.

Open access

Ann-Cathrin Koschker, Bodo Warrings, Caroline Morbach, Florian Seyfried, Nicole Rickert, Pius Jung, Andreas Geier, Ulrich Dischinger, Maike Krauthausen, Martin J. Herrmann, Christine Stier, Stefan Frantz, Uwe Malzahn, Stefan Störk, and Martin Fassnacht

Obesity is a rapidly emerging health problem and an established risk factor for cardiovascular diseases. Bariatric surgery profoundly reduces body weight and mitigates sequelae of obesity. The open, randomized controlled WAS trial compares the effects of Roux-en-Y gastric bypass (RYGB) versus psychotherapy-supported lifestyle modification in morbidly obese patients. The co-primary endpoint addresses 1-year changes in cardiovascular function (peak VO2 during cardiopulmonary exercise testing) and quality of life (Short-Form-36 physical functioning scale). Prior to randomization, all included patients underwent a multimodal anti-obesity treatment for 6-12 months. Thereafter, patients were randomized and followed through month 12 to collect primary endpoints. Afterwards, patients in the lifestyle group could opt for surgery, and final visit was scheduled for all patients 24 months after randomization. Sample size calculation suggested to enroll 90 patients in order to arrive at minimally 22 patients per group evaluable for the primary endpoint. Secondary objectives were to quantify changes in body weight, left ventricular hypertrophy, systolic and diastolic function (by echocardiography and cardiac magnet resonance imaging [MRI]), functional brain MRI, psychometric scales, endothelial and metabolic function. WAS enrolled 93 patients (72 women, median age 38 years, BMI 47.5 kg/m2) exhibiting a relevantly compromised exercise capacity (median peakVO2 18.3 ml/min/kg) and quality of life (median physical functioning scale 50). WAS is the first randomized controlled trial focusing on the effects of RYGB on cardiovascular function beyond hypertension. In addition, it will provide a wealth of high-quality data on cerebral, psychiatric, hepatic, and metabolic function in obese patients after RYGB. The trial is registered at (NCT01352403).

Open access

Jennifer K. Y. Ko, Jinghua Shi, Raymond H. W. Li, William S. B. Yeung, and Ernest H. Y. Ng

Objective: Vitamin D receptors are present in the female reproductive tract. Studies on the association between serum vitamin D level and pregnancy rate of in vitro fertilization (IVF) showed inconsistent results and focused on a single fresh or frozen embryo transfer cycle. The objective of our study was to evaluate if serum vitamin D level before ovarian stimulation was associated with the cumulative live birth rate (CLBR) of the first IVF cycle.

Design: Retrospective cohort study.

Methods: Women who underwent the first IVF cycle from 2012 to 2016 at a university-affiliated reproductive medicine center were included. Archived serum samples taken before ovarian stimulation were analyzed for 25(OH)D levels using liquid chromatography-mass spectrometry.

Results: 1,113 had pregnancy outcome from the completed IVF cycle. The median age (25th-75th percentile) of the women was 36 (34-38) years and serum 25(OH)D level was 53.4 (41.9-66.6)nmol/L. The prevalence of vitamin D deficiency (less than 50nmol/L) was 42.2%. The CLBR in the vitamin D deficient group was significantly lower compared to the non-deficient group (43.9%,208/474 vs 50.9%,325/639, p=0.021, unadjusted), and after controlling for women’s age, body mass index, antral follicle count, type and duration of infertility. There were no differences in the clinical/ongoing pregnancy rate, live birth rate and miscarriage rate in the fresh cycle between the vitamin D deficient and non-deficient groups.

Conclusions: Vitamin D deficiency was prevalent in infertile women in subtropical Hong Kong. The CLBR of the first IVF cycle in the vitamin D deficient group was significantly lower compared to the non-deficient group.

Open access

Michelle J Galvan, Michael J Sanchez, Andrew J McAinch, Jeffrey D Covington, Jason B Boyle, and Sudip Bajpeyi

Introduction/Purpose: Most U.S. adults (54%) do not meet minimum exercise recommendations by American College of Sports Medicine (ACSM). Neuromuscular electrical stimulation (NMES) is a novel alternate strategy to induce muscle contraction. However, effectiveness of NMES to improve insulin sensitivity and energy expenditure is unclear. The purpose of this study was to investigate the effects of four weeks of NMES on glucose tolerance in a sedentary overweight or obese population.

Methods: Participants (n=10; age: 36.8 ± 3.8 years; BMI=32 ± 1.3 kg/ m2) were randomized into either control or NMES group. All participants received bilateral quadriceps stimulation (12 sessions; 30 minutes/session; 3 times/week at 50 Hz and 300 µs pulse width) altering pulse amplitude to either provide low intensity sensory level (control; tingling sensation) or at high intensity neuromuscular level (NMES; maximum tolerable levels with visible muscle contraction). Glucose tolerance was assessed by three-hour oral glucose tolerance test (OGTT), substrate utilization was measured by indirect calorimetry and body composition via dual X-ray absorptiometry at baseline and after four weeks of NMES intervention.

Results: Control and NMES groups had comparable fasting blood glucose, glucose tolerance, substrate utilization, and muscle mass at baseline. Four weeks of NMES resulted in a significant improvement in glucose tolerance measured by OGTT, whereas no change was observed in control group. There was no change in substrate utilization and in muscle mass in both control and NMES groups.

Conclusion: NMES is a novel and effective strategy to improve glucose tolerance in an at-risk overweight or obese sedentary population.

Open access

Lizhi Zhang, Jinwei He, Xiang Sun, Dongyue Pang, Jingjing Hu, and Bo Feng

Our previous studies have demonstrated that there is a correlation between GLP-1R SNP and the BMD in postmenopausal women. GLP-1 and GIP are both incretins. Whether the mutation of GIPR gene affects bone metabolism. SNP rs10423928 is a GIPR gene polymorphism that has been studied more frequently. The aim of this study was to investigate the association between GIPR SNP rs10423928 and bone-mineral density (BMD) in postmenopausal women in Shanghai. The GIPR SNP rs10423928 was detected in 884 postmenopausal women in Shanghai, the correlation between the GIPR SNP and BMD was further assessed. The dominant T/T genotype of the GIPR SNP rs10423928 was significantly related to BMD of the femoral neck (P = 0.035) and Ward’s triangle area (P = 0.033). Our research found that the dominant T/T genotype of GIPR SNP rs10423928 in postmenopausal women is significantly associated with higher BMD. The T/T genotype seems to have bone protection.

Open access

Kevin D Cashman


Internationally, concern has been repeatedly raised about the little notable progress in the collection, analysis and use of population micronutrient status and deficiency data globally. The need for representative status and intake data for vitamin D has been highlighted as a research priority for well over a decade.

Aim and methods

A narrative review which aims to provide a summary and assessment of vitamin D nutritional status data globally. This review divides the world into the Food and Agriculture Organisation’s (FAO) major regions: the Americas, Europe, Oceania, Africa and Asia. Emphasis was placed on published data on the prevalence of serum 25-hydroxyvitamin D (25(OH)D) < 25/30 and <50 nmol/L (reflecting vitamin D deficiency and inadequacy, respectively) as well as vitamin D intake, where possible from nationally representative surveys.


Collating data from the limited number of available representative surveys from individual countries might suggest a relatively low overall prevalence of vitamin D deficiency in South America, Oceania and North America, whereas there is more moderate prevalence in Europe and Asia, and possibly Africa. Overall, the prevalence of serum 25(OH)D < 25/30 and <50 nmol/L ranges from ~5 to 18% and 24 to 49%, respectively, depending on FAO world region. Usual intakes of vitamin D can also vary by FAO world region, but in general, with a few exceptions, there are very high levels of inadequacy of vitamin D intake.


While the burden of vitamin D deficiency and inadequacy varies by world regions and not just by UVB availability, the global burden overall translates into enormous numbers of individuals at risk.

Open access

Qian Wang, Jiacheng Wang, Yunhui Xin, Ziyang He, Xiang Zhou, Xing Liu, Teng Zhao, Lihan He, Hong Shen, Mulan Jin, and Bojun Wei

Background: Parathyroid carcinoma (PC), often misdiagnosed as parathyroid adenoma (PA), is prone to local relapse due to the initial surgery being restricted to parathyroid lesions instead of en bloc resection of parathyroid lesions with negative incision margins. However, it is very challenging to distinguish PC from PA preoperatively; hence, this study investigated an effective biomarker for increasing accuracy in PC diagnosis.

Method: First, differentially expressed the circular RNAs between three PC tissues and three PA tissues were screened by high-throughput circular RNA sequencing, and the expression of hsa_circ_0005729 was verified by qRT-PCR in 14 patients with PC and 40 patients with PA. Second, the receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to analyze the diagnostic efficiency of hsa_circ_0005729 in PC by combining with laboratory data. Third, RNF138 mRNA, the corresponding linear transcript of hsa_circ_0005729 was measured, and the relationship between hsa_circ_0005729 and RNF138 mRNA was analyzed in patients with PA and patients with PC.

Results: Hsa_circ_0005729 expression was significantly higher in patients with PC than in patients with PA. Serum calcium (p = 0.045), alkaline phosphatase (ALP) (p = 0.048), and creatinine levels (p = 0.036) were significantly higher in patients with PC than in patients with PA. The AUC increased to 0.86 when hsa_circ_0005729 combined with serum calcium, creatinine, and ALP. In addition, hsa_circ_0005729 was positively correlated with RNF138 mRNA in patients with PA but not in patients with PC.

Conclusion: The novel circular RNA hsa_circ_0005729 was found to have a higher expression in patients with PC, and indicating its usefulness for distinguishing PC from PA.

Open access

Hanna Karhapää, Siru Mäkelä, Hanna Laurén, Marjut Jaakkola, Camilla Schalin-Jäntti, and Micaela Hernberg

Objective: Immune checkpoint inhibitors (ICI) can cause endocrine adverse events. However, endocrine AEs could be related to better treatment outcomes. Our aim was to investigate whether this holds true in a real-world setting of metastatic melanoma patients.

Design: A retrospective single-institution study.

Methods: We included 140 consecutive metastatic melanoma patients treated with ICI between January 2012 and May 2019. We assessed endocrine toxicity and best possible treatment outcomes from electronic patient records, including laboratory parameters, and radiological images.

Results: Of the treated patients, 21 patients (15%) were treated with ipilimumab, 46 (33%) with nivolumab, 67 (48%) with pembrolizumab, and six (4%) with combination therapy (ipilimumab + nivolumab). Endocrine AEs appeared in 29% (41/140) patients. Three patients had two different endocrine AEs. Thyroid disorders were the most common: 26% (36/140), followed by hypophysitis: 4% (5/140). Three subjects (2%, 3/140) were diagnosed with autoimmune diabetes. Three patients had to terminate treatment due to endocrine toxicity. Radiological manifestations of endocrine AEs were found in 16 patients (39%, 16/41). Endocrine toxicity was associated with significantly better treatment outcomes. Median progression-free survival (8.1 months, range 5.1 – 11.1 months vs. 2.7 months, range 2.4 – 3.0 months, P < 0.001), and median overall survival (47.5 months, range 15.5 – 79.5 months vs. 23.7 months, range 15.3 – 32.1 months, P = 0.035) were longer for patients experiencing endocrine AEs.

Conclusions: The higher number of endocrine AEs suggest regular laboratory monitoring aids in AE detection. Endocrine AEs in metastatic melanoma may correlate with better treatment outcomes.

Open access

Chengnan Guo, Yixi Xu, Yange Ma, Xin Xu, Fang Peng, Hui-hui Li, Dongzhen Jin, Shu-zhen Zhao, Zhezheng Xia, Mengyuan Lai, Mingzhu Che, Ruogu Huang, Yanan Wang, Depeng Jiang, Chao Zheng, and Guangyun Mao

Although previous studies demonstrate that trehalose can help maintain glucose homeostasis in healthy humans, its role and joint effect with glutamate on diabetic retinopathy (DR) remain unclear. We aimed to comprehensively quantify the associations of trehalose and glutamate with DR. This study included 69 pairs of DR and matched type 2 diabetic (T2D) patients. Serum trehalose and glutamate were determined via ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry system. Covariates were collected by a standardized questionnaire, clinical examinations and laboratory assessments. Individual and joint association of trehalose and glutamate with DR were quantified by multiple conditional logistic regression models. The adjusted odds of DR averagely decreased by 86% [odds ratio (OR): 0.14; 95% confidence interval (CI): 0.06,0.33] with per interquartile range increase of trehalose. Comparing with the lowest quartile, adjusted OR (95% CI) were 0.20 (0.05,0.83), 0.14 (0.03,0.63) and 0.01 (<0.01,0.05) for participants in the 2nd, 3rd and 4th quartiles of trehalose, respectively. In addition, as compared to their counterparts, T2D patients with lower trehalose (<median) and higher glutamate (≥ median) had the highest odds of DR (OR: 36.81; 95% CI: 6.75, 200.61). Apparent super-multiplicative effect of trehalose and glutamate on DR was observed, whereas relative excess risk due to interaction (RERI) was not significant. The study suggests that trehalose is beneficial to inhibit the occurrence of DR and synergistically decreases the risk of DR with reduced glutamate. Our findings also provide new insights into the mechanisms of DR and further longitudinal studies are required to confirm these findings.