Metabolomics was used to explore the effect of exercise intervention on type 2 diabetes. The rat model of type 2 diabetes was induced by an injection of streptozocin (30 mg/kg), after fed with 8-week high-fat diet. The rats were divided into three groups: the control group, the diabetic model group (DM) and the diabetes + exercise group (DME). After exercise for 10 weeks, blood samples were collected to test biomedical indexes, and 24-h urine samples were collected for the metabolomics experiment. In the DME group, fasting blood glucose (FBG), both total cholesterol (TC) and total plasma triglycerides (TG), were decreased significantly, compared with those in the DM group. Based on gas chromatography-mass spectrometry (GC/MS), a urinary metabolomics method was used to study the mechanism of exercise intervention on diabetes mellitus. Based on the principal component analysis (PCA), it was found that the DM group and control group were separated into two different clusters. The DME group was located between the DM group and the control group, closer to the control group. Twelve significantly changed metabolites of diabetes mellitus were detected and identified, including glycolate, 4-methyl phenol, benzoic acid, 1H-indole, arabinitol, threitol, ribonic acid, malic acid, 2,3-dihydroxy-butanoic, aminomalonic acid, l-ascorbic acid and 3-hydroxy hexanedioic acid. After exercise, seven metabolites were significantly changed, compared with the control group, the relative contents of benzoic acid, aminomalonic acid, tetrabutyl alcohol and ribonucleic acid in the diabetic exercise group decreased significantly. The relative contents of 2,3-dihydroxybutyric acid, l-ascorbic acid and 3-hydroxy adipic acid increased significantly. l-ascorbic acid and aminomalonic acid which related with the oxidative stress were significantly regulated to normal. The results showed that exercise could display anti-hyperglycemic and anti-hyperlipidemic effects. The exercise had antioxidation function in preventing the occurrence of complications with diabetes mellitus to some extent. The work illustrates that the metabolomics method is a useful tool to study the mechanism of exercise treatment.
Li Jing and Wang Chengji
Li Li, Qifa Song and Xi Yang
Insufficient insulin release plays a crucial role in the development of unhealthy status in patients with obesity; the present study aimed to classify these patients by the indices for insulin resistance and insulin release. After the indices from OGTT were assessed to achieve high differentiability and low redundancy in classifying patients, HOMA-IR and IGI30min were chosen to classify the patients using K-means clustering method. A total of 249 non-diabetic patients with obesity were classified into four groups. In Group 1, 19 patients were characteristic of high insulin resistance and high insulin release, as well as well-controlled glucose levels, the highest BMI, the youngest age, and the highest early phase release of insulin. In Group 2, 38 patients were unhealthiest in terms of high insulin resistance, reduced insulin release and IGT status. Group 3 consisted of 63 patients that were healthiest with low insulin resistance and high insulin release. In Group 4, 46 IGT patients and 14 IFG patients were identified among 129 patients that showed low insulin resistance, low insulin release, moderate obesity and older age. These concurrent impotent insulin release, older age, and moderate obesity indicated decreasing obesity with increasing age and reduced insulin release. The classification of patients with obesity using K-means clustering method by HOMA-IR and IGI30min provides more information about the development of obesity and unhealthy status. The patients with distinct insulin resistance and insulin release should be followed up, especially for those with reduced or even absent insulin response to glucose stimulation.
Jia Li, Yan Zhao, Caoxin Huang, Zheng Chen, Xiulin Shi, Long Li, Zhong Chen and Xuejun Li
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.
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.
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.
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.
Ping Li, Fei Cheng and Lei Xiu
This study sought to determine the effect of the recombinant human growth hormone (rhGH) treatment of Turner syndrome (TS) on height outcome.
We searched in MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. A literature search identified 640 records. After screening and full-text assessment, 11 records were included in the systematic review. Methodological quality was assessed using the Cochrane Risk of Bias tool. RevMan 5.3 software was used for meta-analysis. We also assessed the quality of evidence with the GRADE system.
Compared with controls, rhGH therapy led to increased final height (MD = 7.22 cm, 95% CI 5.27–9.18, P < 0.001, I2 = 4%; P = 0.18), height standard deviation (HtSDS) (SMD = 1.22, 95% CI 0.88–1.56, P < 0.001, I2 = 49%; P = 0.14) and height velocity (HV) (MD 2.68 cm/year; 95% CI 2.34, 3.02; P < 0.001, I2 = 0%; P = 0.72). There was a small increase in bone age (SMD 0.32 years; 95% CI 0.1, 0.54; P = 0.004, I2 = 73%; P = 0.02) after rhGH therapy for 12 months. What is more, the rhGH/oxandrolone combination therapy suggested greater final height (MD 2.46 cm; 95% CI 0.73, 4.18; P = 0.005, I2 = 32%; P = 0.22), increase and faster HV (SMD 1.67 cm/year; 95% CI 1.03, 2.31; P < 0.03, I2 = 80%; P < 0.001), with no significant increase in HtSDS and bone maturation compared with rhGH therapy alone.
For TS patients, rhGH alone or with concomitant use of oxandrolone treatment had advantages on final height.
Wei Li, Qing Huang, Danyang Sun, Guizhi Zhang and Jian Tan
RAD52 motif containing 1 (RDM1) encodes the RAD52 protein involved in DNA double-strand break repair and recombination events. However, the importance of RDM1 in papillary thyroid carcinoma (PTC) is largely unknown. In the present study, we examined the role of RDM1 in thyroid cancer. The RDM1 expression in PTC patients was examined using immunohistochemistry. The expression levels of RDM1 mRNA in thyroid cancer cells were measured by quantitative real-time PCR (qRT-PCR). Lentivirus-mediated small interfering RNAs (siRNAs) were used to knock down the RDM1 expression in the K1 and TPC1 cells. Then, changes in the RDM1 target gene expression were determined by qRT-PCR and Western blot. Cell proliferation was examined by a high content screening assay. Cell cycle distribution and apoptosis were detected by flow cytometric analysis and MTT analysis. We showed that the RDM1 expression was higher in PTC tissue compared to pericarcinous tissue. RDM1 mRNA was found to be expressed by qRT-PCR. Using a lentivirus-based RNA interference (RNAi) approach, the RDM1 expression was significantly inhibited. The inhibition of RDM1 expression by RNAi significantly impaired cell proliferation, increased apoptosis and arrested cells in the G2/M phase. These data showed that RDM1 was highly expressed in PTC tissue and thyroid cancer cell lines. Moreover, RDM1 may play an important role in cell proliferation, cell cycle distribution and apoptosis of human PTC cells.
Yongping Liu, Shuo Wang, Qingling Guo, Yongze Li, Jing Qin, Na Zhao, Yushu Li, Zhongyan Shan and Weiping Teng
Hashimoto’s thyroiditis (HT) is characterized by elevated specific auto-antibodies, including TgAb and TPOAb. Increasing evidence has demonstrated the essential role of Th17 cells in HT. However, the underlying mechanism is still unclear. Semaphorin 5A (Sema 5A) is involved in several autoimmune diseases through the regulation of immune cells. The aim of the present study was to explore the role of Sema 5A in HT.
We measured serum Sema 5A levels in HT (n = 92) and healthy controls (n = 111) by enzyme-linked immunosorbent assay (ELISA). RNA levels of Sema 5A and their receptors (plexin-A1 and plexin-B3), as well as several cytokines (IFN-γ, IL-4 and IL-17), were detected by real-time polymerase chain reaction in peripheral blood mononuclear cells from 23 patients with HT and 31 controls. In addition, we investigated the relationship between serum Sema 5A and HT.
Serum Sema 5A in HT increased significantly compared with healthy controls (P < 0.001). Moreover, serum Sema 5A levels were positively correlated with TgAb (r = 0.511, P < 0.001), TPOAb (r = 0.423, P < 0.001), TSH (r = 0.349, P < 0.001) and IL-17 mRNA expression (r = 0.442, P < 0.001). Increased Sema 5A RNA expression was observed (P = 0.041) in HT compared with controls. In receiver-operating characteristic (ROC) analysis, serum Sema 5A predicted HT with a sensitivity of 79.35% and specificity of 96.40%, and the area under the curve of the ROC curve was 0.836 (95% CI: 0.778–0.884, P < 0.001).
These data demonstrated elevated serum Sema 5A in HT patients for the first time. Serum Sema 5A levels were correlated with thyroid auto-antibodies and IL-17 mRNA expression. Sema 5A may be involved in immune response of HT patients.
Lu Liu, Chunyan Li, Peng Yang, Jian Zhu, Dongmei Gan, Le Bu, Manna Zhang, Chunjun Sheng, Hong Li and Shen Qu
Alendronate (ALN) is a commonly used drug for the treatment of osteoporosis. Atypical femur fractures (AFFs) have been associated with long-term use of ALN and have recently become the subject of considerable attention as ALN use increases. This meta-analysis aimed to determine the relationship between ALN and AFF. The Embase, PubMed, and Cochrane library databases were searched for relevant studies published before November 6, 2014. Studies clearly reporting the relationship between ALN and AFF were selected for our analysis. From these results, the relationship between ALN and AFF was analyzed. Weighted mean differences were calculated using a random-effects model. Five studies were included in this meta-analysis. The results revealed that the use of ALN will not increase the risk of AFF in short term (P>0.05), but there will be a risk of AFF (P<0.05) with long-term (>5 years) use of ALN. These findings indicate that long-term use of ALN is a risk factor for AFF and that more attention should be paid to the clinical applications of ALN.
Tao Yuan, Lanping Jiang, Chen Chen, Xiaoyan Peng, Min Nie, Xuemei Li, Xiaoping Xing, Xuewang Li and Limeng Chen
Impaired glucose metabolism and insulin sensitivity have been reported in patients with Gitelman syndrome (GS), but insulin secretion and the related mechanisms are not well understood.
Design and methods
The serum glucose levels, insulin secretion and insulin sensitivity were evaluated in patients with GS (n = 28), patients with type 2 diabetes mellitus (DM) and healthy individuals (n = 20 in both groups) using an oral glucose tolerance test. Serum and urine sodium, potassium and creatinine levels were measured at 0, 30, 60, 120 and 180 min after an oral glucose load was administered.
The areas under the serum glucose curves were higher in the GS patients than those in the healthy controls (17.4 ± 5.1 mmol·h/L vs 14.5 ± 2.8 mmol·h/L, P = 0.02) but lower than those in the DM patients (24.8 ± 5.3 mmol·h/L, P < 0.001). The areas under the serum insulin curves and the insulin secretion indexes in GS patients were higher than those in DM patients and lower than those in healthy subjects. The insulin secretion-sensitivity index of GS patients was between that of healthy subjects and DM patients, but the insulin sensitivity indices were not different among the three groups. After one hour of glucose administration, the serum potassium level significantly decreased from baseline, and the urinary potassium-to-creatinine ratio increased gradually and peaked at 2 h.
Glucose metabolism and insulin secretion were impaired in GS patients, but insulin sensitivity was comparable between GS patients and patients with type 2 DM. After administration of an oral glucose load, the plasma potassium level decreased in GS patients due to the increased excretion of potassium in the urine.
Chunyun Fu, Shiyu Luo, Yingfeng Li, Qifei Li, Xuehua Hu, Mengting Li, Yue Zhang, Jiasun Su, Xuyun Hu, Yun Chen, Jin Wang, Bobo Xie, Jingsi Luo, Xin Fan, Shaoke Chen and Yiping Shen
The incidence of congenital hypothyroidism (CH) differs significantly among different ethnicities and regions, and early differentiation of transient CH is important to avoid unnecessary prolonged treatment with L-T4.
To investigate the incidence of CH based on the newborn screening program in Guangxi Zhuang Autonomous Region, China, and to analyze the predictors that might allow for an early differentiation between permanent (P) and transient (T) CH.
Design and methods
Data from newborn screening program over a seven-year period (January 2009 to January 2016) at Guangxi Maternal and Child Health Hospital are analyzed. Blood samples were collected on filter paper between 3 and 7 days after birth, and TSH level was measured by time-resolved fluorescence assay. Individuals with increased TSH (TSH ≥ 8 IU/L) levels detected by newborn screening were recalled for further evaluation. Serum TSH, FT3 and FT4 were determined by electrochemiluminescence assay using venous blood samples. Diagnosis of CH is based on elevated TSH levels (>10 IU/L) and decreased FT4 levels (<12 pmol/L). Patients with elevated TSH levels and normal FT4 levels were diagnosed as hyperthyrotropinemia. Permanent or transient CH was determined by using the results of thyroid function tests after temporary withdrawal of L-T4 therapy at approximately 2–3 years of age.
Among 1,238,340 infants in the newborn screening program, 14,443 individuals were recalled for reevaluation (re-call rate 1.18%), 911 and 731 individuals were subsequently determined to have hyperthyrotropinemia and CH respectively; thus, a prevalence of 1:1359 and 1:1694 for hyperthyrotropinemia and CH. Of the 731 patients with CH, 161 patients were diagnosed with permanent CH (PCH), and 159 patients were diagnosed with transient CH (TCH), the other 411 patients are too young to determine their subtypes. Patients with PCH required an increasing dose of L-T4 during the first few years, whereas patients with TCH required a decreased dose of L-T4. The TSH levels at diagnosis and the dose of L-T4 used were significantly higher in PCH cases than in transient cases. The FT4 levels at diagnosis were significantly lower in PCH cases than in TCH cases. The TSH levels at diagnosis, FT4 levels at diagnosis and L-T4 doses at 90 days were evaluated as predictors for differentiating PCH and TCH, and their accuracy at their respective optimal cutoffs were determined to be 60.6%, 66.7% and 93.9%, respectively.
The CH incidence in Guangxi Zhuang Autonomous Region is slightly higher (1:1694) compared to the worldwide levels (1/2000–1/4000). The PCH and TCH ratio is close to 1; thus, the estimated PCH incidence is 1/3388, which is similar to reported worldwide average incidence (1/3000). The L-T4 dose required at 90 days (>30 μg/day) has the highest predictive value for PCH. Earlier differentiation of PCH and TCH helps to determine appropriate treatment course.
Jing Wang, Leishen Wang, Huikun Liu, Shuang Zhang, Junhong Leng, Weiqin Li, Tao Zhang, Nan Li, Wei Li, Andrea A Baccarelli, Lifang Hou and Gang Hu
Previous studies found conflicting results about the associations between the exposure to hyperglycemia in utero and the later risks of childhood overweight and obesity. The aim of the present study is to compare the children’s BMI growth between offspring exposed to maternal gestational diabetes mellitus (GDM) and those not exposed and assess the associations between maternal GDM and their offspring’s overweight and obesity risk. We performed a large observational study in 1156 women and their offspring (578 GDM and 578 non-GDM mother–child pairs, matched by their offspring’s gender and age). Maternal GDM was diagnosed according to the World Health Organization criteria. Childhood height, weight, waist circumference, body fat and skinfold were measured using standardized methods. After adjustment for maternal and children’s characteristics, children born to mothers with GDM during pregnancy had higher mean values of Z scores for BMI-for-age, Z scores for weight-for-age, waist circumferences, body fat, subscapular skinfold and suprailiac skinfold, in comparison with their counterparts born to mothers with normal glucose during pregnancy (all P values <0.05). Moreover, maternal GDM was associated with a higher risk of childhood overweight and obesity with multivariate-adjusted odds ratios of 1.42 (95% confidence interval (CI): 1.02–1.97) and 1.18 (95% CI: 1.11–1.24), respectively, compared with the children of mothers without GDM during pregnancy. This study demonstrates that maternal GDM is an independent risk factor of childhood overweight and obesity and is associated with higher BMI in the offspring.