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Open access

Serum metabolomic analysis of the effect of exercise on nonalcoholic fatty liver disease

Jia Li, Yan Zhao, Caoxin Huang, Zheng Chen, Xiulin Shi, Long Li, Zhong Chen, and Xuejun Li

Objective

Exercise benefits people with nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify a panel of biomarkers and to provide the possible mechanism for the effect of exercise on NAFLD patients via an untargeted mass spectrometry-based serum metabolomics study.

Methods

NAFLD patients were classified randomly into a control group (n = 74) and a 6-month vigorous exercise (n = 68) group. Differences in serum metabolic profiles were analyzed using untargeted ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) technology. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to validate the differences between these two groups, and altered metabolites were obtained by ANOVA (fold change >2, P < 0.05) and identified with the online database Metlin and an in-house database.

Results

Metabolic profiling and multiple statistical analyses of the serum samples indicated significant differences between the NAFLD patients in the control and the 6-month vigorous exercise groups. Finally, 36 metabolites were identified between the control vs exercise groups. These metabolites were mainly associated with glycerophospholipid- and sphingolipid-related pathways.

Conclusion

Our study demonstrates that glycerophospholipid and sphingolipid alterations may contribute to the mechanism underlying the effect of exercise on NAFLD patients. A LC-MS-based metabolomics approach has a potential value for screening exercise-induced biomarkers.

DOI:
https://doi.org/10.1530/EC-19-0023
Volume 8: Issue 4,
Pages:
299–308 (10 total)
Open access

Machine learning identifies baseline clinical features that predict early hypothyroidism in patients with Graves’ disease after radioiodine therapy

Lian Duan, Han-Yu Zhang, Min Lv, Han Zhang, Yao Chen, Ting Wang, Yan Li, Yan Wu, Junfeng Li, and Kefeng Li

Background and objective

Radioiodine therapy (RAI) is one of the most common treatment solutions for Graves’ disease (GD). However, many patients will develop hypothyroidism as early as 6 months after RAI. This study aimed to implement machine learning (ML) algorithms for the early prediction of post-RAI hypothyroidism.

Methods

Four hundred and seventy-one GD patients who underwent RAI between January 2016 and June 2019 were retrospectively recruited and randomly split into the training set (310 patients) and the validation set (161 patients). These patients were followed for 6 months after RAI. A set of 138 clinical and lab test features from the electronic medical record (EMR) were extracted, and multiple ML algorithms were conducted to identify the features associated with the occurrence of hypothyroidism 6 months after RAI.

Results

An integrated multivariate model containing patients’ age, thyroid mass, 24-h radioactive iodine uptake, serum concentrations of aspartate aminotransferase, thyrotropin-receptor antibodies, thyroid microsomal antibodies, and blood neutrophil count demonstrated an area under the receiver operating curve (AUROC) of 0.72 (95% CI: 0.61–0.85), an F1 score of 0.74, and an MCC score of 0.63 in the training set. The model also performed well in the validation set with an AUROC of 0.74 (95% CI: 0.65–0.83), an F1 score of 0.74, and a MCC of 0.63. A user-friendly nomogram was then established to facilitate the clinical utility.

Conclusion

The developed multivariate model based on EMR data could be a valuable tool for predicting post-RAI hypothyroidism, allowing them to be treated differently before the therapy. Further study is needed to validate the developed prognostic model at independent sites.

DOI:
https://doi.org/10.1530/EC-22-0119
Volume 11: Issue 5
Open access

The association of adiponectin with risk of pre-diabetes and diabetes in different subgroups: cluster analysis of a general population in south China

Xun Gong, Lili You, Feng Li, Qingyu Chen, Chaogang Chen, Xiaoyun Zhang, Xiuwei Zhang, Wenting Xuan, Kan Sun, Guojuan Lao, Chuan Wang, Yan Li, Mingtong Xu, Meng Ren, and Li Yan

Objective

Adiponectin is an adipocyte-derived hormone with an important role in glucose metabolism. The present study explored the effect of adiponectin in diverse population groups on pre-diabetes and newly diagnosed diabetes.

Methods

A total of 3300 individuals were enrolled and their data were collected in the analyses dataset from December 2018 to October 2019. Cluster analysis was conducted based on age, BMI, waistline, body fat, systolic blood pressure, triglycerides, and glycosylated hemoglobin 1c. Cluster analysis divided the participants into four groups: a young-healthy group, an elderly-hypertension group, a high glucose–lipid group, and an obese group. Odds ratio (OR) and 95% CIs were calculated using multivariate logistic regression analysis.

Results

Compared with the first quartile of adiponectin, the risk of pre-diabetes of fourth quartile was decreased 61% (aOR = 0.39, 95% CI (0.20–0.73)) in the young-healthy group; and the risk of diabetes of fourth quartile was decreased 85% (aOR = 0.15, 95% CI (0.02–0.67)) in the obese group. There were no significant correlations between the adiponectin level and diabetes/pre-diabetes in the other two groups. Additionally, receiver operating characteristic curve analysis indicated that adiponectin could significantly improve the diagnosis based on models in the young-healthy group (from 0.640 to 0.675) and the obese group (from 0.714 to 0.761).

Conclusions

Increased adiponectin levels were associated with decreased risk of pre-diabetes in the young-healthy population, and with a decreased the risk of diabetes in the obese population. An increased adiponectin level is an independent protective factor for pre-diabetes and diabetes in a specific population in south China.

DOI:
https://doi.org/10.1530/EC-21-0235
Volume 10: Issue 11,
Pages:
1410–1419 (10 total)
Open access

Relationship between BRAF V600E and clinical features in papillary thyroid carcinoma

Changjiao Yan, Meiling Huang, Xin Li, Ting Wang, and Rui Ling

Objective

To investigate the mutant status of BRAF gene and analyze its relationship to epidemiological risk factors and clinical outcomes among patients with papillary thyroid cancer (PTC) in the largest, single-institution Chinese cohort to date.

Methods

The medical records of 2048 PTC patients were reviewed in this retrospective study. Single-factor and multiple logistic regression analyses were applied to identify risk factors for BRAF V600E mutation. Survival outcomes including distant metastatic and persistent or recurrent PTC were examined, with a mean follow-up time of 23.4 (5–47) months.

Results

The BRAF V600E mutation was present in 83.7% of patients (1715 of 2048). Correlation was found between BRAF V600E mutation and several epidemiological features, including age, concomitant hypertension and Hashimoto thyroiditis (HT). For the clinicopathological features, BRAF V600E was significantly associated with bilateral multifocality (odds ratio (OR) 1.233, 95% confidence interval (CI) 1.063–1.431, P < 0.01) and less lateral lymph node metastases (OR 0.496, 95% CI 0.357–0.689, P < 0.01). Smaller tumor size and advanced disease stage were significant in single-factor analyses but became insignificant after multivariate adjustment. No association was found between BRAF V600E mutation and extrathyroidal invasion, distant metastatic and disease persistence or recurrence.

Conclusion

Part of epidemiological features are independent risk or protective factors for BRAF V600E mutation. The presence of BRAF V600E mutation is not an aggressive prognosis on poor clinical outcomes in PTC. However, the high prevalence of BRAF V600E may provide guidance for surgery strategy and opportunity for targeted treatment in recurrent and advanced stage disease.

DOI:
https://doi.org/10.1530/EC-19-0246
Volume 8: Issue 7,
Pages:
988–996 (9 total)
Open access

Prevalence of antibodies targeting ubiquitin-conjugating enzyme 2L3 and eukaryote translation elongation factor 1 α1 in Chinese Han and American Caucasian populations with type 1 diabetes

Li Qian, Yuxiao Zhu, Yan Luo, Mu Zhang, Liping Yu, Yu Liu, and Tao Yang

We assessed the prevalence of two novel islet autoantibodies, those targeting ubiquitin-conjugating enzyme 2L3 (UBE2L3) and eukaryote translation elongation factor 1 α1 (eEF1A1), in type 1 diabetes mellitus (T1DM) to evaluate their utility in T1DM diagnosis with comparison to other islet autoantibodies. We also aimed to determine whether age and ethnicity impacted their diagnostic value. Electrochemiluminescence assay was used to detect UBE2L3-Ab and eEF1A1-Ab in 193 Chinese Han and 570 American Caucasian subjects with T1DM, and 282 Chinese Han and 199 American Caucasian controls. In Chinese and American cohorts, the UBE2L3-Ab cut-off indices were 0.039 and 0.038, and the eEF1A1-Ab cut-off indices were 0.048 and 0.050, respectively. The prevalence of UBE2L3-Ab was significantly higher in the Chinese (9.33%) and American (3.86%) subjects with T1DM than in the controls (P < 0.05). The prevalence of UBE2L3-Ab in T1DM was significantly higher in Chinese than in American (P < 0.05). Albeit not statistically significant, the prevalence of UBE2L3-Ab in T1DM was slightly higher in children than in adults of both ethnicities. The differences in eEF1A1-Ab levels between subjects with T1DM and controls were not significant. Meanwhile, all American subjects with UBE2L3-Ab also harbored glutamic acid decarboxylase autoantibody (GADA) or insulin autoantibody (IAA). In contrast, 2.07% of the Chinese subjects with UBE2L3-Ab positive were previously classified as autoantibody-negative based on GADA and IAA. So the prevalence of UBE2L3-Ab in T1DM patients was significantly higher than in controls and was variable according to ethnicity as well as tended to be higher in children than adults. However, UBE2L3-Ab and eEF1A1-Ab may not be reliable diagnostic biomarkers forT1DM.

DOI:
https://doi.org/10.1530/EC-22-0325
Volume 11: Issue 12
Open access

IL-34 causes inflammation and beta cell apoptosis and dysfunction in gestational diabetes mellitus

Chenghao Piao, Xiaojie Wang, Shiqiao Peng, Xinyu Guo, Hui Zhao, Li He, Yan Zeng, Fan Zhang, Kewen Zhu, and Yiwei Wang

Objective

Gestational diabetes mellitus (GDM) is characterized by glucose intolerance during gestation. It is associated with a series of maternal and foetal complications. Interleukin (IL)-34 is a recently discovered pro-inflammatory cytokine that functions as a ligand for colony-stimulating factor-1 receptor (CSF-1R). The contribution of IL-34 in the development of multiple chronic inflammatory diseases and autoimmune diseases has been recently discovered. The aim of this study was to evaluate whether IL-34 participates in the pathogenesis of GDM.

Method

A total of 120 women were enrolled in this study, which included 60 GDM patients and age- and sex-matched healthy pregnant women. The expression of IL-34 in serum, cord blood and placental tissues was analysed by ELISA and Western blot assays. The association between IL-34 levels and clinical features was also studied. We additionally evaluated the effect of recombinant mouse IL-34 (rmIL-34) on apoptosis and pancreatic β cell function.

Results

We found that IL-34 expression is highly increased in serum, cord blood and placental tissues in patients with GDM. In addition, there was a positive association between serum IL-34 and insulin resistance and glucose concentrations. Our data also revealed that IL-34 contributes to the apoptosis of pancreatic β cells in GDM caused by CSF-1R. Furthermore, functional studies found that IL-34 inhibited pancreatic β cell function and cell viability, while CSF-1R inhibitor blocked this effect.

Conclusion

IL-34 plays a crucial role in the development of GDM by targeting CSF-1R, insulin production and β cell function.

DOI:
https://doi.org/10.1530/EC-19-0436
Volume 8: Issue 11,
Pages:
1503–1512 (10 total)
Open access

Serum anti-Mullerian hormone predicts ovarian response in (Macaca fascicularis) monkeys

Hui Long, Yanhong Nie, Li Wang, Yong Lu, Yan Wang, Yijun Cai, Zhen Liu, Miaomiao Jia, Qifeng Lyu, Yanping Kuang, and Qiang Sun

AMH as a promising predictor of ovarian response has been studied extensively in women undergoing assisted reproductive technology treatment, but little is known about its prediction value in monkeys undergoing ovarian stimulation. In the current study, a total of 380 cynomolgus monkeys ranging from 5 to 12 years received 699 ovarian stimulation cycles. Serum samples were collected for AMH measure with enzyme-linked immunosorbent assay. It was found that serum AMH levels were positive correlated with the number of retrieved oocytes (P < 0.01) in the first, second and third stimulation cycles. In the first cycles, area under the curve (ROCAUC) of AMH is 0.688 for low response and 0.612 for high response respectively, indicating the significant prediction values (P = 0.000 and P = 0.005). The optimal AMH cutoff value was 9.68 ng/mL for low ovarian response and 15.88 ng/mL for high ovarian response prediction. In the second stimulation cycles, the significance of ROCAUC of AMH for high response rather than the low response was observed (P = 0.001 and P = 0.468). The optimal AMH cutoff value for high ovarian response was 15.61 ng/mL. In the third stimulation cycles, AMH lost the prediction value with no significant ROCAUC. Our data demonstrated that AMH, not age, is a cycle-dependent predictor for ovarian response in form of oocyte yields, which would promote the application of AMH in assisted reproductive treatment (ART) of female cynomolgus monkeys. AMH evaluation would optimize candidate selection for ART and individualize the ovarian stimulation strategies, and consequentially improve the efficiency in monkeys.

DOI:
https://doi.org/10.1530/EC-18-0189
Volume 7: Issue 9,
Pages:
983–989 (7 total)
Open access

Iodine nutritional status, the prevalence of thyroid goiter and nodules in rural and urban residents: a cross-sectional study from Guangzhou, China

Yuerong Yan, Lili You, Xiaoyi Wang, Zhuo Zhang, Feng Li, Hongshi Wu, Muchao Wu, Jin Zhang, Jiayun Wu, Caixia Chen, Xiaohui Li, Biwen Xia, Mingtong Xu, and Li Yan

Objectives

A variety of factors differed between rural and urban areas may further influence iodine status and thyroid structure. Hence, this study compared iodine nutrition, the prevalence of thyroid goiter, and nodules between rural and urban residents in Guangzhou, a southern coastal city of China.

Methods

A total of 1211 rural residents and 1305 urban residents were enrolled in this cross-sectional study. A questionnaire regarding personal characteristics was administered. Urinary iodine concentration (UIC) was examined. Ultrasonography of the thyroid was performed to evaluate thyroid goiter and nodules. Multiple logistic analysis was used to identify the potential associated factors.

Results

The median UIC was significantly lower in rural residents than in urban residents (120.80 μg/L vs 136.00 μg/L, P < 0.001). Although the coverage rate of iodized salt was much higher in rural residents than in urban residents (99.59% vs 97.29%, P < 0.001), the percentages of seafood intake (8.60% vs 29.29%, P < 0.001), iodine-containing drug consumption (0.33% vs 1.24%, P = 0.011), and iodine contrast medium injection (0.58% vs 1.87%, P = 0.004) were lower in rural residents than in urban residents. Both the prevalence of thyroid goiters and nodules was significantly higher in rural residents than in urban residents (goiter: 8.06% vs 1.20%, P < 0.001; nodules: 61.89% vs 55.04%, P = 0.023). Living in rural areas was associated with thyroid goiter (OR 5.114, 95% CI 2.893–9.040, P < 0.001).

Conclusions

There were differences in iodine nutrition and the prevalence of thyroid goiter and nodules in rural and urban residents in Guangzhou. Differentiated and specialized monitoring is recommended in our area.

DOI:
https://doi.org/10.1530/EC-21-0418
Volume 10: Issue 12,
Pages:
1550–1559 (10 total)
Open access

Serum levels of ghrelin and LEAP2 in patients with type 2 diabetes mellitus: correlation with circulating glucose and lipids

Jiaxi Li, Pu Huang, Jing Xiong, Xinyue Liang, Mei Li, Hao Ke, Chunli Chen, Yang Han, Yanhong Huang, Yan Zhou, Ziqiang Luo, Dandan Feng, and Chen Chen

Objective

Ghrelin regulates body weight, food intake, and blood glucose. It also regulates insulin secretion from pancreatic islet cells. LEAP2 is a newly discovered endogenous ligand of the growth hormone secretagogue’s receptor (GHSR). It not only antagonizes the stimulation of GHSR by ghrelin but also inhibits the constitutive activation of GHSR as an inverse agonist. Type 2 diabetes (T2D) patients have endocrine disorders with metabolic imbalance. Plasma levels of ghrelin and LEAP2 may be changed in obese and T2D patients. However, there is no report yet on circulating LEAP2 levels or ghrelin/LEAP2 ratio in T2D patients. In this study, fasting serum ghrelin and LEAP2 levels in healthy adults and T2D patients were assessed to clarify the association of two hormones with different clinical anthropometric and metabolic parameters.

Design

A total of 16 females and 40 males, ages 23–68 years old normal (n  = 27), and T2D patients (n  = 29) were enrolled as a cross-sectional cohort.

Results

Serum levels of ghrelin were lower but serum levels of LEAP2 were higher in T2D patients. Ghrelin levels were positively correlated with fasting serum insulin levels and HOMA-IR in healthy adults. LEAP2 levels were positively correlated with age and hemoglobin A1c (HbA1c) in all tested samples. Ghrelin/LEAP2 ratio was negatively correlated with age, fasting blood glucose, and HbA1c.

Conclusions

This study demonstrated a decrease in serum ghrelin levels and an increase in serum LEAP2 levels in T2D patients. LEAP2 levels were positively correlated with HbA1c, suggesting that LEAP2 was associated with T2D development. The ghrelin/LEAP2 ratio was closely associated with glycemic control in T2D patients showing a negative correlation with glucose and HbA1c.

DOI:
https://doi.org/10.1530/EC-22-0012
Volume 11: Issue 5
Open access

Single-cell transcriptomics of hepatic stellate cells uncover crucial pathways and key regulators involved in non-alcoholic steatohepatitis

Weiwei He, Caoxin Huang, Xiulin Shi, Menghua Wu, Han Li, Qiuhong Liu, Xiaofang Zhang, Yan Zhao, and Xuejun Li

Background

Fibrosis is an important pathological process in the development of non-alcoholic steatohepatitis (NASH), and the activation of hepatic stellate cell (HSC) is a central event in liver fibrosis. However, the transcriptomic change of activated HSCs (aHSCs) and resting HSCs (rHSCs) in NASH patients has not been assessed. This study aimed to identify transcriptomic signature of HSCs during the development of NASH and the underlying key functional pathways.

Methods

NASH-associated transcriptomic change of HSCs was defined by single-cell RNA-sequencing (scRNA-seq) analysis, and those top upregulated genes were identified as NASH-associated transcriptomic signatures. Those functional pathways involved in the NASH-associated transcriptomic change of aHSCs were explored by weighted gene co-expression network analysis (WGCNA) and functional enrichment analyses. Key regulators were explored by upstream regulator analysis and transcription factor enrichment analysis.

Results

scRNA-seq analysis identified numerous differentially expressed genes in both rHSCs and aHSCs between NASH patients and healthy controls. Both scRNA-seq analysis and in-vivo experiments showed the existence of rHSCs (mainly expressing a-SMA) in the normal liver and the increased aHSCs (mainly expressing collagen 1) in the fibrosis liver tissues. NASH-associated transcriptomic signature of rHSC (NASHrHSCsignature) and NASH-associated transcriptomic signature of aHSC (NASHaHSCsignature) were identified. WGCNA revealed the main pathways correlated with the transcriptomic change of aHSCs. Several key upstream regulators and transcription factors for determining the functional change of aHSCs in NASH were identified.

Conclusion

This study developed a useful transcriptomic signature with the potential in assessing fibrosis severity in the development of NASH. This study also identified the main pathways in the activation of HSCs during the development of NASH.

DOI:
https://doi.org/10.1530/EC-22-0502
Volume 12: Issue 2