Publications by authors named "Weiqiong Gu"

66 Publications

Deciphering CT texture features of human visceral fat to evaluate metabolic disorders and surgery-induced weight loss effects.

EBioMedicine 2021 Jul 3;69:103471. Epub 2021 Jul 3.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address:

Background: Metabolic syndrome (MetS) is highly related to the excessive accumulation of visceral adipose tissue (VAT). Quantitative measurements of VAT are commonly applied in clinical practice for measurement of metabolic risks; however, it remains largely unknown whether the texture of VAT can evaluate visceral adiposity, stratify MetS and predict surgery-induced weight loss effects.

Methods: 675 Chinese adult volunteers and 63 obese patients (with bariatric surgery) were enrolled. Texture features were extracted from VATs of the computed tomography (CT) scans and machine learning was applied to identify significant imaging biomarkers associated with metabolic-related traits.

Findings: Combined with sex, ten VAT texture features achieved areas under the curve (AUCs) of 0.872, 0.888, 0.961, and 0.947 for predicting the prevalence of insulin resistance, MetS, central obesity, and visceral obesity, respectively. A novel imaging biomarker, RunEntropy, was identified to be significantly associated with major metabolic outcomes and a 3.5-year follow-up in 338 volunteers demonstrated its long-term effectiveness. More importantly, the preoperative imaging biomarkers yielded high AUCs and accuracies for estimation of surgery responses, including the percentage of excess weight loss (%EWL) (0.867 and 74.6%), postoperative BMI group (0.930 and 76.1%), postoperative insulin resistance (0.947 and 88.9%), and excess visceral fat loss (the proportion of visceral fat reduced over 50%; 0.928 and 84.1%).

Interpretation: This study shows that the texture features of VAT have significant clinical implications in evaluating metabolic disorders and predicting surgery-induced weight loss effects.

Funding: The complete list of funders can be found in the Acknowledgement section.
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http://dx.doi.org/10.1016/j.ebiom.2021.103471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264112PMC
July 2021

Association of night-time sleep and day napping with the prevalence of MOSH in young obese men.

Andrology 2021 Jul 1. Epub 2021 Jul 1.

Department of Endocrine and Metabolic Diseases, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China.

Background: Obesity in men is also shown to be associated with reduced reproductive potential, and this particular subtype was described as male obesity-associated secondary hypogonadism (MOSH). Recent studies showing the influence of sleep disorders on testosterone levels suggested a potential role of sleep disorders in determining the development of MOSH.

Objectives: To assess the association between night-time sleep duration and day napping and the prevalence of MOSH.

Materials And Methods: In this cross-sectional study, 226 obese male participants aged 18-30 years were enrolled. Daytime napping and night-time sleep duration data were collected using a standardized self-reported Chinese-language questionnaire. MOSH was defined as obese men (BMI ≥ 30 kg/m ) with hypogonadal symptoms and decreased total testosterone level and/or free testosterone level, excluding other causes of hypogonadism.

Results: The overall prevalence of MOSH was 48.2% in this study. An inverse association was observed between night sleep duration and the risk of prevalent MOSH. Men who reported fewer than 6 h of night-time sleep had reduced total testosterone and free testosterone levels and an increased risk of MOSH. Further regression analysis revealed that after adjustment for potential confounders, the odds ratio of MOSH for the short night-time sleep group (<6 h vs. 6-8 h) was 6.17 (p = 0.040). No significant association was observed between day napping status and prevalence of MOSH.

Discussion And Conclusion: Short night sleep duration was associated with an increased risk of MOSH in the young obese Chinese population. Chronic sleep curtailment has a negative effect on obese men's health in terms of hypogonadism.
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http://dx.doi.org/10.1111/andr.13074DOI Listing
July 2021

Reversal of Functional Brain Activity Related to Gut Microbiome and Hormones After VSG Surgery in Patients With Obesity.

J Clin Endocrinol Metab 2021 Aug;106(9):e3619-e3633

Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of Chinese Health Commission, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200025, China.

Context: Vertical sleeve gastrectomy (VSG) is becoming a prioritized surgical intervention for obese individuals; however, the brain circuits that mediate its effective control of food intake and predict surgical outcome remain largely unclear.

Objective: We investigated VSG-correlated alterations of the gut-brain axis.

Methods: In this observational cohort study, 80 patients with obesity were screened. A total of 36 patients together with 26 normal-weight subjects were enrolled and evaluated using the 21-item Three-Factor Eating Questionnaire (TFEQ), MRI scanning, plasma intestinal hormone analysis, and fecal sample sequencing. Thirty-two patients underwent VSG treatment and 19 subjects completed an average of 4-month follow-up evaluation. Data-driven regional homogeneity (ReHo) coupled with seed-based connectivity analysis were used to quantify VSG-related brain activity. Longitudinal alterations of body weight, eating behavior, brain activity, gastrointestinal hormones, and gut microbiota were detected and subjected to repeated measures correlation analysis.

Results: VSG induced significant functional changes in the right putamen (PUT.R) and left supplementary motor area, both of which correlated with weight loss and TFEQ scores. Moreover, postprandial levels of active glucagon-like peptide-1 (aGLP-1) and Ghrelin were associated with ReHo of PUT.R; meanwhile, relative abundance of Clostridia increased by VSG was associated with improvements in aGLP-1 secretion, PUT.R activity, and weight loss. Importantly, VSG normalized excessive functional connectivities with PUT.R, among which baseline connectivity between PUT.R and right orbitofrontal cortex was related to postoperative weight loss.

Conclusion: VSG causes correlated alterations of gut-brain axis, including Clostridia, postprandial aGLP-1, PUT.R activity, and eating habits. Preoperative connectivity of PUT.R may represent a potential predictive marker of surgical outcome in patients with obesity.
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http://dx.doi.org/10.1210/clinem/dgab297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372652PMC
August 2021

Stronger association of triglyceride glucose index than the HOMA-IR with arterial stiffness in patients with type 2 diabetes: a real-world single-centre study.

Cardiovasc Diabetol 2021 04 22;20(1):82. Epub 2021 Apr 22.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: The triglyceride-glucose index (TyG index) has been proposed as a simple and reliable alternative insulin resistance (IR) marker, while the homeostasis model assessment for IR (HOMA-IR) is the most frequently used index. Few studies have evaluated the role of IR assessed by the TyG index and HOMA-IR on arterial stiffness in a type 2 diabetes (T2D) population with a high risk of increased arterial stiffness. We aimed to investigate the association of the TyG index and HOMA-IR with arterial stiffness in patients with T2D.

Methods: We recruited 3185 patients with T2D, who underwent brachial-ankle pulse wave velocity (baPWV), an indicator of arterial stiffness, but without previous cardiovascular disease. Increased arterial stiffness was defined as a baPWV value greater than the 75th percentile (18.15 m/s) in the present study. The TyG index was determined as ln(fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2), and the HOMA-IR was calculated as (fasting insulin [μIU/mL] × fasting glucose [mmol/L])/22.5.

Results: The mean age of the study participants was 54.6 ± 12.0 years, and 1954 (61.4%) were men. Seemingly unrelated regression estimation analysis demonstrated that the TyG index had stronger associations with baPWV than the HOMA-IR (all P < 0.001). In the multivariable logistic analyses, each one-unit increase in the TyG index was associated with a 1.40-fold (95% CI 1.16-1.70, P < 0.001) higher prevalence of increased arterial stiffness, but the prominent association of the HOMA-IR with the prevalence of increased arterial stiffness was not observed. Subgroup analyses showed that a more significant association between the TyG index and the prevalence of increased arterial stiffness was detected in older patients with a longer duration of diabetes and poor glycaemic control (all P < 0.05).

Conclusions: Compared with the HOMA-IR, the TyG index is independently and more strongly associated with arterial stiffness in patients with T2D.
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http://dx.doi.org/10.1186/s12933-021-01274-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063289PMC
April 2021

Association of Metabolic Syndrome With Prevalence of Obstructive Sleep Apnea and Remission After Sleeve Gastrectomy.

Front Physiol 2021 31;12:650260. Epub 2021 Mar 31.

Department of Endocrine and Metabolic Diseases, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Obesity is an important risk factor for metabolic syndrome and obstructive sleep apnea (OSA). Bariatric surgery has been shown to effectively reduce weight and obesity-related comorbidities. However, the prevalence and severity of OSA in obese patients with different baseline metabolic states and the improvements of OSA after bariatric surgery remain unknown. The main aims of this study were to ascertain the prevalence of OSA in young Chinese obese patients with different metabolic states and to evaluate their respective OSA remission after laparoscopic sleeve gastrectomy. We first performed a cross-sectional study involving 123 metabolically healthy obese patients and 200 metabolically unhealthy obese patients (who had the same age and BMI ranges) to estimate the prevalence of OSA at baseline. Then we performed a retrospective study, which was registered at ClinicalTrials.gov (ref. NCT02653430) of 67 patients who underwent laparoscopic sleeve gastrectomy to evaluate the remission of OSA. Metabolically healthy and unhealthy obese patients had similar apnea-hypopnea index levels (16.6 ± 22.0 vs. 16.7 ± 18.7 events/h, = 0.512) and prevalence of OSA (66.7% vs. 69.0%, = 0.662). Male sex, age, waist circumference and lower liver-to-spleen ratio were independent risk factors for OSA. After laparoscopic sleeve gastrectomy, no difference was found in the decrease in body mass index (BMI) change (10.8 ± 4.8 vs. 10.8 ± 3.0 kg/m, = 0.996) or the decrease in the apnea-hypopnea index (18.9 ± 24.6 vs. 17.0 ± 24.0 events/h, = 0.800). The remission of moderate-to-severe OSA was observed in the MHO (36.3%; 54.5-18.2%, = 0.125) and MUO (32.2%; 66.1-33.9%, = 0.001) patients. These results suggest that, in patients with obesity, metabolic syndrome does not add extra risk for the prevalence or severity of OSA. Both metabolically healthy and unhealthy obese patients could benefit equally from laparoscopic sleeve gastrectomy in terms of weight loss and obstructive sleep apnea remission.
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http://dx.doi.org/10.3389/fphys.2021.650260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044302PMC
March 2021

Overexpression Enhances Expression .

Front Endocrinol (Lausanne) 2021 10;12:634191. Epub 2021 Mar 10.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Objective: The Iroquois homeobox 3 () gene was recently reported to be a functional downstream target of a common polymorphism in the gene, which encodes an obesity-associated protein; however, the role of in energy expenditure remains unclear. Studies have revealed that the overexpression of a dominant-negative form of IRX3 in the mouse hypothalamus and adipose tissue promoted energy expenditure by enhancing brown/browning activities. Meanwhile, we and others recently demonstrated that knockdown impaired the browning program of primary preadipocytes . In this study, we aimed to further clarify the effects of overexpressing human (h) on brown/beige adipose tissues .

Methods: Brown/beige adipocyte-specific h-overexpressing mice were generated and the browning program of white adipose tissues was induced by both chronic cold stimulation and CL316,243 injection. Body weight, fat mass, lean mass, and energy expenditure were measured, while morphological changes and the expression of thermogenesis-related genes in adipose tissue were analyzed. Moreover, the browning capacity of primary preadipocytes derived from h-overexpressing mice was assessed. RNA sequencing was also employed to investigate the effect of h on the expression of thermogenesis-related genes.

Results: h overexpression in embryonic brown/beige adipose tissues ( ;Cre) led to increased energy expenditure, decreased fat mass, and a lean body phenotype. After acute cold exposure or CL316,243 stimulation, brown/beige tissue h-overexpressing mice showed an increase in expression. Consistent with this, induced h overexpression in adult mice ( ;Cre) also promoted a moderate increase in expression. experiments further revealed that h overexpression induced by -driven Cre recombinase activity upregulated brown/beige adipocytes expression and oxygen consumption rate (OCR). RNA sequencing analyses indicated that h overexpression in brown adipocytes enhanced brown fat cell differentiation, glycolysis, and gluconeogenesis.

Conclusion: Consistent with the findings, brown/beige adipocyte-specific overexpression of h promoted expression and thermogenesis, while reducing fat mass.
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http://dx.doi.org/10.3389/fendo.2021.634191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988233PMC
March 2021

Missense Variants in PAX4 Are Associated with Early-Onset Diabetes in Chinese.

Diabetes Ther 2021 Jan 20;12(1):289-300. Epub 2020 Nov 20.

Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200025, China.

Introduction: East Asians are more susceptible to early-onset diabetes than Europeans and exhibit reduced insulin secretion at earlier stages. PAX4 plays a critical role in the development of β-cells. The dysfunction-missense variants PAX4 R192H and PAX4 R192S are common in East Asians but rare in Europeans. Therefore, we aim to investigate the diabetes-associated genes, including PAX4 R192H/S, in East Asians with early-onset diabetes.

Methods: Exome variants of 80 Chinese early-onset diabetes patients (onset age < 35 years) after the exclusion of type 1 diabetes (T1D) were detected by a customized gene panel covering 32 known diabetes-associated genes. Then, 229 subjects with early-onset diabetes (T1D excluded) and 1679 controls from the Chinese population were genotyped to validate the association of PAX4 R192H/S with early-onset diabetes and related phenotypes.

Results: The gene panel detected 11 monogenic diabetes patients with five novel mutations among the 80 early-onset diabetes patients. Asian-specifically enriched PAX4 R192H and R192S were associated with early-onset diabetes (R192H: OR 1.88, 95% CI 1.37-2.60, P = 8.41 × 10; R192S: OR 1.71, 95% CI 1.17-2.51, P = 0.005). In early-onset diabetes patients, PAX4 R192H carriers had higher haemoglobin A1c (HbA1c) levels (P = 0.030) and lower 2 h C-peptide levels in the oral glucose tolerance test (OGTT) (P = 0.040); R192S carriers had lower fasting C-peptide (FCP) (P = 0.011) and 2 h C-peptide levels (P = 0.033) in OGTT than non-variant carriers.

Conclusions: The ethnic-specific enrichment of PAX4 R192H/S predisposing East Asians to early-onset diabetes with decreased C-peptide levels may be one explanation of the discrepancy of diabetes between East Asians and Europeans.

Clinical Trial Registration: ClinicalTrials.gov (NCT01938365).
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http://dx.doi.org/10.1007/s13300-020-00960-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843779PMC
January 2021

Sex-influenced association between free triiodothyronine levels and poor glycemic control in euthyroid patients with type 2 diabetes mellitus.

J Diabetes Complications 2020 11 31;34(11):107701. Epub 2020 Jul 31.

Shanghai National Clinical Research Center for Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address:

Objective: The study investigated the association between free triiodothyronine (FT3) and poor glycemic control with different definitions in euthyroid patients with type 2 diabetes mellitus (T2DM).

Methods: This was a cross-sectional study which included 2172 patients from National Metabolic Management Center in Ruijin Hospital. The association between thyroid function and glycated hemoglobin A1c (HbA1c) was determined by multiple liner regression models. The association between FT3 and poor glycemic control was further determined by binary logistic regression models. Two definitions of poor glycemic control (HbA1c ≥ 7% and HbA1c ≥ 8%) were applied when we analyzed the association.

Results: Prevalence of HbA1c ≥ 7% and HbA1c ≥ 8% were 63.8% and 39.3%, respectively. After adjusting for confounding factors, FT3, rather than free tetraiodothyronine (FT4) or thyroid stimulating hormone (TSH), was independently associated with HbA1c (β = -0.104, P = 0.002). Further analysis after gender stratification showed that the association was only found in males (β = -0.164, P < 0.001). We further analyzed the association between FT3 quartiles and poor glycemic control. FT3 quartiles were not significantly associated with the risk of HbA1c ≥ 7% before and after adjusting for confounding factors in both genders. FT3 quartiles were negatively associated with the risk of HbA1c ≥ 8% only in males, independent of traditional risk factors for poor glycemic control (P for trend = 0.030).

Conclusions: FT3 in the reference range was significantly associated with reduced risk of HbA1c ≥ 8% in males, independent of traditional risk factors for poor glycemic control.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107701DOI Listing
November 2020

Care for diabetes with COVID-19: Advice from China.

J Diabetes 2020 05 13;12(5):417-419. Epub 2020 Apr 13.

Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.

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http://dx.doi.org/10.1111/1753-0407.13036DOI Listing
May 2020

Correlation between glucose metabolism and serum steroid hormones in patients with polycystic ovary syndrome.

Clin Endocrinol (Oxf) 2020 04 29;92(4):350-357. Epub 2020 Jan 29.

Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, State Key Laboratory of Medical Genomics, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Objective: Polycystic ovary syndrome (PCOS) is associated with an increased prevalence of dysglycaemia, which includes impaired glucose tolerance and type 2 diabetes mellitus (T2DM). Patients with PCOS demonstrate abnormal patterns of steroid hormones. Here, we analyse the correlation between glucose metabolism and serum steroid hormones in PCOS.

Design: Observational double-centre study.

Patients: 914 patients with PCOS.

Measurements: We assessed the glucose metabolism status of all patients according to the 1999 WHO criteria. Serum steroid hormones were measured by liquid chromatography-tandem mass spectrometry.

Results: The median age of the patients was 26 years (interquartile range: 21-30), and 40.6% (371/914) had abnormal glucose metabolism: 29.3% (268/914) had prediabetes, and 11.3% (103/914) had T2DM. Correlation analysis not adjusting for confounding factors revealed that serum aldosterone, androstenedione, oestrone, pregnenolone and the free androgen index were positively correlated, while progesterone was negatively correlated with the risk of abnormal glucose metabolism. After adjusting for age, body mass index and fasting insulin levels in the logistic regression model, only aldosterone (P = .013), androstenedione (P = .046) and oestrone (P = .014; in quartiles) were correlated with the risk of abnormal glucose metabolism.

Conclusions: This study indicates a high prevalence of prediabetes and T2DM in patients with PCOS. Furthermore, there were positive correlations of serum aldosterone, androstenedione and oestrone with the risk of abnormal glucose metabolism after adjusting for confounding factors.
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http://dx.doi.org/10.1111/cen.14154DOI Listing
April 2020

β dysfunction contributes to adiposity by regulating the cross-talk of mature adipocytes and preadipocytes.

Sci Adv 2020 01 8;6(2):eaax9605. Epub 2020 Jan 8.

Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of Chinese Health Commission, Department of Endocrinology and Metabolism, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.

Overnutrition results in adiposity and chronic inflammation with expansion of white adipose tissue (WAT). However, genetic factors controlling fat mass and adiposity remain largely undetermined. We applied whole-exome sequencing in young obese subjects and identified rare gain-of-function mutations in β-catenin associated with increased obesity risk. Specific ablation of β-catenin in mature adipocytes attenuated high-fat diet-induced obesity and reduced sWAT mass expansion with less proliferated Pdgfrα preadipocytes and less mature adipocytes. Mechanistically, β-catenin regulated the transcription of (), an adipocyte-derived chemokine, through β-catenin-TCF (T-Cell-Specific Transcription Factor) complex in mature adipocytes, and Saa3 activated macrophages to secrete several factors, including Pdgf-aa, which further promoted the proliferation of preadipocytes, suggesting that β-catenin/Saa3/macrophages may mediate mature adipocyte-preadipocyte cross-talk and fat expansion in sWAT. The identification of β-catenin as a key regulator in fat expansion and human adiposity provides the basis for developing drugs targeting Wnt/β-catenin pathway to combat obesity.
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http://dx.doi.org/10.1126/sciadv.aax9605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949042PMC
January 2020

The impact of shift work on glycemic characteristics assessed by CGM and its association with metabolic indices in non-diabetic subjects.

Acta Diabetol 2020 Jan 24;57(1):53-61. Epub 2019 Jun 24.

Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Aim: To explore the glycemic characteristics of non-diabetic shift workers and associations with metabolic indices.

Methods: In this cross-sectional study, 450 non-diabetic males, including 238 shift workers, aged 23-58 years, were recruited after a screening oral glucose tolerance test. Blood samples and anthropometric data were collected. Hundred and fifty of them finished a continuous glucose monitoring for 3-7 days.

Results: Compared to daytime workers, shift workers presented with larger WHR (p < 0.001), higher HOMA-IR (p < 0.001), higher hs-CRP level (p < 0.001) and worse lipid profiles. In glycemic characteristics, shift workers with normal glucose regulation had a similar mean blood glucose (MBG), daytime MBG, percentage of time of hyperglycemia, hypoglycemia, euglycemia, and fluctuation parameters, including standard deviation of blood glucose (SDBG), mean amplitude of glycemic excursions (MAGE) and mean of daily differences (p > 0.05, respectively), while they had a higher nighttime MBG (p = 0.026) and blood glucose (BG) at 3 a.m. (p = 0.015). For subjects with impaired glucose regulation, both groups had no difference in any clinical characteristics or glycemic parameters (p > 0.05, respectively). Further regression analysis revealed the association between MBG/SDBG/MAGE/nighttime MBG/BG at 3 a.m. and age/WHR/hs-CRP/TC.

Conclusion: For non-diabetic shift workers, the glycemic characteristic was the elevated nighttime glycemia, presented as higher nighttime MBG and BG at 3 a.m. And both metrics were closely associated with central obesity. Elevated nighttime glycemia was an early signal of glucose metabolism disorder in shift workers.
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http://dx.doi.org/10.1007/s00592-019-01372-zDOI Listing
January 2020

Saxagliptin alters bile acid profiles and yields metabolic benefits in drug-naïve overweight or obese type 2 diabetes patient.

J Diabetes 2019 Dec 29;11(12):982-992. Epub 2019 Jul 29.

Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai Key Laboratory for Endocrine Tumours, Shanghai Clinical Centre for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases and Shanghai Institute for Endocrinology, Shanghai, China.

Background: The aim of the present study was to investigate the metabolic benefits of saxagliptin and its effects on serum bile acids (BAs) in normal weight and overweight/obese drug-naïve type 2 diabetes (T2D) patients.

Methods: In all, 282 drug-naïve T2D patients (123 normal weight [NW], with body mass index [BMI] between 19.0 and <25.0 kg/m ; 159 overweight/obese [OW/OB], with BMI ≥25.0 kg/m ) were enrolled in the study and treated with saxagliptin 5 mg daily for 24 weeks. Serum BAs were assayed by liquid chromatography with tandem mass spectrometry.

Results: At 24 weeks, HbA1c was significantly reduced in both groups, but the HbA1c levels were lower in the OW/OB than NW group. Moreover, significant decreases were seen at 24 weeks in C-reactive protein (CRP), aspartate aminotransferase, alanine aminotransferase, waist circumference, and systolic blood pressure in the OW/OB group. Interestingly, cholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid (GDCA), and glycoursodeoxycholic acid (GUDCA) were increased in both groups after treatment, whereas chenodeoxycholic acid and deoxycholic acid (DCA) were specifically increased in the OW/OB group. Increased DCA and GDCA concentrations were significantly associated with decreased HbA1c or fasting blood glucose and CRP levels, whereas increased GDCA and GUDCA concentrations were associated with decreased waist circumference in the OW/OB group during treatment. In the NW group, increased GUDCA concentrations were significantly associated with a decrease in HbA1c.

Conclusions: Type 2 diabetes patients with OW/OB exhibited greater improvement in glycemic control and additional metabolic benefits after saxagliptin treatment. Saxagliptin significantly increased the BA pool, and DCA and GDCA were associated with metabolic improvements in OW/OB T2D patients.
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http://dx.doi.org/10.1111/1753-0407.12956DOI Listing
December 2019

Prognosis for residual islet β-cell secretion function in young patients with newly diagnosed type 1 diabetes.

J Diabetes 2019 Oct 22;11(10):818-825. Epub 2019 Apr 22.

Department of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao-Tong University, Shanghai, China.

Background: This study investigated possible predictors of residual islet β-cell function (RBF) in young patients with newly diagnosed type 1 diabetes (T1D).

Methods: After analyzing RBF in 443 patients with T1D according to age at diagnosis and disease duration, 110 were followed-up over 18-60 months. A nomogram was developed by logistic regression to explore factors associated with long-term RBF.

Results: Of the 443 T1D patients (mean [±SD] age 20.28 ± 5.50 years; mean [±SD] diabetes duration 28.5 ± 14.6 months), RBF was preserved in 64.3%. Independent predictors for poor RBF outcome among the 110 patients in the follow-up cohort were age at onset (odds ratio [OR] 0.82; 95% confidence interval [CI] 0.73-0.92; P < 0.001), high-risk human leukocyte antigen (HLA) status (OR 4.73; CI 1.28-17.52; P = 0.020), female sex (OR 3.39; CI 1.03-11.22; P = 0.045), and a history of diabetic ketoacidosis (DKA; OR 8.71; CI 2.31-32.83; P < 0.001). Baseline glutamic acid decarboxylase (GAD) antibody, family history of diabetes, body mass index, insulin dosage, and C-peptide and HbA1c levels were not associated with poor RBF outcome. Intensive glycemic control after T1D diagnosis may improve RBF within a mean (±SD) follow-up of 35.1 ± 13.8 months. The calibration plot for the probability of 2-, 3-, and 4-year RBF showed optimal agreement between nomogram-predicted and actual observed probabilities.

Conclusions: Younger age of onset, female sex, higher HLA risk status, and a history of DKA were the main factors predicting long-term poor preserved β-cell function. Glycemic control could improve RBF during the course of diabetes. The nomogram provides an individualized risk estimate of RBF in patients with newly diagnosed T1D within Chinese Han populations.
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http://dx.doi.org/10.1111/1753-0407.12912DOI Listing
October 2019

Comprehensive assessment of T-cell repertoire following autologous hematopoietic stem cell transplantation for treatment of type 1 diabetes using high-throughput sequencing.

Pediatr Diabetes 2018 11 29;19(7):1229-1237. Epub 2018 Aug 29.

Department of Endocrine and Metabolic diseases, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai Key Laboratory for Endocrine Tumors, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases and Shanghai E-institute for Endocrinology, Shanghai, China.

Objective: We aimed to investigate T-cell receptor (TCR) repertoires in type 1 diabetes (T1D) patients receiving autologous hematopoietic stem cell transplantation (AHSCT) treatment.

Methods: High-throughput deep TCR beta (TCRB) chain sequencing was performed to assess millions of individual TCRs in five T1D patients receiving AHSCT treatment and another five patients receiving insulin treatment during 12 months of follow-up.

Results: No significant changes in TCRB sequence reads, complementarity-determining region 3 (CDR3) sequences, or the usage of TCRB VJ gene-segments were observed at 12 months after AHSCT. Compared with the baseline, the usage of TCRB VJ gene-segments at 12 months decreased in the insulin treatment group (1836.4 ± 437.7 vs 2763.6 ± 390.6, P = 0.015), and the change rates were larger than those undergoing AHSCT (-0.62 ± 0.16 vs 0.06 ± 0.45, P = 0.002). Changes in the TCR repertoire were smaller after AHSCT than those with insulin treatment (P = 2.2*10 ). TCRBV 7-7/TCRBJ 2-5 was depleted after AHSCT while expanded with insulin treatment. TCRBV 12-4, TCRBV 10-3, TCRBV 12-3/TCRBJ 1-2 were expanded after AHSCT while ablated with insulin treatment.

Conclusions: We found that AHSCT is safe without reduction in the diversity of TCR repertoires and TCR repertoires tend to be more stable after AHSCT. Furthermore, these four candidate TCRBV/TCRBJ gene usages on CDR3 regions may act as therapeutic targets and biomarkers.
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http://dx.doi.org/10.1111/pedi.12728DOI Listing
November 2018

Plasma bile acid changes in type 2 diabetes correlated with insulin secretion in two-step hyperglycemic clamp.

J Diabetes 2018 Nov 28;10(11):874-885. Epub 2018 May 28.

Shanghai National Research Centre for Endocrine and Metabolic Diseases, State Key Laboratory of Medical Genomics, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Bile acids (BAs) conduct crucial signals in human metabolism. Correlations between changes in plasma BA concentrations, insulin secretion defects, and progression of type 2 diabetes mellitus (T2DM) in humans have not been sufficiently investigated. This study explored the trajectories of changes in human plasma BA concentrations and their association with insulin secretion dynamics during a two-step hyperglycemic clamp.

Methods: Eleven healthy subjects with normal glucose tolerance (NGT) and 33 drug-naïve T2DM subjects were enrolled in the study. The two-step hyperglycemic clamp consisted of a classic clamp as Step 1 with fasting, followed by a Step 2 clamp after ingestion of a carbohydrate meal, illustrating basal and incretin-amplified insulin responses to glucose. Plasma BA were assayed using liquid chromatography-tandem mass spectrometry. Nine T2DM subjects were followed-up, and the two-step clamp was repeated after 3 months sulfonylurea treatment.

Results: Ursodeoxycholic acid (UDCA) was lower and lithocholic acid (LCA) and taurocholic acid (TCA) were higher in T2DM compared with NGT subjects. The dynamics of plasma UDCA concentrations and the UDCA/LCA ratio was positively correlated with insulin secretion in T2DM subjects and were corrected after treatment. Moreover, fasting ratios of UDCA/LCA and unconjugated/conjugated BAs were correlated with the first phase of insulin secretion in T2DM subjects.

Conclusion: The abnormal BA composition in T2DM subjects and its correlation with insulin secretion during the clamp suggest an interaction between BA signals and insulin secretion capacity, and the potential to use fasting plasma BA composition indices to predict and evaluate the progression and prognosis of T2DM.
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http://dx.doi.org/10.1111/1753-0407.12771DOI Listing
November 2018

Clinical and Physiological Characterization of Elevated Plasma Glucagon-Like Peptide-1 Levels (Hyperglipemia) in a Dipeptidyl Peptidase IV Mutation Carrier.

Front Endocrinol (Lausanne) 2018 5;9:62. Epub 2018 Mar 5.

Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.

The clinical application of dipeptidyl peptidase IV inhibitors (DPP4i) increasing active glucagon-like peptide-1 (AGLP-1) levels has been linked to pancreatitis, pancreatic tumors, and cardiovascular events. However, mutations in humans or the long-term outcomes of high glucagon-like peptide-1 (GLP-1) level exposure have not been reported. A trio family with a proband showing an extremely high AGLP-1 level [defined here as hyperglipemia (hyper-glucagon-like peptide-1-emia)] were conducted whole-exome sequencing for potential pathogenic genetic defects. One novel mutation, p.V486M (c.1456 G>A), was identified in the proband and showed damaged enzymatic activity of DPP4. functional study further showed that the serum from the proband markedly enhanced insulin production of primary rat islet cells. Furthermore, V486M variant and another eight variants were identified in our in-home database and seven showed decreased enzymatic activities than wild-type DPP4, consistent with their alterations in their protein expression levels. Of note, the levels of glucose, lipids, and tumor markers (especially for CA15-3 and CA125), increased gradually in the proband during a 4-year follow-up period, although no abnormal physical symptoms or imaging results were observed at present. The other two old carriers in the pedigree both had type 2 diabetes, and one of them also had hyperlipidemia and myocarditis. We first identified hyperglipemia in a female subject harboring a loss-of-function mutation with decreased DPP4 activity. Other sporadic mutations verified the low-frequent occurrence of genetic inhibition of DPP4 activity, at least in the Chinese population studied. These results may provide new evidence for evaluation of the potential long-term effects of DPP4i and GLP-1 analogs.
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http://dx.doi.org/10.3389/fendo.2018.00062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845420PMC
March 2018

Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment.

Nat Commun 2017 11 27;8(1):1785. Epub 2017 Nov 27.

Shanghai National Research Centre for Endocrine and Metabolic Diseases, State Key Laboratory of Medical Genomics, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025, Shanghai, China.

Antidiabetic medication may modulate the gut microbiota and thereby alter plasma and faecal bile acid (BA) composition, which may improve metabolic health. Here we show that treatment with Acarbose, but not Glipizide, increases the ratio between primary BAs and secondary BAs and plasma levels of unconjugated BAs in treatment-naive type 2 diabetes (T2D) patients, which may beneficially affect metabolism. Acarbose increases the relative abundances of Lactobacillus and Bifidobacterium in the gut microbiota and depletes Bacteroides, thereby changing the relative abundance of microbial genes involved in BA metabolism. Treatment outcomes of Acarbose are dependent on gut microbiota compositions prior to treatment. Compared to patients with a gut microbiota dominated by Prevotella, those with a high abundance of Bacteroides exhibit more changes in plasma BAs and greater improvement in metabolic parameters after Acarbose treatment. Our work highlights the potential for stratification of T2D patients based on their gut microbiota prior to treatment.
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http://dx.doi.org/10.1038/s41467-017-01682-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702614PMC
November 2017

Steroid hormone profiling in obese and nonobese women with polycystic ovary syndrome.

Sci Rep 2017 10 26;7(1):14156. Epub 2017 Oct 26.

Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of Chinese Ministry of Health, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.

The study explored differences in the steroidogenic pathway between obese and nonobese women with polycystic ovary syndrome (PCOS) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). 1044 women with PCOS (including 350 lean, 312 overweight and 382 obese) and 366 control women without PCOS (including 203 lean, 32 overweight and 131 obese) were enrolled. The differences in steroid hormones were amplified in lean PCOS versus lean controls compared with obese PCOS versus obese controls. Compared with obese PCOS, lean PCOS demonstrated increased dehydroepiandrosterone sulfate (P = 0.015), 17-hydropregnenolone (P = 0.003), 17-hydroprogesterone (17-OHP) (P < 0.001), progesterone (P < 0.001) and estrone (P < 0.001) levels. Enzyme activity evaluation showed that lean PCOS had increased activity of P450c17 (17-hydropregnenolone/pregnenolone, P < 0.001), P450aro (P < 0.001), 3βHSD2 (progesterone/ pregnenolone and 17-OHP/17-hydropregnenolone, both P < 0.001) and decreased activity of P450c21(11-deoxycorticorsterone/progesterone and 11-deoxycortisol/17-OHP, P < 0.001). Moreover, we found higher frequencies of CYP21A2- (encoding P450c21) c.552 C > G (p. D184E) in lean PCOS compared with obese PCOS patients (P = 0.006). In conclusion, this study demonstrated for the first time that the adrenal-specific enzyme P450c21 showed decreased activity in lean PCOS patients, and that the adrenal androgen excess may play different roles in lean and obese PCOS patients, which represents as different enzyme activity in the steroidogenic pathway.
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http://dx.doi.org/10.1038/s41598-017-14534-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658378PMC
October 2017

IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk.

EBioMedicine 2017 Oct 13;24:64-75. Epub 2017 Sep 13.

Department of Endocrinology and Metabolism, National Key Laboratory for Medical Genomes, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200025, China. Electronic address:

Background: IRX3 was recently reported as the effector of the FTO variants. We aimed to test IRX3's roles in the browning program and to evaluate the association between the genetic variants in IRX3 and human obesity.

Methods: IRX3 expression was examined in beige adipocytes in human and mouse models, and further validated in induced beige adipocytes. The browning capacity of primary preadipocytes was assessed with IRX3 knockdown. Luciferase reporter analysis and ChIP assay were applied to investigate IRX3's effects on UCP1 transcriptional activity. Moreover, genetic analysis of IRX3 was performed in 861 young obese subjects and 916 controls.

Results: IRX3 expression was induced in the browning process and was positively correlated with the browning markers. IRX3 knockdown remarkably inhibited UCP1 expression in induced mouse and human beige adipocytes, and also repressed the uncoupled oxygen consumption rate. Further, IRX3 directly bound to UCP1 promoter and increased its transcriptional activity. Moreover, 17 rare heterozygous missense/frameshift IRX3 variants were identified, with a significant enrichment in obese subjects (P=0.038, OR=2.27; 95% CI, 1.02-5.05).

Conclusions: IRX3 deficiency repressed the browning program of white adipocytes partially by regulating UCP1 transcriptional activity. Rare variants of IRX3 were associated with human obesity.
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http://dx.doi.org/10.1016/j.ebiom.2017.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652024PMC
October 2017

Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention.

Nat Med 2017 Jul 19;23(7):859-868. Epub 2017 Jun 19.

BGI-Shenzhen, Shenzhen, China.

Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of Bacteroides thetaiotaomicron, a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with B. thetaiotaomicron reduced plasma glutamate concentration and alleviated diet-induced body-weight gain and adiposity in mice. Furthermore, weight-loss intervention by bariatric surgery partially reversed obesity-associated microbial and metabolic alterations in obese individuals, including the decreased abundance of B. thetaiotaomicron and the elevated serum glutamate concentration. Our findings identify previously unknown links between intestinal microbiota alterations, circulating amino acids and obesity, suggesting that it may be possible to intervene in obesity by targeting the gut microbiota.
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http://dx.doi.org/10.1038/nm.4358DOI Listing
July 2017

Intensive insulin therapy combined with metformin is associated with reduction in both glucose variability and nocturnal hypoglycaemia in patients with type 2 diabetes.

Diabetes Metab Res Rev 2017 10 13;33(7). Epub 2017 Jul 13.

Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of Chinese Ministry of Health, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Background: The effect on glucose variability in patients with intensive insulin therapy has not been fully understood. This observational study investigated the different glucose variability and hypoglycaemia patterns in type 2 diabetes patients treated with continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI) with or without metformin administration.

Methods: During hospitalization, a total of 501 patients with poor glycaemic control and in initial treatment with either CSII alone (n = 187), CSII + Metformin (n = 81), MDI alone (n = 146), or MDI + Metformin (n = 87) were involved in the final analysis. Data obtained from continuous glucose monitoring were used to assess blood glucose fluctuation and nocturnal hypoglycaemia.

Results: Among the 4 groups, no difference was found in mean blood glucose levels. Results in parameters reflecting glucose fluctuation: continuous overlapping net glycaemic action in CSII + Metformin and mean amplitude of glycaemic excursions in MDI + Metformin were significantly lower than those in either CSII alone or MDI alone, respectively, even after adjustment (P = .031 and .006). Frequency of nocturnal hypoglycaemia was significantly decreased in CSII + Metformin as compared with CSII alone (0.6% vs 1.8%) and in MDI + Metformin as compared with MDI alone (1.6% vs 2.3%), with the highest frequency observed in MDI alone and the lowest in CSII + Metformin (all between group P < .001). Consistent results were obtained in between-group comparisons for hypoglycaemia duration. Subgroup analysis matched with baseline body mass index, and glycated haemoglobin and fasting blood glucose further confirmed these findings.

Conclusion: Metformin added to initial CSII or MDI therapy is associated with a reduction in both glucose fluctuation and nocturnal hypoglycaemic risk in patients with type 2 diabetes.
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http://dx.doi.org/10.1002/dmrr.2913DOI Listing
October 2017

Glycated Hemoglobin is Independently Associated with Albuminuria in Young Nondiabetic People with Obesity: A Cross-Sectional Study.

Med Sci Monit 2017 May 29;23:2612-2618. Epub 2017 May 29.

Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China (mainland).

BACKGROUND The aim of this study was to explore the association between glycated hemoglobin (HbA1c) level and albuminuria in young nondiabetic people with obesity. MATERIAL AND METHODS A total of 537 young nondiabetic people with obesity were enrolled in this cross-sectional study, which was approved by the Rui-jin Hospital Ethics Committee. Albuminuria was defined as a urinary albumin-to-creatinine ratio (ACR) ≥30 mg/g. Multivariate logistic regression was used to analyze the association between HbA1c level and albuminuria. RESULTS Urinary ACR progressively increased across the tertiles of HbA1c level (P for trend <0.05). HbA1c levels were positively associated with the risk of albuminuria in the logistic regression analysis after adjustment for confounding factors. The adjusted odds ratio (OR) for albuminuria was 3.72 (95% confidence interval [CI], 1.25-11.00; P=0.017) when comparing between the highest (≥5.7%) and lowest tertiles of HbA1c level (≤5.3%). Moreover, an increment of 1 SD in HbA1c level increased the risk of albuminuria in a fully adjusted model (OR, 1.73; 95% CI, 1.25-2.46). CONCLUSIONS These data suggest that HbA1c level was independently associated with albuminuria in young nondiabetic people with obesity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461886PMC
http://dx.doi.org/10.12659/msm.902450DOI Listing
May 2017

Immune response after autologous hematopoietic stem cell transplantation in type 1 diabetes mellitus.

Stem Cell Res Ther 2017 04 18;8(1):90. Epub 2017 Apr 18.

The Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai Institution of Endocrine and Metabolism Diseases, Endocrine and Metabolic E-Institutes of Shanghai Universities and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, No. 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.

Background: This study explored the details of the immune response after autologous hematopoietic stem cell transplantation (AHSCT) treatment in type 1 diabetes mellitus.

Methods: Peripheral blood mononuclear cells (PBMCs) from 18 patients with type 1 diabetes mellitus were taken at baseline and 12 months after AHSCT or insulin-only therapy. The lymphocyte proliferation, mRNA expression and secretion of pro-inflammatory and anti-inflammatory cytokines belonging to T-helper type 1 (Th1), T-helper type 17 (Th17) and regulatory T (Treg) cells in PBMC culture supernatants were assessed.

Results: Compared with patients receiving insulin-only treatment, the patients receiving AHSCT treatment showed better residual C-peptide secretion, lower anti-GAD titers and less exogenous insulin dosages after 12 months of follow-up. AHSCT treatment was associated with significantly reduced Th1 and Th17 cell proportions as well as decreased IFN-γ, IL-2, IL-12p40 and IL-17A levels in the PBMC culture supernatants (all P < 0.05). Although there was no significant Treg cell expansion after AHSCT treatment, we observed increased IL-10, TGF-β and Foxp3 mRNA expression and increased TGF-β levels. However, we found no significant changes in the T-cell subpopulations after insulin treatment, except for higher IL-12p40 mRNA expression and a lower proportion of Treg cells.

Conclusions: AHSCT treatment was associated with decreased expansion and function of Th1 and Th17 cells, which may explain the better therapeutic effect of AHSCT compared with the traditional intensive insulin therapy.

Trial Registration: Clinicaltrials.gov NCT00807651 . Registered 18 December 2008.
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http://dx.doi.org/10.1186/s13287-017-0542-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395765PMC
April 2017

Prevalence of polycystic ovary syndrome in Chinese obese women of reproductive age with or without metabolic syndrome.

Fertil Steril 2017 Apr 24;107(4):1048-1054. Epub 2017 Feb 24.

Shanghai Clinical Center for Endocrine and Metabolic Diseases at Ruijin Hospital, Shanghai; Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai; Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China. Electronic address:

Objective: To compare the prevalence of polycystic ovary syndrome (PCOS) and related clinical characteristics between metabolically unhealthy obese (MUO) and metabolically healthy obese (MHO) women of reproductive age.

Design: Cross-sectional clinical study.

Setting: Tertiary hospital.

Patient(s): We studied 299 MUO and 122 MHO Chinese women matched on body mass index. Metabolically healthy obese was defined as obesity with no more than one metabolic abnormality. Diagnosis of PCOS was based on the revised Rotterdam criteria.

Intervention(s): Each subject underwent physical examination, laboratory evaluation, and gynecologic ultrasound for a diagnosis of PCOS or metabolic syndrome (MetS).

Main Outcome Measure(s): Prevalence of PCOS was calculated in both groups. Insulin resistance was determined by homeostasis model assessment of insulin resistance or by the insulin sensitivity index derived from Bergman's minimal model. Fat distribution was measured with computerized tomography scan.

Result(s): Prevalence of PCOS and its components did not differ between MUO and BMI-matched MHO groups (67.89% and 66.96%, respectively). In logistic regression analysis, MetS did not predict the presence of PCOS after adjusting for confounding factors. The MHO group had lower visceral adipose tissue, relatively higher insulin sensitivity, and better β-cell function, compared with those in the MUO group; but there were no significant differences in sex hormones (except for free T and sex hormone-binding globulin) and ultrasound manifestations between MHO and MUO women.

Conclusion(s): For the first time, our findings suggest that MetS does not add additional risk for PCOS. In addition, we found that both MUO and MHO are associated with insulin resistance to some extent.
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http://dx.doi.org/10.1016/j.fertnstert.2016.12.029DOI Listing
April 2017

Rare Loss-of-Function Variants in Predispose to Human Obesity.

Diabetes 2017 04 27;66(4):935-947. Epub 2017 Jan 27.

Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD.

Some Shanghai Clinical Center f a role of Niemann-Pick type C1 () for obesity traits. However, whether the loss-of-function mutations in cause adiposity in humans remains unknown. We recruited 25 probands with rare autosomal-recessive Niemann-Pick type C (NP-C) disease and their parents in assessment of the effect of heterozygous mutations on adiposity. We found that male carriers had a significantly higher BMI than matched control subjects or the whole population-based control subjects. Consistently, male mice had increased fat storage while eating a high-fat diet. We further conducted an in-depth assessment of rare variants in the gene in young, severely obese subjects and lean control subjects and identified 17 rare nonsynonymous/frameshift variants in (minor allele frequency <1%) that were significantly associated with an increased risk of obesity (3.40% vs. 0.73%, respectively, in obese patients and control subjects, = 0.0008, odds ratio = 4.8, 95% CI 1.7-13.2), indicating that rare variants were enriched in young, morbidly obese Chinese subjects. Importantly, participants carrying rare variants with severely damaged cholesterol-transporting ability had more fat accumulation than those with mild/no damage rare variants. In summary, rare loss-of-function mutations were identified as being associated with human adiposity with a high penetrance, providing potential therapeutic interventions for obesity in addition to the role of in the familial NP-C disease.
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http://dx.doi.org/10.2337/db16-0877DOI Listing
April 2017

HLA-A*33-DR3 and A*33-DR9 haplotypes enhance the risk of type 1 diabetes in Han Chinese.

J Diabetes Investig 2016 Jul 3;7(4):514-21. Epub 2016 May 3.

Department of Endocrine and Metabolic diseases, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai Key Laboratory for Endocrine Tumors, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases and Shanghai E-institute for Endocrinology, Shanghai, China.

Aims/introduction: To investigate the typing for human leukocyte antigen (HLA) class I in Chinese patients with type 1 diabetes as a complement screening for HLA class II.

Materials And Methods: A total of 212 type 1 diabetic patients and 200 healthy controls were enrolled. The genetic polymorphisms of HLA class I and II were examined with a high-resolution polymerase chain reaction sequence-based typing method.

Results: The haplotype, A*33:03-B*58:01-C*03:02(A33), was associated with type 1 diabetes (P = 1.0 × 10(-4) , odds ratio 3.2 [1.738-5.843]). The A33-DR3 and A33-DR9 haplotypes significantly enhanced the risk of type 1 diabetes (A33-DR3, odds ratio 5.1 [2.40-10.78], P = 4.0 × 10(-6) ; A33-DR9, odds ratio 13.0 [1.69-100.32], P = 0.004). In type 1 diabetic patients, compared with A33-DR3-negative carriers, A33-DR3-positive carriers had significantly lower percentages of CD3(+) CD4(+) T cells (42.5 ± 7.72 vs 37.0 ± 8.35%, P = 0.023), higher percentages of CD3(+) CD8(+) T cells (27.4 ± 7.09 vs 32.8 ± 5.98%, P = 0.005) and T-cell receptor α/β T cells (70.0 ± 7.00 vs 73.6 ± 6.25%, P = 0.031), and lower CD4/CD8 ratios (1.71 ± 0.75 vs 1.16 ± 0.35, P = 0.003).

Conclusions: It is the first time that the haplotypes A33-DR3 and A33-DR9 were found with an enhanced predisposition to type 1 diabetes in Han Chinese. A33-DR3 was associated with a reduction in the helper-to-cytotoxic cell ratio and preferential increase of T-cell receptor α/β T cell. The typing for HLA class I and its immunogenetic effects are important for more accurate HLA class II haplotype risk prediction and etiology research in type 1 diabetic patients.
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http://dx.doi.org/10.1111/jdi.12462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931201PMC
July 2016

Efficacy and safety of saxagliptin monotherapy or added to metformin in Chinese patients with type 2 diabetes mellitus: results from the 24-week, post-marketing SUNSHINE study.

J Diabetes 2016 Nov 6;8(6):809-815. Epub 2016 Mar 6.

Ruijin Hospital, Shanghai.

Background: The aim of the present study was to explore the efficacy and safety of saxagliptin in a large Chinese population with type 2 diabetes mellitus (T2DM).

Methods: In all, 1423 T2DM patients from 92 research centers, either drug naïve or uncontrolled by metformin, were enrolled in this single-arm cohort study; patients were treated with saxagliptin 5 mg once daily for 24 weeks. The primary efficacy endpoint was the change from baseline in HbA1c at 24 weeks in the per-protocol analysis set. Secondary endpoints included the proportion of patients achieving HbA1c <7% and changes from baseline in fasting plasma glucose (FPG) and 2-h postprandial plasma glucose (PPG) concentrations at 24 weeks. Safety endpoints included adverse events (AEs) and the incidence of hypoglycemia.

Results: Among 1210 patients in the per-protocol analysis set, mean HbA1c, FPG and 2-h PPG decreased by 1.61 ± 0.04%, 0.55 ± 0.07 mmol/L, and 2.83  ±  0.27 mmol/L, respectively, at week 24. The proportion of patients achieving HbA1c <7% was 44.1%. No new (previously unreported) AEs occurred. The incidence of serious AEs and hypoglycemia was low (1.8% and 1.2%, respectively). There were no significant differences in efficacy endpoints in subgroup analyses by age, creatinine clearance, body mass index, or treatment background. In elderly patients (≥65 years) and those with mild renal impairment (50 < CCr ≤ 80 mL/min), the incidence of AEs was similar to that of the entire study population.

Conclusions: Saxagliptin significantly improved glycemic control and was well tolerated in Chinese T2DM patients, including the elderly and patients with mild renal impairment.
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http://dx.doi.org/10.1111/1753-0407.12360DOI Listing
November 2016

Resistance to high-fat diet-induced obesity in male heterozygous Pprc1 knockout mice.

Endocr J 2015 20;62(7):633-44. Epub 2015 May 20.

Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrinology and Metabolism, Endocrine and Metabolic E-Institutes of Shanghai Universities and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Rui-jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shang Hai 200025, China.

Peroxisome proliferator-activated receptor gamma, co-activator-related 1 (Pprc1) is the third member of the Pgc1 family. Other than the well-characterized Pgc1a and Pgc1b that act as regulators of mitochondrial biogenesis and oxidative metabolism, the function of Pprc1 in vivo is rarely reported, due to embryonic lethality of whole-body Pprc1 knockout mice. To investigate the biological and physiological function of Pprc1 in metabolic processes, male Pprc1(+/-) mice fed with a high fat diet (HFD) showed resistance to diet-induced obesity with a decrease of adipose tissue in Pprc1(+/-) mice, which was a result of elevated energy expenditure. In skeletal muscle of Pprc1(+/-) mice, Pprc1 level showed haplo-insufficiency with down-regulation of Pgc1b and Pgc1a, whereas in adipose tissue, Pprc1 expression remained normal, with significant compensatory increase of other Pgc1 family members to induce an up-regulation of respiratory chain genes. Taken together, as the first report on the metabolic roles of Pprc1 in vivo, these results indicated an elevated basal metabolic rate and lipid metabolic alteration of male Pprc1(+/-) mice on HFD, suggesting the significant role of Pprc1 in controlling mitochondrial gene expression and energy metabolic processes, synergistically with Pgc1a and Pgc1b.
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http://dx.doi.org/10.1507/endocrj.EJ14-0383DOI Listing
May 2016

miR-144/451 Promote Cell Proliferation via Targeting PTEN/AKT Pathway in Insulinomas.

Endocrinology 2015 Jul 28;156(7):2429-39. Epub 2015 Apr 28.

Shanghai Clinical Center for Endocrine and Metabolic Diseases (X.J., A.S., Y.S., Y.C., W.G., W.W., G.N., Y.C.), Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, and Laboratory of Endocrinology and Metabolism (G.N.), Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China.

Insulinoma is the main type of functional pancreatic neuroendocrine tumors. The functional microRNAs (miRNAs) regulating tumor growth and progression in insulinomas are still unknown. We conducted the miRNA expression profile analysis using miRNA quantitative RT-PCR array and identified 114 differentially expressed miRNAs in human insulinomas compared with normal pancreatic islets. Forty-one differentially expressed miRNAs belonged to 7 miRNA families, and 28 miRNAs in 3 of the families localized in the epigenetically regulated imprinted chromosome 14q32 region. We validated the most significant differentially expressed miRNA cluster miR-144/451 in another 8 human normal islet samples and 25 insulinomas. Our data showed that the overexpression of miR-144/451 in mouse pancreatic β-cells promoted cell proliferation by targeting the β-cell regulator phosphatase and tensin homolog deleted on chromosome ten/v-akt murine thymoma viral oncogene homolog pathway and cyclin-dependent kinase inhibitor 2D. Our findings highlight the importance of functional miRNAs in insulinomas.
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http://dx.doi.org/10.1210/en.2014-1966DOI Listing
July 2015
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