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γ-Aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent β-cell survival and function. In human β-cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1RA drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin (Sita), a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic β-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human β-cell. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, Sita, or both. The oral administration of either GABA or Sita ameliorated blood glucose levels, increased transplanted human β-cell counts and plasma human insulin levels. Importantly, the combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. The proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, PDX-1+, or Nkx6.1+ β-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of α-Klotho, a protein with protective and stimulatory effects on β cells, was also augmented. Our study indicates that combined use of GABA and Sita produced greater therapeutic benefits, which are likely due to an enhancement of β-cell proliferation and a decrease in apoptosis.

Vascular muscle cells (VSMCs) participate in the pathophysiology of atherosclerosis. Resistin-like molecule beta (Relmβ) contributes to atherosclerosis development by activating macrophage. This study aims to investigate whether Relmβ regulates VSMC phenotypic modulation under high glucose environment. Human aortic vascular smooth muscle cells were cultured and treated with Relmβ in the presence or absence of high glucose. VSMC phenotypic modulation was assessed by expression of related markers. The migration of VSMCs was detected by wound healing assay and transwell assay. The proliferation of VSMCs was measured using CCK-8 assay. In this study, we observed that Relmβ modulated VSMC phenotypic modulation by down-regulating expression of smooth muscle α-actin (α-SMA), smooth muscle myosin heavy chain (SM-MHC), and calponin while up-regulating expression of osteopontin (OPN). Relmβ increased the expression of inflammatory genes in VSMCs. Relmβ also augmented VSMCs migration as well as proliferation. It is worth noting that all the effects of VSMCs were enhanced upon high glucose stimulation. The phosphorylation levels of p38MAPK and ERK1/2 were increased by co-treatment with Relmβ and high glucose. The p38 MAPK pathway inhibitor RWJ64809 and pERK1/2 inhibitor PD98059 significantly inhibited the proliferation of VSMCs induced by Relmβ and high glucose. Our results provide evidence that Relmβ augments phenotypic modulation and migration of human aortic smooth muscle cell induced by high glucose. Relmβ might be a potential target for treatment of atherosclerosis induced by hyperglycemia.

Background Islet autoantibodies occur in type 2 diabetes. Our study aimed to investigate the prevalence of positive islet autoimmunity in community patients with type 2 diabetes. Methods A total of 495 community patients with type 2 diabetes were recruited using the method of cluster sampling in this cross-sectional study. Three islet autoantibodies including glutamic acid decarboxylase antibody (GADA), insulin autoantibody (IAA) and islet cell antibody (ICA) were measured, and clinical characteristics involved in those individuals were evaluated. Results The positive rate of islet autoantibodies was 28.5% in total, while combinations of different autoantibodies were rarely seen. Compared with GADA-negative group, positive counterparts significantly tended to have lower levels of body mass index (BMI), waist-hip ratio (WHR), and urinary microalbumin (mALB) (P P P P P = 0.064). Conclusion These data suggested that type 2 diabetic community patients with positive GADA tended to be lean and were able to maintain normal lipid metabolism, while patients with positivity of IAA were frequently accompanied with insulin treatment and more closely associated with diabetic liver damage.

BackgroundSolitary intracranial hypothalamic mass occurs rarely. The etiological diagnosis of solitary hypothalamus lesion is challenging and often unachievable. Although previous studies indicated that lesions affecting the hypothalamus often cause significant metabolic disorders, few reports about the metabolic disturbances of patients with solitary hypothalamic mass have been reported.MethodTwenty-five patients with solitary hypothalamus lesions who had been evaluated and treated in Huashan Hospital from January 2010 to December 2020 were retrospectively enrolled. The clinical manifestations, radiological features, endocrine and metabolic disorders, and pathology were analyzed.ResultsThe male to female ratio was 5/20. The median age of onset was 22 (19, 35) years old. The most common initial symptom was polydipsia/polyuria (19/25, 76.0%) and amenorrhea (9/20, 45.0%). A high prevalence of hypopituitarism of different axes was found, with almost all no less than 80%. Central hypogonadism (21/22, 95.5%) and central diabetes insipidus (19/21, 90.5%) were the top two pituitary dysfunctions. Conclusive diagnoses were achieved by intracranial surgical biopsy/resection or stereotactic biopsy in 16 cases and by examining extracranial lesions in 3 cases. The pathological results were various, and the most common diagnoses were Langerhans cell histiocytosis (7/19) and hypothalamitis (5/19). The mean timespan from onset to diagnosis in the 19 cases was 34 ± 26 months. Metabolic evaluations revealed remarkable metabolic disorders, including hyperlipidemia (13/16, 81.3%), hyperglycemia (10/16, 62.5%), hyperuricemia (12/20, 60%), overweight/obesity (13/20, 65.0%), and hepatic adipose infiltration (10/13, 76.6%).ConclusionEither surgical or stereotactic biopsy will be a reliable and relatively safe procedure to help to confirm the pathological diagnosis of solitary hypothalamic mass. Metabolic disorders were severe in patients with solitary hypothalamic mass. The management of such cases should cover both the treatment of the primary disease, as well as the endocrine and metabolic disorders

Background Exercise is generally recognized as beneficial to prevent obesity; however, it is not clear which indicator can better reflect the benefits, especially in adolescents. The aim of this study was to describe the effects of exercise on body mass and fat indexes and to clarify the significance of different indexes in clinical use. Methods We conducted a prospective cohort study involving 1,941 freshmen from 2014, followed-up biennially until 2018. Various body mass and fat indexes, including weight, height, waist and hip circumference and body fat percentage (BFP), were measured. Physical activity and other variables were collected by questionnaire. All study participants were divided into two groups according to the frequency and intensity of exercise. Results Compared with the low frequency and intensity exercise group, the high frequency and intensity exercise group had a lower increase in BFP during the 4-year follow-up, and no significant differences were observed in the changes of other indexes between the groups. Even after adjusting, the high frequency and intensity exercise group still exhibited a higher likelihood of reducing BFP. Conclusions High frequency and intensity exercise provides benefits for reducing BFP. No other body mass or fat indexes showed any association. BFP could be a much more sensitive indicator to detect and control obesity in adolescents.

Qilin Sun,1,* Xiaoyan Wu,1,* Hao Wang,2 Wenjie Chen,1 Xuelan Zhao,1 Yehong Yang,3 Wei Chen1,* 1Department of Geriatrics, Huashan Hospital, Fudan University, Shanghai 200040, People’s Republic of China; 2Experimental Teaching Center of Basic Medicine, Fudan University, Shanghai 200032, People’s Republic of China; 3Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai 200040, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei ChenDepartment of Geriatrics, Huashan Hospital, Fudan University, No.12 Wu-lu-mu-qi Road, Shanghai 200040, People’s Republic of ChinaTel +86 21 5288999ext 7190 Email chenwei_0424@163.comYehong YangDepartment of Endocrinology, Huashan Hospital, Fudan University, No.12 Wu-lu-mu-qi Road, Shanghai 200040, People’s Republic of ChinaTel +86 21 5288999Email yehongyang@126.comBackground: Oxidative stress in cardiac myocytes is an important pathogenesis of diabetic cardiomyopathy (DCM). Previously, we reported that astragalus polysaccharide (APS) has protective effects against the oxidative stress of DCM. This study aimed to determine the effect of APS on the oxidative stress induced by hyperglycemia in H9C2 cells.Methods: Rat H9C2 cells were cultured in vitro and randomly divided into the control group, HG group, APS-HG group, siRNASOD2 group, and APS-siRNASOD2 group. The cellular ultrastructure was measured by transmission electron microscopy. Cell apoptosis was examined by TUNEL staining. Levels of reactive oxygen species (ROS) were detected by a quantitative fluorescence assay (DHE). 8-OH-dG and nitrotyrosine, the indicators of oxidative stress injury, were detected by immunohistochemistry. A PCR array was used to evaluate the expression levels of 84 oxidative stress genes in cultured cells, and the PCR array results were partially verified by Western blot.Results: APS treatment protected the H9C2 cell ultrastructure, reduced the level of cell apoptosis, inhibited cellular ROS production, and reduced the levels of oxidative stress injury indicators 8-OH-dG and nitrotyrosine in high glucose-induced or SOD2-silenced H9C2 cells. It also altered oxidative stress-related genes at the mRNA and protein levels.Conclusion: APS may improve antioxidant capacity and inhibit oxidative stress injury in high glucose induced H9C2 cells.Keywords: diabetic cardiomyopathy, cardiomyocyte, oxidative stress, ROS, PCR array, astragalus polysaccharide

Background Postprandial hypoglycemia and early dumping syndrome are common complications after bariatric surgery. Although sleeve gastrectomy (SG) has become a primary option for many bariatric surgeons, limited information was available for the prevalence and risk factors of the complications. Objective To assess the prevalence and possible risk factors for postprandial hypoglycemia and early dumping syndrome based on self-reported symptoms of SG patients. Setting The study was conducted at a bariatric surgery center in a university hospital. Methods In this study, all patients who underwent an SG (n = 222) between December 2011 and May 2018 in our center were invited to participate in a questionnaire survey. The Edinburgh Hypoglycemia Scoring System and the Dumping Symptom Rating Scale were used to evaluate symptoms, and clinical data of the patients were collected. The median follow-up time was 1.1 years. Results The questionnaire was completed and returned by 54.95% (122/222) of the patients and 62.30% (76/122) of the responders were women. The prevalence rates of mild and moderate symptoms suggestive of hypoglycemia were 65.57% (80/122) and .82%, respectively. An associated risk factor was younger age (adjusted for sex, body mass index, and waist circumference at baseline: odds ratio 3.69; 95% confidence interval [1.22–11.21]), but this association disappeared after further adjustment of low-density protein cholesterol (LDL-C) (odds ratio 6.42; 95% confidence interval [.38–108],;P > .05). The prevalence rate of mild symptoms suggestive of early dumping was 40.98% (50/122), associated risk factor was lower LDL-C. Conclusion Mild-to-moderate symptoms suggestive of hypoglycemia and early dumping syndrome were common in patients after SG, with the prevalence rates of 66.39% (81/122) and 40.98% (50/122), respectively. Patients with both symptoms suggestive of early dumping syndrome and hypoglycemia accounted for 33.61% (41/122) of all patients. Younger age indicated higher risk of hypoglycemia after SG and lower LDL-C may play an important role in this relationship. Lower LDL-C was associated with higher risk of early dumping syndrome after SG.

Objective The aim of this study was to evaluate thyroid functions in Cushing’s syndrome (CS), the dynamic changes of thyroid hormones and antithyroid antibodies in Cushing’s disease (CD) pre- and postoperatively. Design and methods This is a retrospective study enrolling 118 patients with CS (102 CD, 10 adrenal CS and 6 ectopic adrenocorticotropic syndrome (EAS)). Thyroid functions (thyroid-stimulation hormone (TSH), T3, free T3 (FT3), T4 and free T4 (FT4)) were measured in all CS at the time of diagnosis and in all CD 3 months after transsphenoidal pituitary tumor resection. Postoperative hormone monitoring within 3 months was conducted in 9 CD patients completing remission. Twenty-eight remitted CD patients experienced hormone and antithyroid antibody evaluation preoperatively and on the 3rd, 6th and 12th month after surgery. Results TSH, T3 and FT3 were below the reference range in 31%, 69% and 44% of the 118 CS patients. Remitted CD patients (81/102) had significantly higher TSH (P = 0.000), T3 (P = 0.000) and FT3 (P = 0.000) than those in the non-remission group (21/102). After remission of CD, TSH, T3 and FT3 showed a significant increase, with a few cases above the reference range. By 12 months, most CD patients’ thyroid functions returned to normal. Thyroid hormones (including TSH, T3 and FT3) were negatively associated with serum cortisol levels both before and after surgery. No significant changes of antithyroid autoantibodies were observed. Conclusions TSH, T3 and FT3 are suppressed in endogenous hypercortisolemia. After remission of CD, TSH, T3 and FT3 increased significantly, even above the reference range, but returned to normal 1 year after surgery in most cases. Antithyroid antibodies did not change significantly after remission of CD.

Objective Craniopharyngiomas have traditionally been resected through the transcranial approaches (TCA). The endoscopic endonasal approach (EEA) has recently been developed as an alternative for surgeons, but controversy remains regarding which approach has better outcomes. We compared the endocrine and metabolic outcomes of TCA and EEA in patients who underwent primary resection of craniopharyngiomas. Methods A retrospective analysis was conducted of patients with craniopharyngioma who were treated by the department of endocrinology and metabolism at our institution between 2011 and 2015. Results Of 43 patients assessed, 26 underwent TCA and 17 underwent EEA. After surgery, 29.4% (5/17) of patients in the EEA group had normal anterior pituitary function, whereas none in the TCA group had complete anterior pituitary function. Higher prevalences of corticotropic deficiency (92.3% vs. 52.9%, P = 0.009), thyrotrophic deficiency (96.2% vs. 52.9%, P = 0.003), and hypogonadotropic hypogonadism (100% vs. 70.6%, P = 0.014) were found in the TCA group. The TCA group showed a trend toward having more patients with at least 3 anterior pituitary deficits (88.5% vs. 58.8%, P = 0.060). The mean body mass index at last follow-up tended to be lower in the EEA group (24.13 ± 3.16 kg/m2 vs. 26.79 ± 4.5 kg/m2, P = 0.079), and the preoperative body mass index was comparable between groups. Similar prevalences of overweight/obesity, hypertension, hyperglycemia, and metabolic syndrome were detected in the 2 groups. Moreover, no significant differences were observed in the rates of cerebrospinal fluid leakage and intracranial infection between the 2 groups. Conclusions EEA may provide the same gross total resection rate for craniopharyngioma as TCA while providing better protection of anterior pituitary function.

BackgroundCathepsin S, as an adipokine, was reported to play a critical role in various disease, including atherosclerosis and diabetes. The present study aims to elucidate the relationship between circulating cathepsin S and cardiovascular disease (CVD) in patients with type 2 diabetes.MethodsA total of 339 type 2 diabetes individuals were enrolled in this cross-sectional community-based study. Basic information, medical and laboratory data were collected. Serum cathepsin S levels were assessed by ELISA.ResultsCompared to the CVD (−) group, levels of serum cathepsin S were significantly higher in the CVD (+) group, with the median 23.68 ng/ml (18.54–28.02) and 26.81 ng/ml (21.19–37.69) respectively (P < 0.001). Moreover, patients with acute coronary syndrome (ACS) had substantially higher levels of serum cathepsin S than those with stable angina pectoris (SAP), with the median 34.65 ng/ml (24.33–42.83) and 25.52 ng/ml (20.53–31.47) respectively (P < 0.01). The spearman correlation analysis showed that circulating cathepsin S was correlated with several cardiovascular risk factors. The univariate and multivariate logistic regression analysis revealed that circulating cathepsin S was an independent risk factor for CVD (all P < 0.001) after adjustment for potential confounders. Restricted cubic spline analysis showed circulating cathepsin S had a linearity association with CVD. In addition, receiver operating characteristic (ROC) curve analysis demonstrated that the area under curve (AUC) values of cathepsin S was 0.80 (95% CI: 0.75–0.84, P < 0.001), with the optimal cutoff value of cathepsin 26.28 ng/ml.ConclusionCirculating cathepsin S was significantly higher in the CVD (+) group than that in the CVD (−) one among type 2 diabetes. The increased serum cathepsin S levels were associated with increased risks of CVD, even after adjusting for potential confounders. Thus, cathepsin S might be a potential diagnostic biomarker for CVD.

Background The TM4 (UBAC2) protein, which contains 4 transmembrane domains and one ubiquitin binding domain, is mainly expressed in cell and nuclear membranes. The current research aimed to explore the role of TM4 in metabolic inflammation and to examine whether the ubiquitin–proteasome inhibitor PS-341 could regulate the function of TM4. Methods The metabolic phenotypes of TM4 knockout (KO) mice were studied. We next explored the association between the polymorphisms of TM4 and obesity in a Chinese Han population. TM4 expression in the visceral fat of obese patients who underwent laparoscopic cholecystectomy was also analysed. Finally, the effect of PS-341 on the degradation and function of the TM4 protein was investigated in vivo and in vitro. Results TM4 KO mice developed obesity, hepatosteatosis, hypertension, and glucose intolerance under a high-fat diet. TM4 counterregulated Nur77, IKKβ, and NF-kB both in vivo and in vitro. The TM4 SNP rs147851454 is significantly associated with obesity after adjusting for age and sex (OR 1.606, 95% CI 1.065–2.422 P = 0.023) in 3394 non-diabetic and 1862 type 2 diabetic adults of Han Chinese. TM4 was significantly downregulated in the visceral fat of obese patients. PS-341 induced TM4 expression through inhibition of TM4 degradation in vitro. In db/db mice, PS-341 administration led to downregulation of Nur77/IKKβ/NF-κB expression in visceral fat and liver, and alleviation of hyperglycaemia, hypertension, and glucose intolerance. The hyperinsulinaemic-euglycaemic clamp demonstrated that PS-341 improved the glucose infusion rate and alleviated insulin resistance in db/db mice. Conclusions PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through inhibition of TM4 degradation.

BackgroundEarly alarm of hypoglycemia, detection of asymptomatic hypoglycemia, and effective control of blood glucose fluctuation make a great contribution to diabetic treatment. In this study, we designed a multi-level hypoglycemia early alarm system to mine potential information in Continuous Glucose Monitoring (CGM) time series and improve the overall alarm performance for different clinical situations.MethodsThrough symbolizing the historical CGM records, the Prefix Span was adopted to obtain the early alarm/non-alarm frequent sequence libraries of hypoglycemia events. The longest common subsequence was used to remove the common frequent sequence for achieving the hypoglycemia early alarm in different clinical situations. Then, the frequent sequence pattern libraries with different risk thresholds were designed as the core module of the proposed multi-level hypoglycemia early alarm system.ResultsThe model was able to predict hypoglycemia events in the clinical dataset of level-I (sensitivity 85.90%, false-positive 23.86%, miss alarm rate 14.10%, average early alarm time 20.61 min), level-II (sensitivity 80.36%, false-positive 17.37%, miss alarm rate 19.63%, average early alarm time 27.66 min), and level-III (sensitivity 78.07%, false-positive 13.59%, miss alarm rate 21.93%, average early alarm time 33.80 min), respectively.ConclusionsThe proposed approach could effectively predict hypoglycemia events based on different risk thresholds to meet different prevention and treatment requirements. Moreover, the experimental results confirm the practicality and prospects of the proposed early alarm system, which reflects further significance in personalized medicine for hypoglycemia prevention.

Background Metformin, a traditional first-line anti-hyperglycemic agent for diabetes, recently exhibits better antitumor effect in hepatocellular carcinoma (HCC). However, its resistance and tolerance mechanism in HCC remains largely unknown. Here, we investigated whether increased matrix stiffness attenuated the intervention effects of metformin on HCC invasion and metastasis, and explored its underlying molecular mechanism. Methods FN-coated gel substrates with 6, 10, and 16 kPa, which simulated the stiffness of normal, fibrotic, and cirrhotic liver tissues respectively, were established to evaluate matrix stiffness-mediated effects on HCC cells. Alterations in morphology, proliferation, motility, and invasive/metastatic-associated genes (PTEN, MMP2, MMP9) of HCC cells grown on different-stiffness substrates were comparatively analyzed before and after metformin intervention. Subsequently, the underlying molecular mechanism by which higher matrix stiffness attenuates antitumor effects of metformin in HCC was further elucidated. Results Metformin significantly inhibited proliferation, migration, and invasion of HCC cells. Compared with the controls on lower-stiffness substrate, HCC cells grown on higher-stiffness substrate exhibited an obvious resistance to intervention effects of metformin on proliferation, migration, invasion and metastasis. High stiffness stimulation significantly activated the miR-17-5p/PTEN/PI3K/Akt signaling pathway in HCC cells via integrin β1 and in turn resulted in MMP2 and MMP9 upregulation. Meanwhile, integrin β1 knockdown or PI3K inhibitor partially reversed the activation of the above signaling molecules. For HCC cells grown on the same-stiffness substrate, metformin remarkably upregulated PTEN expression and suppressed the activation of the PI3K/Akt/MMP pathway, but no effect on integrin β1 expression. Importantly, the increase in fold of PTEN expression and decrease in folds of Akt phosphorylation level and MMP2 and MMP9 expressions in the treated HCC cells with metformin on 16-kPa stiffness substrate were evidently weakened compared with those in the controls on the 6-kPa stiffness substrate. Conclusions Increased matrix stiffness significantly attenuates the inhibitory effect of metformin on HCC invasion and metastasis, and a common pathway of PTEN/PI3K/Akt/MMPs activated by mechanical stiffness signal and inactivated by metformin contributes to matrix stiffness-caused metformin resistance. To the best of our knowledge, this is the first report to clarify the mechanism of metformin intervention resistance from the perspective of tumor biophysical microenvironment.

Objective:To evaluate the endocrine abnormalities in intracranial germ cell tumors (iGCTs) treated with radio-therapy (RT), and to discuss the effects of RT on pituitary functions. Methods: Seventy-seven patients diagnosed with iGCTs who had received RT and endocrine follow-up in Huashan Hospital between January 2010 and July 2017 were retrospectively analyzed, consisting of 49 germinomas and 28 NGGCTs. The median follow-up period was 50.0 months. Fifty-one patients had radiologically proved suprasellar/sellar lesions. Results: The male to female ratio was 62/15. The median endocrine follow-up period was 19 (4, 42) months. The median age at the last endocrine visit was 18 (16, 20) years old. The 5-year overall and recurrence-free survival were both 98.7%. The overall prevalence of central adrenal insufficiency (CAI), central hypothyroidism (CHT), central hypogonadism (CHG), hyperprolactinemia, and central diabetes insipidus (CDI) was 57.3%, 56%, 56.6%, 35.3%, and 52.1%, respectively, after RT. Patients having suprasellar/sellar lesions showed significantly higher post-therapeutic prevalence of hypopituitarism than those who didn’t. Compared to that before RT, CAI, CHT, and CHG weren’t significantly improved while the levels of prolactin and the prevalence of CDI declined significantly (P =.03 and.001). The radiation doses to pituitary and hypothalamus between those with and without CAI, CHT, and CHG weren’t significantly different. Conclusion: The prevalence of hypopituitarism was high in iGCTs, especially in those with suprasellar/sellar involvement. The levels of prolactin and the prevalence of CDI declined significantly after RT. The hypopituitarism in iGCTs was mainly induced by tumor effects, and RT showed no additional damage to pituitary functions in our study. Abbreviations: AFP = alpha-fetoprotein; CAI = central adrenal insufficiency; CDI = central diabetes insipidus; CHG = central hypogonadism; CHT = central hypothyroidism; CT = computed tomography; DA = dopamine; GH = growth hormone; βHCG = beta-human chorionic gonadotropin; HPA = hypothalamus-pituitary-adrenal; HPG = hypothalamus-pituitary-gonadal; HPL = hyperprolactinemia; HPT = hypothalamus-pituitary-thyroid; iGCT = intracranial germ cell tumor; IGF-1 = insulin-like growth factor 1; NGGCT = nongerminomatous germ cell tumors; OS = overall survival; PFS = progression-free survival; PRL = hypothalamus-pituitary-prolactin; RT = radiotherapy

Background Heat shock protein 27 (HSP27) has been proposed as a vital protective factor in atherosclerosis. The objective of the present study was to evaluate the association between circulating HSP27 and carotid intima–media thickness (IMT) in individuals with type 2 diabetes and to determine whether HSP27 represents an independent marker of subclinical atherosclerosis in this patient population. Methods We performed a cross-sectional community-based study in 186 Chinese subjects with a median duration of type 2 diabetes of 8.2 years who underwent ultrasound carotid IMT measurement. Serum HSP27 levels were assessed by ELISA. Results Serum HSP27 levels were significantly higher in the IMT (+, > 1.0 mm) group than in the IMT (−, ≤1.0 mm) group, with the median values of 8.80 ng/mL (5.62–12.25) and 6.93 ng/mL (4.23–9.60), respectively (P = 0.006). The discriminative value of HSP27 to evaluate IMT was 7.16 ng/mL and the area under the curve was 0.72 (95%CI = 0.64–0.80, P = 0.0065). Spearman’s rank correlation analysis demonstrated that the concentrations of circulating HSP27 were positively associated with carotid IMT (r = 0.198, P = 0.007) and blood urea nitrogen (r = 0.170, P P = 0.022). Conclusions Circulating HSP27, positively correlates with carotid IMT, is an independent predictor for early atherosclerotic changes in diabetes, and may represent a novel marker of subclinical atherosclerosis in type 2 diabetes.

Introduction Oxidative stress plays an important role in the development of diabetic cardio-myopathy (DCM). Previously, we reported that Astragalus polysaccharides (APS) improved DCM by inhibition of cardiac oxidative stress. In this study, we evaluated the beneficial effect of APS on high glucose-induced oxidative stress in cardiomyocytes in vitro. Materials and methods H9C2 cells were cultured in the presence of high concentration of glucose or transfected with siRNASOD2, followed by APS treatment. The cellular mitochondrial ultrastructure was observed using a transmission electron microscope. Cell apoptosis was detected using hairpin oligonucleotide probes and quantified by flow cytometry analysis. Superoxide production was determined by immunohistochemistry using the fluorescent dye dihydroethidium (DHE). Nitrotyrosine and 8-OH-dG antibodies were employed to detect oxidative damage to cytoplasmic proteins and oxidative stress in the nuclei, respectively. Superoxide dismutase (SOD) activity was measured utilizing the SOD Assay Kit, and SOD protein levels were analyzed by Western blotting. Results APS treatment protected cellular mitochondrial ultrastructure, reduced cell apoptosis (hairpin-1), inhibited cellular superoxide production (DHE), and reduced oxidative damage to cytoplasmic proteins (nitrotyrosine) and oxidative stress in the nuclei (8-OH-dG) in high glucose-induced and/or SOD2-silenced H9C2 cells, together with induction of SOD2 enzyme activity and increase of protein levels. Conclusion Our findings indicated the beneficial effect of APS on high glucose-challenged H9C2 cells, which was associated with inhibition of oxidative stress in vitro.

Wei Chen,1 Jing Ju,1 Yehong Yang,2 Hao Wang,3 Wenjie Chen,1 Xuelan Zhao,1 Hongying Ye,2 Yu Zhang1 1Department of Geriatrics, Huashan Hospital, Fudan University, Shanghai, China; 2Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China; 3Core Center of Animal Facility, School of Medicine, Fudan University, Shanghai, China Introduction: Diabetic cardiomyopathy is characterized by an imbalance between myocyte death and regeneration mediated by the progressive loss of cardiac stem and progenitor cells (CSPCs) by apoptosis and necrosis due to the activation of oxidative stress with diabetes. In this study, we evaluated the beneficial effect of astragalus polysaccharides (APS) therapy on the protection of CSPCs through its antioxidative capacity in diabetic hearts.Materials and methods: Streptozotocin (STZ)-induced diabetic mice and heterozygous (SOD2+/-) knockout mice were employed and administered with APS. Ventricular CSPCs were isolated for oxidative evaluation. The abundance, apoptosis and proliferation, reactive oxygen species (ROS) formation, oxidative damage, and SOD2 protein levels and activities were evaluated in ventricular CSPCs.Results: We confirmed that APS increased the CSPC abundance, reduced the apoptosis of CSPCs, and enhanced the proliferation of CSPCs in both STZ-induced diabetic mice and nondiabetic SOD2+/- mice. In addition, therapy of APS enhanced SOD2 protein levels and enzyme activities, and inhibited ROS formation and oxidative damage of CSPCs from both STZ-induced diabetic mice and nondiabetic SOD2+/- mice.Conclusion: Our findings demonstrated the positive effect of APS on the rescue of CSPC preservation in diabetes, dependent on the inhibition of oxidative stress-mediated apoptosis. Keywords: diabetes, cardiac stem cells, cardiac progenitor cells, oxidative stress, cardio­myopathy, oxidation

To explore the relationship between miR-145 and ADP ribosylation factor 6 (Arf6) in regulating macrophage-mediated inflammation. THP-1 cells were induced by 160 nM of phorbol 12−myristate 13-acetate (PMA) for 48 h to differentiate to macrophages and then were treated with LPS (100 ng/ml) for 8 h to simulate chronic metabolic inflammation in vitro. Dual-luciferase reporter assay was performed. MiR-145 siRNA and LV-ARF6-RNAi were used to up or down regulate miR-145 and Arf6 expression in THP-1 cells, respectively. Omental adipose tissue from patients in surgical ward were collected to detect the expression of miR-145, Arf6 and production of proinflammatory cytokines. Patients were divided into three groups according to their body mass index and history of diabetes. Dual-luciferase reporter assays showed the direct down-regulation of Arf6 by miR-145. Forty-eight-hour-transfection of miR-145 inhibitor resulted in significant increase of Arf6, IL-1beta, TNF-alpha and IL-6 as well as phosphorylation of p65 in NF-kappaB pathway in THP-1 cells, which, inversely, were reversed by overexpressing miR-145. In addition, down-regulation of Arf6 in macrophages reduced expression and secretion of cytokines. Expression of miR-145 was found to be attenuated in the omental adipose tissue of obese patients and diabetics with greater Arf6 expression, confirming the role of miR-145 in regulating macrophage-mediated inflammation targeting Arf6. By means of reducing the expression of Arf6 and subsequent signal transduction via NF-kappaB, miR-145 plays a role in inhibiting the secretion of inflammatory factors and then improving the inflammatory status. MiR-145 might be one of the candidates for anti-inflammatory treatment for metabolic diseases.

The aim of this study was to systematically evaluate the efficacy and safety of anti-interleukin-1 therapy for type 2 diabetes. A literature search of PubMed and Embase for available trials on anti-interleukin-1 therapy in type 2 diabetes was performed. The baseline characteristics, changes in HbA1c and other metabolic parameters, and adverse events were extracted from included randomized controlled trials (RCTs) and were analysed with Review Manager. Mean differences (MDs) and 95% confidence intervals (Cis) were calculated to measure differences in metabolic parameters. Odds ratio and 95% CIs were calculated for adverse event rates. Five RCTs were included in the current meta-analysis with 357 subjects undergoing anti-interleukin-1 therapy (IL-1 receptor antagonist or anti-IL-1beta antibody) and 221 controls who received placebo. The HbA1c decrement (%) of anti-interleukin-1 group was significantly higher than that of the placebo group (MD = 0.23; 95% CI, -0.39 to -0.07; P = .005). AUC of C-peptide was improved also (MD = 14.55; 95% CI, 1.81-27.28; P = .03) after anti-interleukin-1 intervention. There was no difference in the rate of adverse events (odds ratio,1.16; 95% CI, 0.90-1.49; P = .25) between 2 groups. Anti-interleukin-1 therapy has mild hypoglycaemic effect in type 2 diabetes.

Introduction: In the past two decades, urbanization in many Asian countries has led to sedentary lifestyle and overnutrition, which has set the stage for the epidemic of obesity. Those who have obesity during adolescence usually have obesity into adulthood, which causes many medical and psychological issues that can result in premature death. Recent data suggest that short sleep duration may contribute to the risk of obesity, opening a new avenue for potential intervention. The aim of this study was to describe the prevalence of sleeping time, body mass index (BMI), and fat mass in Chinese freshmen and to indicate the relationship among them. Methods: We conducted a cross-sectional study consisting of 1,938 freshmen aged from 18 to 24 years, including 684 (35.3%) men and 1,254 (64.7%) women. BMI, sleeping time, and other potential related variables were collected by questionnaire. Obesity and overweight were defined as BMI ≥28.0 and ≥24.0, respectively. All students were divided into three groups according to the tertiles of body fat percentage (Fat%), which were measured by bioelectrical impedance analysis. Sleeping time was divided into 3 categories based on the duration, 8 h per day. Results: Participants who slept longer had lower BMI and Fat%. Sex, diet control, and maternal obesity were all significantly associated with BMI or Fat% after adjustment. There were significant differences between sleeping time 8 h in both overweight group and Fat% tertiles independent of adjustment used. The significant difference between sleeping time 6–8 and >8 h only existed in overweight group, while irrelevant relation was observed in both models of obesity group. Conclusion: Longer sleeping time was associated with a lower BMI in Chinese freshmen, even after adjustment for multiple confounders. The overweight stage is a critical period of weight management intervention by changing sleeping time. If adolescents have entered the obesity stage, the effect size of lifestyle intervention might be significantly limited.

Glucagon-like peptide-1 (GLP-1), an incretin hormone plays an important role in regulating glucose homeostasis. The therapeutic use of native GLP-1 is inadequate due to its short in vivo half-life. We recently developed a novel GLP-1 mimetics supaglutide, and demonstrated that this formulation retained native GLP-1 biological activities and possessed long-lasting GLP-1 actions. In this study, we further examined its abilities in regulating blood glucose in diabetic mice. We found that supaglutide stimulated insulin secretion in both mouse and human islets in a dose-dependent fashion. Oral glucose tolerance test conducted in normal ICR mice showed that supaglutide significantly decreased postprandial glucose excursions in a dose-dependent fashion. In type 2 diabetic db/db mice, a single-dose injection of supaglutide significantly decreased blood glucose levels, and this efficacy was lasted for at least 72 h in a dose-dependent fashion. During a 4-weeks intervention course supaglutide (twice injections per week) dose-dependently and significantly decreased fasting and random blood glucose levels in hyperglycemic db/db mice. Supaglutide, at a dose of 1.2 mg/kg, significantly reduced serum fructosamine levels. This was associated with significant enlargement of beta-cell mass, increased pancreatic insulin content, and increased plasma insulin level. Notably, during the intervention course supaglutide significantly reduced body-weight gain in these obese diabetic mice, associated with reduced fat mass (but not the lean mass), improved lipid profile, i.e., declined serum triglyceride, and free fatty acid levels compared to the placebo control. These finding reveals that supaglutide exerts beneficial effects in regulating blood glucose and lipid homeostasis in diabetic db/db mice.

Myocardial infarction (MI) is a disease characterized by high morbidity and mortality rates. MI biomarkers are frequently used in clinical diagnosis; however, their specificity and sensitivity remain unsatisfactory. Urinary proteome is an easy, efficient and noninvasive source to examine biomarkers associated with various diseases. The present study, to the best of the authors' knowledge, is the first to examine the urinary proteome using the isobaric tags for relative and absolute quantitation (iTRAQ) technology to identify potential diagnostic biomarkers of MI. The urinary proteome was analyzed within 12 h following the first symptoms of early-onset MI and at day 7 following percutaneous coronary intervention via iTRAQ labeling and two-dimensional liquid chromatography-tandem mass spectrometry. Candidate biomarkers were validated by multiple reaction monitoring (MRM) analysis. A total of 233 urinary proteins were differentially expressed. Gene enrichment analysis identified that the urinary proteome in patients with MI was associated with atherosclerosis, abnormal coagulation and abnormal cell metabolism. In total, 12 differentially expressed urinary proteins were validated by MRM analysis, five of which were associated with MI for the first time in the present study. Binary logistic regression analysis suggested that the combination of five urinary proteins (antithrombin-III, complement C3, α-1-acid glycoprotein 1, serotransferrin and cathepsin Z) may be used to diagnose MI with 94% sensitivity and 93% specificity. In addition, the protein expression levels of three proteins were significantly restored to normal levels following surgical treatment. The verified candidate biomarkers may be used for the diagnosis of MI, and for monitoring the disease status and the effects of treatments for MI. The present results may facilitate future clinical applications of the urinary proteome to diagnose MI.

Purpose We investigated the expression of vasopressin receptor 2 and 3 on corticotrophin tumor cells, their role in regulating ACTH secretion, and their potential therapeutic implications. Methods We retrospectively assessed 52 hospitalized patients with pathologically confirmed ACTH-secreting tumors. The expression of vasopressin receptor 2 and 3 was explored via qualitative and quantitative immunohistochemistry analyses. The role of vasopressin receptors in regulating ACTH secretion was further studied in the AtT-20 cell line. Results Among 50 cases of pituitary corticotrophin adenoma, 31 were vasopressin receptor 2 positive, 38 were vasopressin receptor 3 positive, and 24 were both vasopressin receptor 2 and 3 positive. Two patients with ectopic ACTH syndrome were vasopressin receptor 3 positive, and one was also vasopressin receptor 2 positive. In 12 patients who underwent bilateral inferior petrosal sinus sampling before surgery, the central ACTH increment ratio after desmopressin stimulation was correlated with vasopressin receptor 2 but not with vasopressin receptor 3 staining intensity. In an in vitro study, the expression of both vasopressin receptor 2 and 3 on AtT-20 cells was confirmed. The vasopressin receptor 2 antagonist Tolvaptan inhibited desmopressin-induced ACTH secretion in a dose-dependent manner. Conclusions Both vasopressin receptor 2 and 3 are expressed in ACTH-secreting tumors. Vasopressin receptor 2 rather than vasopressin receptor 3 is the primary receptor that seems to mediate the ACTH response in corticotrophin tumors. A vasopressin receptor 2 antagonist can inhibit ACTH secretion induced by desmopressin in AtT-20 cells.

Objective. Oxidant stress plays an important role in the development of diabetic cardiomyopathy. Previously we reported that Astragalus polysaccharides (APS) rescued heart dysfunction and cardinal pathological abnormalities in diabetic mice. In the current study, we determined whether the effect of APS on diabetic cardiomyopathy was associated with its impact on oxidant stress. Methods. Db/db diabetic mice were employed and administered with APS. The hematodynamics, cardiac ultra-structure, apoptosis, and ROS formation of myocardium were assessed. The cardiac protein expression of apoptosis target genes (Bax, Bcl-2, and caspase-3) and oxidation target genes (Gpx, SOD2, t/p-JNK, catalase, t/p-p38 MAPK, and t/p-ERK) were evaluated, respectively. Results. APS therapy improved hematodynamics and cardinal ultra-structure with reduced apoptosis and ROS formation in db/db hearts. In addition, APS therapy inhibited the protein expression of apoptosis target genes (Bax, Bcl-2, and caspase-3) and regulated the protein expression of oxidation target genes (enhancing Gpx, SOD2, and catalase, while reducing t/p-JNK, t/p-ERK, and t/p-p38 MAPK) in db/db hearts. Conclusion. Our findings suggest that APS has benefits in diabetic cardiomyopathy, which may be partly associated with its impact on cardiac oxidant stress.

Background Some elderly citizens with a clinical diagnosis of type 2 diabetes had evidence of positive islet autoantibodies. We aimed to discover their islet autoantibody patterns and independent correlative factors that might lead to a better understanding of significance of islet autoimmunity in the progression of elderly diabetes. Methods A total of 541 inpatients of clinically diagnosed type 2 diabetes aged 60 and over were recruited. Three islet autoantibodies including insulin autoantibody (IAA), islet cell antibody (ICA), and glutamic acid decarboxylase antibody (GADA) as well as clinical and biochemical characteristics were tested and collected in Huashan Hospital. Associations between these antibodies and clinical features were analyzed by Spearman correlation and binary logistic analyses. Results In our current study, total positive rate of islet autoantibodies (IAA, ICA, and GADA) was 35.67% with 26.62% for individual IAA, 5.55% for ICA, and 5.91% for GADA, in elderly with type 2 diabetes. None of combinations of such autoantibodies were observed, with the exception of IAA + ICA (0.74%, n = 4), IAA + GADA (1.48%, n = 8), and ICA + GADA (0.18%, n = 1). Compared with GADA negative group, patients in positive group tended to have lower level of fasting and postprandial C peptide, fasting blood glucose (FBG), and body mass index (BMI). After adjusted for the BMI, FBG, and postprandial C peptide, fasting C peptide seemed to be an independent factor related to GADA positivity (OR = 0.52, p = 0.02). As for patients with positive IAA, they were more likely to have insulin treatment with longer duration of diabetes, higher level of BMI, and lower level of postprandial C peptide. After adjusted for the duration of diabetes, BMI, and postprandial C peptide, insulin treatment was a significant predictor for IAA positivity (OR = 5.20, p

The purpose of this work is to examine the serum proteomic profiles associated with the subsequent development of diabetic nephropathy (DN) in patients with type 2 diabetes and to develop and validate a decision tree based on the profiles to predict the risk of DN in advance by albuminuria. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry was used to obtain the proteomic profiles from baseline serum samples of 84 patients with type 2 diabetes with normal albuminuria, including 42 case subjects who developed DN after 4 years and 42 control subjects who remained normoalbuminuric over the same 4 years. From signatures of protein mass, a decision tree was established for predicting DN. At baseline, urinary albumin/creatinine ratio was similar between the case and control groups. The intensities of 5 peaks detected by CM10 chips appeared up-regulated, whereas 18 peaks were down-regulated more than twofold in the case group than compared with the control group in the training set. An optimum discriminatory decision tree for case subjects created with four nodes using four distinct masses was challenged with testing set. The positive predictive value was 77.8 % (7/9), and the negative predictive value was 72.7 % (8/11). We developed and validated a decision tree to predict DN in patients with type 2 diabetes.

Biomarkers are measurable changes associated with the disease. Urine can reflect the changes of the body while blood is under control of the homeostatic mechanisms; thus, urine is considered an important source for early and sensitive disease biomarker discovery. A comprehensive profile of the urinary proteome will provide a basic understanding of urinary proteins. In this paper, we present an in-depth analysis of the urinary proteome based on different separation strategies, including direct one dimensional liquid chromatography–tandem mass spectrometry (LC/MS/MS), two dimensional LC/MS/MS, and gel-eluted liquid fraction entrapment electrophoresis/liquid-phase isoelectric focusing followed by two dimensional LC/MS/MS. A total of 6085 proteins were identified in healthy urine, of which 2001 were not reported in previous studies and the concentrations of 2571 proteins were estimated (spanning a magnitude of 106) with an intensity-based absolute quantification algorithm. The urinary proteins were annotated by their tissue distribution. Detailed information can be accessed at the “Human Urine Proteome Database” (www.urimarker.com/urine).

Prolactin may reduce false-negative results in diagnosing Cushing's disease (CD) during inferior petrosal sinus sampling (IPSS). Prolactin normalization could improve the accuracy of IPSS in predicting adenoma lateralization in CD. However, none of the previous studies had involved the use of desmopressin during IPSS. Our objective was to examine the utility of prolactin measurement during IPSS with desmopressin stimulation. We conducted a retrospective analysis of 40 patients (including 31 females) with ACTH-dependent Cushing's syndrome who underwent IPSS between 2010 and 2013. Thirty-eight CD patients were partitioned into true positive (n = 35) and false negative (n = 3). The proportion of improper IPSS venous sampling defined by corresponding IPS:P (inferior petrosal sinus to peripheral) prolactin ratio1.8 was significantly different between two groups (P = 0.004). Applying a prolactin-normalized ACTH IPS:P ratio0.8 cutoff could increase the sensitivity of IPSS to 38/38 (100 %). Among the 31 patients with histopathologically proven adenoma localization, correct prediction of adenoma lateralization was obtained in 14/31 (45 %) patients by a peak intersinus ACTH gradient of ≥1.4 in baseline and was not improved by desmopressin stimulation. Left-right intersinus gradients of unilateral prolactin-adjusted ACTH IPS:P ratios could increase the correct prediction of adenoma lateralization to 20/31 (65 %) in baseline and 24/31 (77 %) (P = 0.006) after desmopressin stimulation, respectively. Prolactin is helpful to adjust negative results of IPSS with desmopressin stimulation. It may improve the accuracy in predicting adenoma lateralization in CD as well.

OBJECTIVE Cathepsin S is highly expressed in subcutaneous and visceral adipose tissue. Cathepsin S correlates with central obesity and contributes to the formation and progression of atherosclerosis. Here, we sought to evaluate the association of serum cathepsin S with metabolic syndrome (MS) in overweight and obese Chinese adults. METHODS We evaluated serum cathepsin S levels in a cross-sectional sample of 781 overweight and obese Chinese adults by ELISA. Glucose, insulin, lipid profile, inflammatory markers, and adipokines were also measured. RESULTS Cathepsin S was significantly associated with BMI, waist circumference, waist-to-hip ratio, fasting glucose, fasting insulin, the homeostatic model assessment of insulin resistance (HOMA-IR), systolic blood pressure, C-reactive protein (CRP), triglycerides, and HDL cholesterol (all P

Elevated serum Angptl2 levels are positively associated with the development of type 2 diabetes. We investigated whether serum Angptl2 levels are associated with diabetic nephropathy in patients with type 2 diabetes.Two hundred and thirty patients with type 2 diabetes and 63 healthy controls participated in this cross-sectional study. Subjects with type 2 diabetes were divided into three groups using urinary albumin-to-creatinine ratio (ACR): a normoalbuminuric group (n=57), a microalbuminuric group (n=130) and a macroalbuminuria group (n=43). Serum Angptl2 concentrations were measured by enzyme-linked immunosorbent assay.Median serum (interquartile range) Angptl2 levels in control subjects and patients with type 2 diabetes with normoalbuminuria, microalbuminuria and macroalbuminuria were 24.03 (16.3-33.45), 36.14 (27.91-43.07), 44.6 (37.47-49.92), 50.19 (45.95-60.13)ng/ml (p0.01) respectively. Angptl2 levels correlated with urinary ACR in participants with type 2 diabetes (r=0.38, p0.01). Significant intercorrelations of Angptl2 were found with age, duration of diabetes, and fasting plasma glucose. After adjustment for significant covariates, albuminuria was still significantly associated with Angptl2 levels in type 2 diabetes (r=0.31, p0.01).Angptl2 levels are elevated in patients with type 2 diabetes with an independent association between increasing Angptl2 levels and increasing levels of albuminuria. This suggests a possible role of Angptl2 in progressive nephropathy in patients with type 2 diabetes.

Among the three major schistosome species infecting human beings, Schistosoma japonicum is the only endemic species in The People's Republic of China. Schistosomiasis is endemic in 78 countries and regions and poses a severe threat to public health and socioeconomic development. Through more than 60years of hard work and endeavour, The People's Republic of China has made considerable achievements and reduced the morbidity and prevalence of this disease to the lowest level ever recorded, especially since the introduction of the new integrated control strategy in 2004. This review illustrates the strategies implemented by giving successful examples of schistosomiasis control from the different types of remaining endemic areas. The challenge to control or eliminate S. japonicum is analysed in order to provide useful information to policy makers and scientists.

Schistosomiasis is a parasitic disease that affects over 200million people worldwide in at least 76 countries, ranking second only after malaria in terms of its socio-economic and public health importance in tropical and subtropical areas of the world. Chinese surveillance data since the mid-1950s have shown that endemic areas are divided into three types based on geographical, ecological and epidemiological factors, such as marshland and lake region, plain region with waterway networks and hilly and mountainous region. As confirmed by numerous epidemiological investigations, schistosomiasis endemic areas of the mountainous type are distributed in 178 counties in 11 provinces of The People's Republic of China. Over the past several decades great success in transmission control has been achieved by implementation of control strategies that were suitable for the mountainous and hilly endemic region.

Neurofilament (NF), one of the major axonal cytoskeletal proteins, plays a critical role in degenerative diseases in both the central and the peripheral nervous systems. The aim of this study is to explore the relationship between serum phosphorylated neurofilament-heavy chain (pNF-H) and diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes. Serum pNF-H concentrations were measured by ELISA in hospitalized patients with and without DPN (n = 118). DPN was assessed by clinical symptoms, signs, and electromyography. Compared with the non-DPN group (311.98 [189.59–634.12] pg/mL), the confirmed group (605.99 [281.17–1332.78] pg/mL) patients had the higher serum pNF-H levels (P = 0.007). DPN was significantly correlated with C-peptide (r = −0.269), total cholesterol (TC) (r = 0.185), and pNF-H (r = 0.258). Serum pNF-H levels were independently associated with DPN (P = 0.004), even after adjusting for age, sex, duration of diabetes, fasting plasma glucose, glycosylated hemoglobin A1c, TC, C-peptide, urinary albuminto/creatinine ratio, and estimated glomerular filtration rate. Compared with pNF-H quartile 1 (referent), patients in quartile 3 (odds ratio [OR], 3.977; 95% confidence interval [CI], 1.243–12.728; P = 0.021) and quartile 4 (OR, 10.488; 95% CI, 3.020–34.429; P = 0.000) had the higher risk of DPN after adjusting for the confounders. Serum pNF-H levels might be associated with the DPN, and the correlationship between serum pNF-H and DPN should be further studied.

Objective Little is known about how the cardiac autonomic nervous function (CAN) changes with gradually increasing systolic blood pressure (SBP). This study investigated cardiac autonomic nervous function in diabetic patients and controls with different grades of SBP.Methods and results We measured heart rate variability (HRV) and spontaneous baroreflex sensitivity (BRS) by power spectral analysis in 118 Chinese type-2 diabetic patients and 137 age-matched controls. Subjects were further subdivided into 4 SBP groups. Results showed total HRV and BRS values were significantly lower in several diabetic SBP groups. Total HRV and BRS decreased with increasing SBP, with significant differences in the 140-159 mm Hg or 160-179 mm Hg groups compared with other groups of diabetic and control subjects.Conclusions We found that HRV and BRS can reflect cardiovascular autonomic dysfunction of diabetes when accompanied by hypertension. In our selected Chinese diabetic and control subjects, HRV and BRS parameters were i...

Aims To determine the prevalence of diabetic peripheral neuropathy (DPN) and risk factors associated with DPN in type 2 diabetic patients. Methods 435 diabetic patients were evaluated on complete foot examination. Body mass measurements, resting blood pressure, fasting blood measures, urinary albumin-to-creatinine ratio (ACR) and the digitally stored fundus images were investigated. Results (1) The prevalence of DPN was 61.8% among the Chinese patients diagnosed with type 2 diabetes aged over 30 in the Shanghai downtown, 59.1% with vibration perception threshold ≥25 V and 13.8% with inability to feel the monofilament. (2) DPN was significantly associated with age ( β : 0.068, S.E.: 0.013, OR: 1.070, CI: 1.043–1.098, P β : 0.224, S.E.: 0.081, OR: 1.251, CI: 1.067–1.466, P = 0.006) by a logistic regression analysis. (3) The percentage of diabetic retinopathy (DR) in the DPN group (26.5%) was significantly higher than that in the non-DPN group (15.2%). (4) The percentage of macroalbuminuria in the DPN group (9.0%) was significantly higher than that in the non-DPN group (1.8%). Conclusions The prevalence of DPN observed in the Chinese patients diagnosed with type 2 diabetes aged over 30 in the Shanghai downtown reached up to 61.8% though the observations in our study might be representative of the diabetic patients of the Shanghai downtown.

Background: The clinical value of the clustering of metabolic diseases linked by the common pathogenesis of metabolic inflammation has not been clarified. Methods: We named the cluster of metabolic inflammatory diseases as ‘metabolic inflammatory syndrome (MIS)’ and included atherosclerosis, type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD) and obesity/overweight as its components. We studied the participants with T2D from six medical centers in China (4,711 participants). MIS, metabolic syndrome (MS) defined by Chinese Diabetes Society and coronary heart disease (CHD) were assessed according to records from the medical centers. We calculated the detective rate of MIS and analyzed its risk for CHD by binary logistic analysis, comparing with MetS. Results: In the participants with T2D, MIS had a detective rate of 96.2%, more highly than MIS (57.0%). MIS components had high detective rates (atherosclerosis: 80.9%, NAFLD: 57.3%, obesity/overweight: 61.7%), compared with MetS components (hypertension: 64.4%, dyslipidemia: 38.2%). MIS had a greater odds ratio to predict CHD than MS [MIS: odds ratio, 4.71; 95% confidence interval (CI), 2.31 to 9.62; P Conclusions: MIS had a high detective rate and appeared to be an independent risk factor of CHD. Therefore, this concept might be used for screening, prevention and researches for metabolic diseases at their early stages. A person who has one of the MIS components, especially atherosclerosis, should screened for the other MIS components, for their high detective rates and the relationship between meta-inflammation and them which was like the melons on one vine.

Gene expression is highly dynamic and plastic. We present a new immunological database, ImmuSort. Unlike other gene expression databases, ImmuSort provides a convenient way to view global differential gene expression data across thousands of experimental conditions in immune cells. It enables electronic sorting, which is a bioinformatics process to retrieve cell states associated with specific experimental conditions that are mainly based on gene expression intensity. A comparison of gene expression profiles reveals other applications, such as the evaluation of immune cell biomarkers and cell subsets, identification of cell specific and/or disease-associated genes or transcripts, comparison of gene expression in different transcript variants and probe set quality evaluation. A plasticity score is introduced to measure gene plasticity. Average rank and marker evaluation scores are used to evaluate biomarkers. The current version includes 31 human and 17 mouse immune cell groups, comprising 10,422 and 3,929 microarrays derived from public databases, respectively. A total of 20,283 human and 20,963 mouse genes are available to query in the database. Examples show the distinct advantages of the database. The database URL is http://immusort.bjmu.edu.cn/.

Cushing’s disease (CD) is remarkably prevalent among females; however, more severe clinical presentation and adverse outcomes have been found in males. The purpose of this study was to investigate the overall clinical profile and biochemical parameters in patients with CD to identify the gender differences. Here we describe our series of CD patients referred to our medical center during 2012-2013. Among 73 cases, females presented a marked preponderance compared to males. Males had significantly higher ACTH, BMI, HbA1c, systolic blood pressure, and hemoglobin than females. For the first time, the incidence of fatty liver and hepatic function was also shown to be elevated in males. Multiple linear regression analysis was performed to further investigate the correlation of risk factors with hypokalemia, HbA1c, and systolic blood pressure. Gender and serum cortisol were associated with hypokalemia. Age, gender, and serum cortisol were significantly associated with HbA1c. Additionally, only gender was significantly associated with systolic blood pressure. Regarding clinical presentation, purple striae seemed to occur more frequently in males than in females. Thus, more severe clinical presentation, biochemical parameters, and complications were found in males than in females. Clinical professionals should pay more attention to the diagnosis and management of males with CD.

Existing methods could not discriminate between inflammation and other diseases, which might occur in hypothalamus, such as neurogliocytoma, germinoma, lymphoma, and so on. Given its location in the brain, it was not practical to obtain tissue using standard surgical methods. We reported the first case of a patient with hypothalamus lesion, who was diagnosed as hypothalamitis by stereotactic biopsy. This precise diagnosis allowed proper medical treatments. We reported a case of a patient with hypothalamus lesion. To confirm the diagnosis, with informed consent from the family, a successful stereotactic hypothalamic biopsy was performed by neurosurgeons. Immunohistochemical results of biopsy specimens from the hypothalamus lesion revealed inflammatory infiltrates, which were composed mainly of lymphocytes, plasma cells, and histiocytes, and were stained with leucocyte common antigen (LCA), κ 1, and cluster of differentiation 18. Final pathological diagnosis was lymphoplasmacytic proliferative, granuloma-like inflammatory pseudotumor, with immunoglobulin G deposition. Based on the pathological diagnosis, we treated the patient with glucocorticoid and azathioprine. Remarkable improvements were observed in both magnetic resonance imaging (MRI) and patient's symptoms. Stereotactic biopsy for intracranial lesions was a reliable and relatively safe procedure, even for hypothalamus. It was an effective method with high diagnostic yield. With correct diagnosis, it was much easier to choose correct treatment.

Knowledge about the normal human cerebrospinal fluid (CSF) proteome serves as a baseline reference for CSF biomarker discovery and provides insight into CSF physiology. In this study, high-pH reverse-phase liquid chromatography (hp-RPLC) was first integrated with a TripleTOF 5600 mass spectrometer to comprehensively profile the normal CSF proteome. A total of 49,836 unique peptides and 3256 non-redundant proteins were identified. To obtain high-confidence results, 2513 proteins with at least 2 unique peptides were further selected as bona fide CSF proteins. Nearly 30% of the identified CSF proteins have not been previously reported in the normal CSF proteome. More than 25% of the CSF proteins were components of CNS cell microenvironments, and network analyses indicated their roles in the pathogenesis of neurological diseases. The top canonical pathway in which the CSF proteins participated was axon guidance signaling. More than one-third of the CSF proteins (788 proteins) were related to neurological diseases, and these proteins constitute potential CSF biomarker candidates. The mapping results can be freely downloaded at http://122.70.220.102:8088/csf/, which can be used to navigate the CSF proteome. For more information about the data, please refer to the related original article [1], which has been recently accepted by Journal of Proteomics.

Knowledge about the normal human cerebrospinal fluid (CSF) proteome serves as a baseline reference for CSF biomarker discovery and provides insight into CSF physiology. In this study, high-pH reverse-phase liquid chromatography (hp-RPLC) was first integrated with a TripleTOF 5600 mass spectrometer to comprehensively profile the normal CSF proteome. A total of 49,836 unique peptides and 3256 non-redundant proteins were identified. To obtain high-confidence results, 2513 proteins with at least 2 unique peptides were further selected as bona fide CSF proteins. Nearly 30% of the identified CSF proteins have not been previously reported in the normal CSF proteome. More than 25% of the CSF proteins were components of CNS cell microenvironments, and network analyses indicated their roles in the pathogenesis of neurological diseases. The top canonical pathway in which the CSF proteins participated was axon guidance signaling. More than one third of the CSF proteins (788 proteins) were related to neurological diseases, and these proteins constitute potential CSF biomarker candidates. The mapping results can be freely downloaded at http://122.70.220.102:8088/csf/ , which can be used to navigate the CSF proteome. Biological significance This study identified and functionally annotated the largest high-precision dataset of the CSF proteome, which offers a baseline reference for CSF biomarker discovery and reveals insight into CSF physiology.

Thyrotropin-secreting pituitary adenoma (TSHoma) is rare and it is also a rare cause of thyrotoxicosis. Failure to detect the presence of TSHoma may result in dramatic consequences. This study is a review of our experience in the management of TSHoma at Huashan Hospital, China. We followed up eight patients with TSHoma (five males and three females) between 2006 and 2011. The patients’ medical records were retrieved, and the demographic data, clinical presentation and management, final outcomes and follow-up were reviewed, and surgery performed. All the eight patients had unsuppressed TSH levels with elevated thyroid hormone levels; and neuroimaging revealed pituitary lesions. Five patients (62.5 %) were previously misdiagnosed as primary hyperthyroidism. They received pituitary adenomectomy, somatostatin analogs, and/or radiotherapy after definitive diagnosis. Serum TSH and thyroid hormone levels of all the patients restored to the normal levels during the follow-up. Adenomectomy is not curative in many TSHoma patients, it should be adjuvantly treated by pharmacological and/or radiotherapy, frequently. A combination of adenomectomy, somatostatin analogs, and radiotherapy is often required for long-term management of the disease.

Background There is debate as to whether the association between C-reactive protein (CRP) and insulin resistance is independent of body fatness, particularly central obesity. Therefore, the association among CRP, insulin resistance and obesity was analyzed in Chinese patients with type 2 diabetes. Methods The study included 520 Chinese patients diagnosed with type 2 diabetes with CRP levels not exceeding 10 mg/L. The degree of insulin resistance was determined with the homeostasis model assessment of insulin resistance (HOMA-IR). The CRP levels were categorized into quartiles from the lowest to the highest concentrations (Q1-Q4). Results Body mass index (BMI) and waist circumference (WC) were both higher in Q4, Q3 and Q2 than those in Q1. HOMA-IR was higher in Q2, Q3 and Q4 than that in Q1 (Q1 vs Q4, P < 0.001; Q1 vs Q3, P < 0.001; Q1 vs Q2, P = 0.028). Log CRP was significantly correlated with log HOMA-IR (correlation coefficient: 0.230, P < 0.001) and BMI (correlation coefficient: 0.305, P < 0.001) and WC (correlation coefficient: 0.240, P < 0.001) by Spearman correlation analysis. Multiple linear regression analysis adjusting for age, gender and components of metabolic syndrome, log CRP was also independently associated with log HOMA-IR (β coefficient, 0.168; P < 0.001) and WC (β coefficient, 0.131; P = 0.006). Conclusion These findings showed that insulin resistance was associated with CRP levels independent of abdominal obesity in Chinese patients with type 2 diabetes, suggesting that abdominal obesity could only partly explain the link between subclinical inflammation and insulin resistance.

Background As urine is less complex than plasma and accumulates substantial physiological and pathophysiological changes from both plasma and the urinary system, it is regarded as an ideal source of sample for biomarker studies. Methods To gain a better understanding of the biological functions of urinary proteins and their association with human diseases, we did an in-depth urinary proteome analysis, using urine samples from 24 healthy individuals, that was based on multiple separation strategies, including direct one-dimensional liquid chromatography–tandem mass spectrometry (1DLC/MS/MS), two-dimensional LC/MS/MS, and gel-eluted liquid fraction entrapment electrophoresis (GELFrEE) and liquid-phase isoelectric focusing (LP-IEF) followed by 2DLC/MS/MS. Findings We identified 6412 proteins, of which 2213 had not been reported in previous studies and 2571 were relatively and absolutely quantitated (spanning a magnitude of 10 6 ) with an intensity-based absolute quantification algorithm. Tissue-based analysis revealed that 514 tissue-enriched proteins from 27 tissues and 917 tissue-enhanced proteins from 32 tissues could be detected in urine, suggesting that the urinary proteome might have an important role in studying the physiological and pathological changes of the related organs, such as the brain and kidney. We selected potential urinary biomarkers that were previously identified for glioma and IgA nephropathy by filtering biomarkers from the publicly accessible Human Urine Proteome Database and verified them by Western blotting. We also observed that deeper separation allowed identification of more tissue-related and disease-specific proteins. All the detailed information—such as protein name, accession number, peptide sequence, sequence coverage, and biomarker application—could be obtained from the Human Urine Proteome Database, which provides information for prediction of urinary candidate biomarkers and modification of targeted proteomics workflow. Interpretation Urine might indicate the physiological and pathological changes of several organs and could therefore be used as a promising source of sample for biomarker discovery, especially for brain and kidney diseases. Funding This work was supported by the National Basic Research Program of China (2013CB530805 and 2014CBA02005), the Key Basic Research Program of the Ministry of Science and Technology of China (2013FY114100), the National Natural Science Foundation of China (31200614 and 31400669), and the Beijing Natural Science Foundation (5132028).

Objective This study aimed to evaluate the prevalence of chronic kidney disease (CKD) and the risk factors associated with CKD among Chinese patients diagnosed with type 2 diabetes aged over 30 in downtown Shanghai and to assess the relationship between CKD and diabetic retinopathy (DR). Methods We investigated 1039 Chinese patients diagnosed with type 2 diabetes aged over 30 by randomized cluster sampling in downtown Shanghai, and 1009 patients in this study were analyzed based on data integrity. Body measurements including height, weight, waist circumference and hip circumference, resting blood pressure, fasting blood measures, and urinary albumin-to-creatinine ratio (ACR), as well as the digitally stored fundus images, were investigated. Glomerular filtration rate (GFR) was estimated using the Cockcroft–Gault equation. The prevalence of CKD was calculated, and the risk factors associated with CKD were evaluated using stepwise logistic regression. The relationship between CKD and DR was evaluated using Spearman correlation and the chi-square test. Results The following were the results found in this study: (a) The prevalence rate of CKD (Stages 1–5) was 63.9% in Chinese patients diagnosed with type 2 diabetes, 8.8% in those with CKD Stage 1, 22.3% in those with CKD Stage 2, and 32.8% in those with CKD Stages 3–5 (GFR 2 ). The prevalence of CKD increased with age. (b) CKD patients were older and had higher duration of diabetes, systolic blood pressure, urea nitrogen, uric acid, creatinine, and ACR of the first urine than those without CKD. (c) Male patients had a higher percentage of CKD Stages 3–5, and female patients had a higher percentage of CKD Stages 1–2. (d) CKD was significantly associated with duration of diabetes, older age, systolic blood pressure, and serum urea nitrogen based on logistic regression analysis. (e) Of the patients without CKD, 15.6% had DR, and of those with CKD, 27.6% had DR. The decrease in GFR was significantly correlated with DR after controlling for sex, age, and albuminuria staging. Conclusion The high prevalence of CKD observed in Chinese patients diagnosed with type 2 diabetes aged over 30 in downtown Shanghai was similar to that in Western patients, and the cause of CKD is likely to be any of the following: type 2 diabetes, IgA nephropathy, hypertension, or any combination of these. The screening program for GFR in type 2 diabetic patients should be performed even on those with normoalbuminuria. The decrease in GFR might predict the occurrence of DR among patients diagnosed with type 2 diabetes.

The objective of the study was to determine the most accurate metabolic syndrome (MS) definition among the definitions proposed by the International Diabetes Federation (IDF), the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATPIII]), and the World Health Organization (WHO) and to evaluate the cutoff point of waist circumference using the IDF definition for optimally defining MS in the Chinese population. One thousand thirty-nine Chinese patients older than 30 years and diagnosed with type 2 diabetes mellitus were investigated by randomized cluster sampling in the Shanghai downtown, and 1008 patients were analyzed in this study. Body mass measurements, resting blood pressure, fasting blood measures, and carotid atherosclerotic measurements including common carotid artery intima-media thickness (IMT) and carotid plaque were investigated. The IDF definition was compared with the other 2 definitions, and the carotid atherosclerosis was evaluated among the patients according to these definitions. (1) The MS prevalence was 50.0%, 55.7%, and 70.0% under the IDF, ATPIII, and WHO definitions, respectively. (2) The percentage of all the participants categorized as either having or not having the MS was 69.9% (under the IDF and ATPIII definitions) and 70.2% (under the IDF and WHO definitions). (3) Common carotid artery IMT of patients with MS determined by the IDF definition was thicker than those determined by the WHO and ATPIII definitions, and the percentage of carotid plaque of patients with MS determined by the IDF definition was greater than those determined by the WHO and ATPIII definitions. (4) When the cutoff point of waist circumference in men determined by the IDF definition was modified from 90 to 85 cm, common carotid artery IMT of the emerging male patients with MS was thicker than that of the male patients with MS determined by the original IDF definition. In conclusion, the prevalence of MS was 50.0%, 55.7%, and 70.0% under the IDF, ATPIII, and WHO definitions, respectively. The preferable IDF definition served as a better predictor of cardiovascular disease risk in the Chinese patients diagnosed with type 2 diabetes mellitus compared with the ATPIII and WHO definitions. The modified cutoff point of waist circumference in men under the IDF definition specific for the Chinese population (from 90 to 85 cm) might be more suitable for predicting atherosclerosis.