Publications by authors named "Haibing Chen"

51 Publications

Musculoskeletal ultrasound features-based scoring system can evaluate the severity of gout and asymptomatic hyperuricaemia.

Ther Adv Musculoskelet Dis 2021 12;13:1759720X211006985. Epub 2021 May 12.

Department of Endocrinology and Metabolism, Shanghai 10th People's Hospital, School of Medicine, Tongji University, 301 Yanchang Road, Shanghai 200072, China.

Objectives: To develop a tool which can evaluate the severity of the joint injury in individuals with gout and asymptomatic hyperuricaemia.

Methods: This retrospective study included 616 male patients: 245 with asymptomatic hyperuricaemia and 371 with intercritical gout. All patients underwent ultrasonography of the knee, ankle and first metatarsophalangeal (MTP) joints. Ultrasound features that were significantly different between groups were entered into a binary logistic regression analysis to identify discriminative factors. The ultrasound signs were scored based on their odds ratios, which were then used to evaluate the severity of gout and asymptomatic hyperuricaemia. The performance of the ultrasound score was validated in an additional population including 163 patients with asymptomatic hyperuricaemia and 196 patients with gout.

Results: Ultrasound signs were scored as follows: knee joint: synovial effusion, 2 points, tophus, 5 points; ankle joint: synovial effusion, 2 points, synovial hypertrophy, 5 points, tophus, 3 points, bone erosion, 7 points; and first MTP joint: double contour sign, 2 points, synovial hypertrophy, 3 points, tophus, 9 points, bone erosion, 4 points. The maximum possible total score was 42. The optimal cut-off score for gout was 6.5. The sensitivity, specificity and area under the receiver operating characteristic curve (AUC) were 86.9%, 75.2% and 0.878, respectively. The patients were stratified according to their ultrasound score (range 0-42). The prevalence of intercritical gout, tophi, and bone erosion increased with the increase of the score. In the validation population, 83.20% of 193 patients with gout had ultrasound scores above 6.5; 76.10% of 163 patients with asymptomatic hyperuricaemia had ultrasound scores under 6.5.

Conclusion: The scoring system based on the differential ultrasound signs can effectively evaluate the severity of joint injury in individuals with gout and asymptomatic hyperuricaemia.
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http://dx.doi.org/10.1177/1759720X211006985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120533PMC
May 2021

A Higher Serum Calcium Level is an Independent Risk Factor for Vision-Threatening Diabetic Retinopathy in Patients with Type 2 Diabetes: Cross-Sectional and Longitudinal Analyses.

Endocr Pract 2021 May 14. Epub 2021 May 14.

Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai engineering center for precise diagnosis and treatment of eye diseases, Shanghai, China. Electronic address: https://orcid.org/0000-0001-8435-0240.

Objective: An elevated serum calcium level is associated with a higher risk of type 2 diabetes (T2D), but its role in microvascular complications remains unclear. This study was conducted to investigate the association between serum calcium levels and vision-threatening diabetic retinopathy (VTDR).

Methods: This study employed a cross-sectional and longitudinal design. The cross-sectional part included all patients treated for T2D at Shanghai General Hospital between 2007 and 2016, while the longitudinal part involved an overlapping cohort of diabetic patients without VTDR who were followed from their admission until December 2019. VTDR was defined as severe nonproliferative, proliferative diabetic retinopathy, or clinically significant macular edema. Multivariable logistic and Cox proportional hazard regression analyses were performed respectively.

Results: A total of 3269 patients were included in the cross-sectional analysis, and 649 patients were included in the longitudinal analysis. In the cross-sectional analysis, the following factors were independently associated with VTDR: higher corrected serum calcium (odds ratio 1.31 per 0.1 mmol/L, 95% confidence interval [CI] 1.16-1.49), younger age, longer diabetes duration, albuminuria, impaired renal function, and lower serum magnesium. In the longitudinal analysis, 95 subjects developed VTDR during follow-up (9.7 years, interquartile range 7.4-10.9 years). The following variables were identified as independent risk factors for VTDR: higher corrected serum calcium (hazard ratio 1.38 per 0.1 mmol/L, 95% CI 1.10-1.72), younger age, longer diabetes duration, sub-VTDR, albuminuria, lower serum magnesium, and higher HbA1c.

Conclusions: A higher serum calcium level may be an independent risk factor for VTDR in patients with T2D.
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http://dx.doi.org/10.1016/j.eprac.2021.05.003DOI Listing
May 2021

Diabetic nephropathy in mice is aggravated by the absence of podocyte IRE1 and is correlated with reduced kidney ADH1 expression.

Ann Transl Med 2021 Apr;9(8):636

Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Inositol-requiring enzyme 1 (IRE1) plays a critical role in attenuating endoplasmic reticulum (ER) stress associated with renal injury which may also be a factor in diabetic nephropathy (DN). Alcohol dehydrogenase type I (ADH1) activity is prominent in the kidney, ADH1 activity is also reported to exert protective effects against ER stress that are not caused by alcohol consumption. However, the role of IRE1 in DN and the correlation between IRE1 and ADH1 activity remain unclear.

Methods: IRE1α floxed mice ( ) of C57BL/6J background were established and crossbred with mice to produce podocyte-specific IRE1α knockout mice. Male db/db mice (C57BLKS/J-leprdb/leprdb mice) were used as a DN model. Male mice were made diabetic by injection of streptozotocin. pLKO.1-based vectors encoding short hairpin RNA (shRNA) specific to the IRE1α gene were transfected into HEK293T cells to knockdown IRE1α in mouse podocytes. ELISA, Masson's staining, and electron microscopy were performed to analyze the development of DN. The ADH1 expression was assayed by qPCR and western blot.

Results: We found that IRE activity was increased in the glomeruli of DN mouse models. In contrast, ADH1 expression was decreased in these models and mice with podocyte-specific disruption of IRE1 (PKO mice). PKO mice that were made diabetic using strepto-zotocin exhibited accelerated proteinuria, enhanced glomerular fibrosis, and podocyte cell death. In addition, in cultured podocytes, the knockdown of IRE1 downregulated the ADH1 mRNA expression and induced ER stress, consistent with the result of PKO mice, while its detrimental effects were reversed by ADH1 overexpression.

Conclusions: Activation of IRE1 in podocytes serves to limit the progress of DN. The dependence of kidney ADH1 expression on podocyte IRE1 further suggests that ADH1 activity may play an important role downstream of IRE1 in protecting against DN.
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http://dx.doi.org/10.21037/atm-20-6356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106116PMC
April 2021

Thyroid Hormone-Regulated Expression of Period2 Promotes Liver Urate Production.

Front Cell Dev Biol 2021 1;9:636802. Epub 2021 Apr 1.

Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

The relationship between thyroid hormones and serum urate is unclear. Our aim is to analyze the correlation between uric acid and thyroid hormones in gout patients and to explore the effect and mechanism of triiodothyronine on liver uric acid production. Eighty men patients with gout were selected to analyze the correlation between blood urate and thyroid function-related hormone levels. Stepwise multiple linear regression was used to analyze factors affecting blood urate in patients with gout. Levels of urate in serum, liver, and cell culture supernatant were measured after triiodothyronine treatment. Purine levels (adenine, guanine, and hypoxanthine) were also measured. Expression levels of Period2 and nucleotide metabolism enzymes were analyzed after triiodothyronine treatment and Period2-shRNA lentivirus transduction. Chromatin immunoprecipitation was used to analyze the effects of triiodothyronine and thyroid hormone receptor-β on Period2 expression. The results showed that in patients FT3 influenced the serum urate level. Furthermore, urate level increased in mouse liver and cell culture supernatant following treatment with triiodothyronine. Purine levels in mouse liver increased, accompanied by upregulation of enzymes involved in nucleotide metabolism. These phenomena were reversed in Period2 knockout mice. Triiodothyronine promoted the binding of thyroid hormone receptor-β to the Period2 promoter and subsequent transcription of Period2. Triiodothyronine also enhanced nuclear expression of Sirt1, which synergistically enhanced Period2 expression. The study demonstrated that triiodothyronine is independently positively correlated with serum urate and liver uric acid production through Period2, providing novel insights into the purine metabolism underlying hyperuricemia/gout pathophysiology.
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http://dx.doi.org/10.3389/fcell.2021.636802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047155PMC
April 2021

Higher Serum Uric Acid Levels Are Associated With an Increased Risk of Vision-Threatening Diabetic Retinopathy in Type 2 Diabetes Patients.

Invest Ophthalmol Vis Sci 2021 Apr;62(4):23

Department of Endocrinology and Metabolism, Shanghai 10th People's Hospital, Tongji University, Shanghai, China.

Purpose: To investigate the association between serum uric acid (SUA) levels and vision-threatening diabetic retinopathy (VTDR) in patients with type 2 diabetes.

Methods: This cross-sectional study evaluated 3481 patients with type 2 diabetes from four communities in China between 2016 and 2019. VTDR was defined as severe nonproliferative, proliferative diabetic retinopathy, or clinically significant macular edema evaluated by fundus photography and optical coherence tomography. Potential association between SUA and VTDR was examined using multivariable logistic regression. Sub-group analyses based on sex were constructed.

Results: A total of 305 participants had VTDR. Both higher SUA (odds ratio [OR], 1.22 per 100 µmol/L; 95% confidence interval [CI], 1.04-1.44; P = 0.013) and hyperuricemia (OR, 1.47; 95% CI, 1.07-2.04; P = 0.019) were positively associated with VTDR after adjustment for relevant covariates. Compared with those in the lowest SUA quartile, participants in the third (OR, 1.60; 95% CI, 1.07-2.39; P = 0.022) and fourth (OR, 2.05; 95% CI, 1.37-3.08; P = 0.001) sex-specific SUA quartiles showed a significantly increased risk of VTDR after adjustment. No sex-related difference was observed.

Conclusions: Higher SUA levels were associated with an increased risk of VTDR in patients with type 2 diabetes in both sexes, although females seemed to be more sensitive to high SUA than males. Prospective cohort studies are needed to verify SUA as a biomarker for predicting the risk of VTDR. Whether decreased SUA levels could decrease the risk of VTDR also requires further investigation.
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http://dx.doi.org/10.1167/iovs.62.4.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083112PMC
April 2021

[Analysis of efficacy of coblation assisted endoscope system for the treatment of parapharyngeal space tumors with transoral approach].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2021 Mar;35(3):204-208

Department of Otorhinolaryngology,the First Affiliated Hospital,Nanjing Medical University,Nanjing,210029,China.

To summarize and analyze the feasibility, safety and efficacy of parapharyngeal space surgery assisted by coblation and endoscopic system with transoral approach. The data of 20 patients with parapharyngeal space tumors were retrospectively analyzed. All the patients underwent CT and/or MRI examination before surgery, and all underwent transoral approach assisted by coblation and endoscopic systems. The patients were followed up strictly after the operation, with a follow-up time of 8-56 months and the median follow-up time of 28 months. Among the 20 patients, 18 (90%) were pathologically benign tumors and 2 (10%) were malignant tumors. The maximum tumor diameter was (4.4±1.6) cm, the operative time was (79.00±30.03) min, the intraoperative blood loss was (23.63±22.20) mL, and the postoperative pain VAS score was 2.8±1.4. There were 17 cases complete resection, and 3 cases of relapse, including 1 patient who died after distant metastasis of synovial sarcoma postoperative complications occurred in 2 cases, hoarseness in 1 case of neurofibroma and tongue extension deflection in 1 case of schwannoma. Coblation assisted endoscopic system for the treatment of parapharyngeal space tumors with transoral approach has no cervical scar, which is a satisfaction for the patients, less intraoperative bleeding, short operative time, mild postoperative reaction and quick recovery. However, external approach is still recommended for primary malignant lesions, extensive or highly vascularized lesions, tumors located on the lateral side of the internal carotid artery, less than 2 cm from the skull base, or lateral invasion of the deep lobe of the parotid gland, or a pleomorphic adenoma is considered or is found to be too large to be completely resected preoperatively or intraoperatively.
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http://dx.doi.org/10.13201/j.issn.2096-7993.2021.03.003DOI Listing
March 2021

Hyperuricemia causes kidney damage by promoting autophagy and NLRP3-mediated inflammation in rats with urate oxidase deficiency.

Dis Model Mech 2021 Mar 24;14(3). Epub 2021 Mar 24.

Department of Endocrinology and Metabolism, Shanghai 10th People's Hospital, Tongji University, Shanghai 200072, China

Epidemiological research has shown that elevated serum urate concentration is a risk factor for the development of kidney disease; however, the mechanisms underlying this process have not yet been elucidated. To examine the role of urate in the kidney, we used Wistar rats to functionally disrupt expression of urate oxidase (UOX) by using the CRISPR/Cas9 system. In comparison to wild-type (WT) rats, serum urate levels spontaneously and persistently increased in -KO rats, without showing a significant decrease in survival rate. Architecture and function of the kidneys in -KO rats were impaired. Injury to the kidney resulted in increased interstitial fibrosis, macrophage infiltration, increased expression of NLRP3 and IL-1β, and activation of multiple cell-signaling pathways associated with autophagy, such as AMPK, p38 MAPK, ERK and JNK pathways. Inhibition of autophagy with the PI3K inhibitor 3-MA abrogated the development of kidney damage and attenuated renal fibrosis, macrophage infiltration, and expression of NLRP3 and IL-1β in injured kidneys. In conclusion, the -KO rat is a great model to study hyperuricemia-related diseases. Hyperuricemia-induced autophagy and NLRP3-dependent inflammation are critically involved in the development of renal damage and, therefore, highlight the inhibition of autophagy and inflammation in search of therapeutic strategies to treat uric acid nephropathy.
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http://dx.doi.org/10.1242/dmm.048041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015218PMC
March 2021

Urate in fingernail represents the deposition of urate burden in gout patients.

Sci Rep 2020 09 23;10(1):15575. Epub 2020 Sep 23.

Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Pharmaceutical Analysis, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China.

Urate in the fingernails of gout patients and healthy volunteers was successfully detected by high-performance liquid chromatography (HPLC) with ultraviolet (UV) in our previous research. This study aimed to further investigate whether nail urate could be a proxy for the burden of monosodium urate (MSU) crystals deposits in gout. To this end, we conducted a study in two parts. Firstly, we successfully detected urate in the nail by HPLC-UV and evaluated nail urate concentrations in control subjects and patients with gout. As expected, we found that levels of nail urate were significantly higher in patients with gout than in healthy controls, and the nail urate level was significantly correlated with the volume of MSU crystals deposits measured by dual-energy CT (DECT). Secondly, we found that nail urate can reflect changes in urate levels in the body during urate lowering therapy through a 3-month follow-up study. Our results provide the possibility of quantification of urate in human fingernails as a non-invasive alternative for assessing MSU crystals deposits in gout.
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http://dx.doi.org/10.1038/s41598-020-72505-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511301PMC
September 2020

Hyposialylated angiopoietin-like-4 induces apoptosis of podocytes via β1 Integrin/FAK signaling in diabetic nephropathy.

Mol Cell Endocrinol 2020 04 22;505:110730. Epub 2020 Jan 22.

Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. Electronic address:

Angiopoietin-like-4 (ANGPTL4) is reported to mediate proteinuria in some types of glomerulonephropathy. However, the mechanism underlying the effect on podocytes of ANGPTL4 under pathologic conditions in diabetic nephropathy (DN) is unclear. We investigated the role of ANGPTL4 in the pathogenesis of DN. In DN rats, elevated ANGPTL4 expression was associated with increased proteinuria, glomerular hypertrophy, and ultrastructural changes in podocytes. In vitro, hyperglycemia induced the upregulation of ANGPTL4, which led to activation of integrin-β1/FAK signaling with increased apoptosis of podocytes and actin cytoskeleton derangement. These pathological changes were reversed by transfection with a lentivirus expressing short hairpin RNA against integrin-β1 or an ANGPTL4-neutralizing antibody in vitro. Furthermore, supplementation with the sialic acid precursor ManNAc reversed these pathological changes and conferred renoprotection in a mouse model of DN. Our findings suggest that ANGPTL4 mediates high glucose-induced loss of podocytes by modulating their detachment and apoptosis in vivo and in vitro. This study deepens our understanding of the mechanisms of podocyte loss in DN and shows targeting ANGPTL4-related signaling has therapeutic potential for DN.
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http://dx.doi.org/10.1016/j.mce.2020.110730DOI Listing
April 2020

Activation of G0/G1 switch gene 2 by endoplasmic reticulum stress enhances hepatic steatosis.

Metabolism 2019 10 2;99:32-44. Epub 2019 Jul 2.

Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center of Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. Electronic address:

Background: Perturbed endoplasmic reticulum (ER) homeostasis and increased levels of G0/G1 Switch Gene 2 (G0S2) have been documented in animal models with fatty liver disease. In this study, we investigated whether G0S2 is regulated by branch of the unfolded protein response (UPR) and contributes to ER stress-induced hepatic steatosis.

Methods: We first analyzed G0S2 expression and the state of the three canonical UPR branches in several hepatic steatosis models, tunicamycin-treated C57BL/6J mice and HepG2 cells, where ER homeostasis was perturbed. We pretreated HepG2 cells with tauroursodeoxycholic acid (TUDCA) to validate whether G0S2 was the downstream target of ER stress. Loss or gain function analysis was conducted to identify which UPR branch specifically linked to G0S2 transcription. The transcription mechanism was estimated by luciferase reporter assay and ChIP assay.

Results: Here we showed that the activation of ER stress was accompanied by elevation of G0S2 expression in the occurrence of fatty liver disease. Furthermore, G0S2 was found to be a novel target gene of activating transcription factor 4(ATF4). We also localized one conserved ATF4-binding sequence in the 5' regulatory region of G0S2, which was responsible for transcriptional activating G0S2 by ATF4.

Conclusion: G0S2 is regulated by the PERK-eIF2α-ATF4 branch of the UPR and mediates ER stress-induced hepatic steatosis.
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http://dx.doi.org/10.1016/j.metabol.2019.06.015DOI Listing
October 2019

Chaetocin attenuates gout in mice through inhibiting HIF-1α and NLRP3 inflammasome-dependent IL-1β secretion in macrophages.

Arch Biochem Biophys 2019 07 28;670:94-103. Epub 2019 Jun 28.

Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, China. Electronic address:

Chaetocin is a fungal metabolite that possesses a potential anti-inflammatory activity. Acute gout is a self-limiting inflammatory response to monosodium urate (MSU) crystals. However, the effect of cheatocin on gout has not been elucidated. In the study, we found that chaetocin could decrease MSU induced IL-1β secretion in bone marrow derived macrophages by several mechanisms, including inhibiting the activation of NLRP3 inflammasome. Chaetocin negatively regulated apoptosis-associated speck-like protein with a CARD domain oligomerization, and caspase-1 processing, key events during inflammasome activation. Furthermore, chaetocin restrain expressions of Hypoxia-inducible factor-1α and Hexokinase 2, mediators of glycolysis, which necessary for synthesis of pro-IL-1β during inflammasome priming. In vivo, chaetocin ameliorate MSU-induced arthritis, which showed as reduced local swelling and inflammatory cell infiltration. In MSU-induced peritonitis model, the peritoneal macrophages of chaetocin-pretreated mice showed significantly decreased mRNA levels of HIF-1α and NLRP3 related genes. These findings suggested that chaetocin has a potent anti-inflammatory effect against gout. More importantly, it is proposed that the inhibiting of glycolysis pathway would be a new avenue for the treatment of gout flare and other IL-1β related diseases.
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http://dx.doi.org/10.1016/j.abb.2019.06.010DOI Listing
July 2019

Wireless Indoor Localization Using Convolutional Neural Network and Gaussian Process Regression.

Sensors (Basel) 2019 May 31;19(11). Epub 2019 May 31.

School of Automation and Electronic Engineering, University of Science and Technology Beijing, Beijing 100083, China.

This paper presents a localization model employing convolutional neural network (CNN) and Gaussian process regression (GPR) based on Wi-Fi received signal strength indication (RSSI) fingerprinting data. In the proposed scheme, the CNN model is trained by a training dataset. The trained model adapts to complex scenes with multipath effects or many access points (APs). More specifically, the pre-processing algorithm makes the RSSI vector which is formed by considerable RSSI values from different APs readable by the CNN algorithm. The trained CNN model improves the positioning performance by taking a series of RSSI vectors into account and extracting local features. In this design, however, the performance is to be further improved by applying the GPR algorithm to adjust the coordinates of target points and offset the over-fitting problem of CNN. After implementing the hybrid model, the model is experimented with a public database that was collected from a library of Jaume I University in Spain. The results show that the hybrid model has outperformed the model using k-nearest neighbor (KNN) by 61.8%. While the CNN model improves the performance by 45.8%, the GPR algorithm further enhances the localization accuracy. In addition, the paper has also experimented with the three kernel functions, all of which have been demonstrated to have positive effects on GPR.
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http://dx.doi.org/10.3390/s19112508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603619PMC
May 2019

Expression of Glutamate Receptor Subtype 3 Is Epigenetically Regulated in Podocytes under Diabetic Conditions.

Kidney Dis (Basel) 2019 Feb 26;5(1):34-42. Epub 2018 Oct 26.

Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Recent studies suggest a role of epigenetics in the pathogenesis of diabetic kidney disease. However, epigenetic changes occurring specifically in kidney cells is poorly understood.

Methods: To examine the epigenetic regulation of genes in podocytes under diabetic conditions, we performed DNA methylation and transcriptomic profiling in podocytes exposed to high glucose conditions.

Results: Comparative analysis of genes with DNA methylation changes and correspondingly altered mRNA expression identified 337 hypomethylated genes with increased mRNA expression and only 2 hypermethyated genes ( and ) with decreased mRNA expression. Glutamate ionotropic receptor AMPA type subunit 3 () belongs to the ionotropic class of glutamate receptors that mediate fast excitatory synaptic transmission in the central nervous system. As podocytes have glutamate-containing vesicles and various glutamate receptors mediate important biological effects in podocytes, we further examined expression and its function in podocytes. Real-time PCR and western blots confirmed the suppression of expression in podocytes under high glucose conditions, which were abolished in the presence of a DNA methyltransferase inhibitor. Sites of DNA hypermethylation were also confirmed by bisulfite sequencing of the promoter region. mRNA and protein expression was suppressed in diabetic kidneys of human and mouse models, and knockdown of exacerbated high glucose-induced apoptosis in cultured podocytes.

Conclusion: These results indicate that decreased expression in podocytes in diabetic condition heightens podocyte apoptosis and loss.
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http://dx.doi.org/10.1159/000492933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388444PMC
February 2019

Protein S Protects against Podocyte Injury in Diabetic Nephropathy.

J Am Soc Nephrol 2018 05 6;29(5):1397-1410. Epub 2018 Mar 6.

Renal Section, James J. Peters Veterans Affairs Medical Center, Bronx, New York;

Diabetic nephropathy (DN) is a leading cause of ESRD in the United States, but the molecular mechanisms mediating the early stages of DN are unclear. To assess global changes that occur in early diabetic kidneys and to identify proteins potentially involved in pathogenic pathways in DN progression, we performed proteomic analysis of diabetic and nondiabetic rat glomeruli. Protein S (PS) among the highly upregulated proteins in the diabetic glomeruli. PS exerts multiple biologic effects through the Tyro3, Axl, and Mer (TAM) receptors. Because increased activation of Axl by the PS homolog Gas6 has been implicated in DN progression, we further examined the role of PS in DN. In human kidneys, glomerular PS expression was elevated in early DN but suppressed in advanced DN. However, plasma PS concentrations did not differ between patients with DN and healthy controls. A prominent increase of PS expression also colocalized with the expression of podocyte markers in early diabetic kidneys. In cultured podocytes, high-glucose treatment elevated PS expression, and PS knockdown further enhanced the high-glucose-induced apoptosis. Conversely, PS overexpression in cultured podocytes dampened the high-glucose- and TNF--induced expression of proinflammatory mediators. Tyro3 receptor was upregulated in response to high glucose and mediated the anti-inflammatory response of PS. Podocyte-specific PS loss resulted in accelerated DN in streptozotocin-induced diabetic mice, whereas the transient induction of PS expression in glomerular cells attenuated albuminuria and podocyte loss in diabetic OVE26 mice. Our results support a protective role of PS against glomerular injury in DN progression.
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http://dx.doi.org/10.1681/ASN.2017030234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967770PMC
May 2018

A non-laboratory-based risk score for predicting diabetic kidney disease in Chinese patients with type 2 diabetes.

Oncotarget 2017 Nov 9;8(60):102550-102558. Epub 2017 Oct 9.

Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.

Aim: To construct a simple screening tool for predicting diabetic kidney disease in Chinese patients with type 2 diabetes.

Materials And Methods: In the development cohort, the clinical and procedural characteristics of the 4,795 patients were considered as candidate univariate predictors of diabetic kidney disease. The β-coefficients derived from a multiple logistic regression model predicting the presence of DKD were used to calculate the risk score. The performance of the risk score was validated in a cross-sectional and a prospective cohort population.

Results: The risk score included sex, body mass index, systolic blood pressure, and duration of diabetes. The total point ranged from 0 to 39. In the development cohort, compared with participants with risk score < 10, those with risk score between 10 to 20, 21 to 30, and > 30 had ORs of 3.21, 7.92 and 17.55 for developing diabetic kidney disease, respectively. In the prospective cohort, 60.9% patients with risk score over 30 were expected to develop DKD at 72 months of follow-up.

Conclusions: Sex, body mass index, systolic blood pressure, and duration of diabetes were independent predictors of diabetic kidney disease, and the derived risk equation was a simple screening tool for screening diabetic kidney disease in Chinese patients with type 2 diabetes.
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http://dx.doi.org/10.18632/oncotarget.21684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731980PMC
November 2017

The chloride/phosphate ratio combined with alkaline phosphatase as a valuable predictive marker for primary hyperparathyroidism in Chinese individuals.

Sci Rep 2017 07 7;7(1):4868. Epub 2017 Jul 7.

Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.

The chloride/phosphate ratio (Cl/PO4) has been suggested to have a role in primary hyperparathyroidism (PHPT), but the associations between Cl/PO4 combined with ALP level and PHPT has not been well-studied. Our aim was to investigate the predictive value of combination Cl/PO4 with ALP for PHPT. A cross-sectional retrospective analysis was conducted to examine 172 patients diagnosed with PHPT categorized into two groups: normocalcaemic primary hyperparathyroidism (NPHPT) group and hypercalcaemia PHPT group. We found that Cl/PO4 levels and ALP levels in the NPHPT and hypercalcaemia PHPT group were both significantly higher than normal controls. Cl/PO4 and ALP levels were an independent risk factor for PHPT. Cl/PO4 combined with ALP increased the receiver-operating characteristic curves (ROC-AUC) and the diagnostic value in NPHPT and hypercalcaemia PHPT group (0.913; 95% CI, 0.744-1.000 and 0.932; 95% CI, 0.897-0.966, respectively), specificity of 92.8% and sensitivity of 98%. In conclusion, combination Cl/PO4 with ALP might be a low-cost, simple, available predictive marker of PHPT in Chinese individuals, particularly Chinese remote region where the method used to measure PTH cannot be done. Moreover, due to serum calcium level in NPHPT, Cl/PO4 combined with ALP level measurement have great potential to predict significant occurrence of NPHPT.
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http://dx.doi.org/10.1038/s41598-017-05183-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501820PMC
July 2017

Hyperuricemia and overexcretion of uric acid increase the risk of simple renal cysts in type 2 diabetes.

Sci Rep 2017 06 19;7(1):3802. Epub 2017 Jun 19.

Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai, 200233, China.

Previous studies have discussed the relationship between simple renal cysts (SRC) and serum uric acid level in healthy individuals. We performed a cross-sectional study to evaluate the association between serum uric acid level and fractional excretion of uric acid (FEUA) and simple renal cysts in males and postmenopausal females with type 2 diabetes. The overall prevalence of SRC was 18.1% in our population. SRC prevalence was significantly higher in hyperuricemic than normouricemic subjects (27.3% vs. 16.8%, P < 0.001). Subjects who overexcreted uric acid had a higher prevalence of SRC than underexcretors (total population: 21.6% vs. 16.3%; normouricemic subjects: 19.8% vs. 13.7%; hyperuricemic subjects: 50.0% vs. 22.7%, all P-values < 0.05). Hyperuricemia (odds ratio [OR] 1.824, 95% confidence interval [CI] 1.332-2.498, P < 0.001); FEUA (OR 1.046, 95% CI 1.002-1.091, P < 0.05); male gender (OR 1.922, 95% CI 1.489-2.480, P < 0.001); age (OR 1.049, 95% CI 1.035-1.064, P < 0.001); and albuminuria (OR 1.492, 95% CI 1.176-1.892, P < 0.01) were independent risk factors for SRC development. These findings suggested that hyperuricemia and high level of FEUA were both independent risk factors for SRC development in males and postmenopausal females with type 2 diabetes. Half of overproduction hyperuricemic patients had SRC.
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http://dx.doi.org/10.1038/s41598-017-04036-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476589PMC
June 2017

5-ALA ameliorates hepatic steatosis through AMPK signaling pathway.

J Mol Endocrinol 2017 08 31;59(2):121-128. Epub 2017 May 31.

Department of Endocrinology and MetabolismShanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Diabetes Institute, Shanghai Clinical Center of Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, China

5-Aminolevulinic acid (5-ALA), the first compound in the porphyrin synthesis pathway, has been reported to ameliorate the diabetic state in Otsuka Long-Evans Tokushima Fatty rats by reducing fat pad weight in the retroperitoneal region. Dietary supplementation with 5-ALA has additionally demonstrated the capacity to lower blood glucose and HbA1c levels among subjects with diabetes. The etiology of nonalcoholic fatty liver disease (NAFLD) is complex and its typical characteristics include obesity and insulin resistance. As 5-ALA supplementation has previously normalized glucose and insulin resistance, we sought to investigate whether 5-ALA had potential therapeutic effects on NAFLD and elucidate the signal pathway mediating these effects. To explore these questions, we fed C57BL/6J mice a high-fat diet (HFD) to induce a fatty liver disease and supplemented the diet-induced obese (DIO) mice with 5-ALA. The mice in the presence of 5-ALA demonstrated a decrease in body weight and hepatic lipid content and moderate improvement in glucose homeostasis compared to untreated controls. Further, we found that 5-ALA activated AMPK signaling pathway, which was correlated with enhanced lipolysis and fatty acid β-oxidation. Human hepatocarcinoma cells (HepG2 cells) treated with 5-ALA were additionally used to investigate the mechanics of 5-ALA. Treated cells had a higher expression of lipolysis-related genes, including PGC-1α. Our data indicated that 5-ALA might represent a novel compound that could be useful for the treatment of nonalcoholic fatty liver disease (NAFLD), likely through the restoration of phosphorylation levels of AMPK (Thr172) and acetyl-CoA (ACC) (Ser79), further enhanced PGC1α and CPT1α expression.
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http://dx.doi.org/10.1530/JME-16-0260DOI Listing
August 2017

Relationship between serum bilirubin concentrations and diabetic nephropathy in Shanghai Han's patients with type 1 diabetes mellitus.

BMC Nephrol 2017 03 31;18(1):114. Epub 2017 Mar 31.

Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, 600Yishan road, Shanghai, 200233, China.

Background: Recent studies highlight a negative association between total bilirubin concentrations and albuminuria in patients with type 2 diabetes mellitus. Our study evaluated the relationship between bilirubin concentrations and the prevalence of diabetic nephropathy (DN) in Chinese patients with type 1 diabetes mellitus (T1DM).

Methods: A total of 258 patients with T1DM were recruited and bilirubin concentrations were compared between patients with or without diabetic nephropathy. Multiple stepwise regression analysis was used to examine the relationship between bilirubin concentrations and 24 h urinary microalbumin. Binary logistic regression analysis was performed to assess independent risk factors for diabetic nephropathy. Participants were divided into four groups according to the quartile of total bilirubin concentrations (Q1, 0.20-0.60; Q2, 0.60-0.80; Q3, 0.80-1.00; Q4, 1.00-1.90 mg/dL) and the chi-square test was used to compare the prevalence of DN in patients with T1DM.

Results: The median bilirubin level was 0.56 (interquartile: 0.43-0.68 mg/dL) in the DN group, significantly lower than in the non-DN group (0.70 [interquartile: 0.58-0.89 mg/dL], P < 0.001). Spearman's correlational analysis showed bilirubin concentrations were inversely correlated with 24 h urinary microalbumin (r = -0.13, P < 0.05) and multiple stepwise regression analysis showed bilirubin concentrations were independently associated with 24 h urinary microalbumin. In logistic regression analysis, bilirubin concentrations were significantly inversely associated with nephropathy. In addition, in stratified analysis, from the first to the fourth quartile group, increased bilirubin concentrations were associated with decreased prevalence of DN from 21.90% to 2.00%.

Conclusion: High bilirubin concentrations are independently and negatively associated with albuminuria and the prevalence of DN in patients with T1DM.
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http://dx.doi.org/10.1186/s12882-017-0531-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376273PMC
March 2017

Decreased levels of Fibroblast Growth Factor 21 are correlated with improved hypoglycemia in patients with insulinoma.

Sci Rep 2017 02 22;7:43123. Epub 2017 Feb 22.

Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, 600Yishan road, Shanghai, 200233 China.

Fibroblast growth factor-21 (FGF-21) improves insulin sensitivity and lipid metabolism in obese or diabetic animal models and has been proposed as a potential therapeutic agent for treating T2DM, obesity, and their related complications. However, little is known about the changes of FGF21 levels in response to endogenous hyperinsulinemic hypoglycemia. To explore its relationship with parameters of glucose metabolism in patients with insulinoma, eleven subjects with pathological insulinoma and twenty-two healthy subjects were recruited for this study. Interestingly, we found that the serum FGF21 levels increased significantly in patients with insulinoma at baseline compared with the control group (381.36 ± 107.12 vs. 62.59 ± 10.48 pg/mL; P = 0.001). Furthermore, FGF21 was positively correlated with insulin (r = 0.80, P = 0.003) and proinsulin (r = 0.72, P = 0.012) in subjects with insulinoma. Multiple stepwise regression analysis showed that FGF21 was independently associated with insulin (β = 0.80, P = 0.003). In addition, FGF21 decreased significantly after surgery, and its change was still correlated positively with the changes in insulin (r = 0.61, P = 0.048) and proinsulin (r = 0.84, P = 0.001). These findings suggested that the serum FGF21 levels could be involved in a complex adaptive response to insulin secretion and glucose metabolism in humans.
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http://dx.doi.org/10.1038/srep43123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320496PMC
February 2017

Diabetes Onset at 31-45 Years of Age is Associated with an Increased Risk of Diabetic Retinopathy in Type 2 Diabetes.

Sci Rep 2016 11 29;6:38113. Epub 2016 Nov 29.

Department of Ophthalmology, Shanghai First People's Hospital of Nanjing Medical University, Shanghai 200080, China.

This hospital-based, cross-sectional study investigated the effect of age of diabetes onset on the development of diabetic retinopathy (DR) among Chinese type 2 diabetes mellitus (DM) patients. A total of 5,214 patients with type 2 DM who were referred to the Department of Ophthalmology at the Shanghai First People's Hospital from 2009 to 2013 was eligible for inclusion. Diabetic retinopathy status was classified using the grading system of the Early Treatment Diabetic Retinopathy Study (ETDRS). Logistic and hierarchical regression analyses were used to identify independent variables affecting the development of DR. Upon multiple logistic regression analysis, patient age at the time of diabetes onset was significantly associated with development of DR. Further, when the risk of retinopathy was stratified by patient age at the onset of diabetes, the risk was highest in patients in whom diabetes developed at an age of 31-45 years (odds ratio [OR] 1.815 [1.139-2.892]; p = 0.012). Furthermore, when patients were divided into four groups based on the duration of diabetes, DR development was maximal at a diabetes onset age of 31-45 years within each group. A diabetes onset age of 31-45 years is an independent risk factor for DR development in Chinese type 2 DM patients.
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http://dx.doi.org/10.1038/srep38113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126680PMC
November 2016

Decreased serum betatrophin levels correlate with improved fasting plasma glucose and insulin secretion capacity after Roux-en-Y gastric bypass in obese Chinese patients with type 2 diabetes: a 1-year follow-up.

Surg Obes Relat Dis 2016 Aug 29;12(7):1343-1348. Epub 2016 Jan 29.

Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiao tong University Affiliated Sixth People's Hospital, Shanghai, China. Electronic address:

Background: There is increasing evidence that serum betatrophin levels, a hormone derived from adipose tissue and liver, are elevated in type 2 diabetes (T2D).

Objective: To investigate the relationships among betatrophin and metabolic control, insulin resistance, and pancreatic β-cell function in obese Chinese patients with T2D who underwent Roux-en-Y gastric bypass (RYGB).

Setting: University hospital, China.

Methods: This 1-year follow-up study included 34 obese individuals with T2D (18 males, 16 females) who underwent RYGB in our hospital. Anthropometric results, glucose levels, lipid profiles, and serum betatrophin levels were determined before and 1 year after RYGB.

Results: The serum betatrophin level decreased significantly after RYGB (72.0 ng/mL [33.4-180.9] versus 35.7 ng/mL [14.8-103.3]); P<.001]. The change in betatrophin was significantly positively correlated with the changes in hemoglobin A1c and fasting plasma glucose and negatively correlated with the changes in the 2-hour C-peptide/fasting C-peptide and homeostasis model of assessment of β-cell function (P<.05). Multiple stepwise regression analysis indicated that the change in the serum betatrophin level was independently and significantly associated with the changes in fasting plasma glucose (β = .586, P<.001) and 2-hour C-peptide/fasting C-peptide (β = -.309, P = .021).

Conclusion: Circulating betatrophin might be involved in the regulation of glucose control and insulin secretion in obese Chinese with T2D soon after RYGB.
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http://dx.doi.org/10.1016/j.soard.2016.01.024DOI Listing
August 2016

Non-alcoholic fatty liver disease is associated with late but not early atherosclerotic lesions in Chinese inpatients with type 2 diabetes.

J Diabetes Complications 2017 01 27;31(1):80-85. Epub 2016 Sep 27.

Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address:

Aims: To investigate the association between non-alcoholic fatty liver disease (NAFLD) and carotid and lower limb atherosclerotic lesions in a large group of hospitalized-based type 2 diabetic population and to assess the prevalence and characteristics of NAFLD in Chinese subjects with type 2 diabetes (T2DM).

Methods: A total of 8571 patients (4804 men) with T2DM were included in this cross-sectional study. The main outcome measures were detection of NAFLD, carotid intima-media thickness (C-IMT), carotid and lower limb atherosclerotic plaque formation, and classical risk factors.

Results: The prevalence of carotid (56.5% vs. 44.5%; p<0.001) and lower limb plaque (56.2% vs. 48.7%; p<0.001), and carotid (11.2% vs. 6.8%; p<0.001) and lower limb stenosis (15.1% vs. 10.3%; p<0.001) was markedly higher in the diabetic patients with NAFLD than in those without, after controlling for age. However, there was no significant difference in C-IMT between diabetic patients with and without NAFLD (0.82±0.30mm vs. 0.85±0.39mm) after controlling for age. Fully adjusted multiple linear regression and logistic regression analyses revealed that NAFLD was significantly associated with increased prevalence of carotid and lower limb atherosclerotic plaque but not with C-IMT. NAFLD, age, sex, longer duration of diabetes and the presence of hypertension were independently associated with carotid and lower limb atherosclerotic plaque (p<0.05).

Conclusion: NAFLD was not associated with elevated C-IMT but was associated with carotid and lower limb atherosclerotic plaque independent of conventional cardiovascular disease risk factors and metabolic syndrome in Chinese inpatients with T2DM.
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http://dx.doi.org/10.1016/j.jdiacomp.2016.09.008DOI Listing
January 2017

Diagnosis of insulinoma using the ratios of serum concentrations of insulin and C-peptide to glucose during a 5-hour oral glucose tolerance test.

Endocr J 2017 Jan 1;64(1):49-57. Epub 2016 Oct 1.

Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, 600 Yishan road, Shanghai 200233, China.

The 72-hour fast test is the current standard for the diagnosis of insulinoma. However, to conduct this test patients require hospitalization due to the chance of severe hypoglycemic episodes. Thus, it is costly and stressful for the patient. An out-patient test would serve the patient better and be more economical. Our aim was to evaluate the value of insulin to glucose and C-peptide to glucose ratios during a prolonged 5-hour oral glucose tolerance test (5-hour OGTT) in qualitative diagnosis of insulinoma, and to identify the optimal threshold for clinical screening. Initially, 15 subjects with pathological insulinoma and 12 control subjects with reactive hypoglycemia were enrolled in the study. A further 75 subjects with symptoms of hypoglycemia as a chief complaint at their initial clinic visit were subsequently screened. Serum insulin, C- peptide levels and blood glucose were quantified after a 5-hour OGTT in all participants and the ratios of serum concentrations of insulin and C-peptide to glucose were calculated. Subjects with insulinoma had significantly different insulin-to-glucose and C-peptide-to-glucose ratios from reactive hypoglycemia at the times of fasting, 4-hour post glucose load and 5-hour post glucose load. Higher specificity (73.08%) and sensitivity (82.67%) were achieved with the combined insulin-to-glucose ratio at the 5-hour post load and the C-peptide-to-glucose ratio at fasting. In combination, ratios of insulin and C-peptide release relative to blood glucose levels, measured during a 5-hour OGTT, may have important clinical value in the diagnosis of insulinoma.
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http://dx.doi.org/10.1507/endocrj.EJ16-0292DOI Listing
January 2017

Nonalcoholic Fatty Liver Disease is Associated with Increased Carotid Intima-Media Thickness in Type 1 Diabetic Patients.

Sci Rep 2016 05 26;6:26805. Epub 2016 May 26.

Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.

A growing body of evidence suggests that NAFLD is associated with an increased risk of incident CVD events both in patients without diabetes and in those with type 2 diabetes (T2DM). However, no published data are available regarding the association between NAFLD and C-IMT in T1DM. A total of 722 patients (371 men) with T1DM were included in this cross-sectional study. The main outcome measures were detection of NAFLD, C-IMT and classical risk factors. The mean age of the subjects was 46.2 years, and 51.1% were male. The prevalence of NAFLD was 15.9%. NAFLD patients had a markedly greater C-IMT (0.81 ± 0.25 vs. 0.69 ± 0.18 mm; p < 0.001) and frequency of carotid plaque (28.9% vs. 16.9%; p < 0.05) than those without fatty liver. Moreover, the differences in C-IMT remained after adjusting for potential confounders. A stepwise linear regression analysis revealed that age (standardized β, 0.326; p < 0.001), NAFLD (standardized β, 0.151, p < 0.001), and hsCRP (standardized β, 0.115, p = 0.008) were independently associated with C-IMT in all subjects. Our data show NAFLD is associated with elevated C-IMT in T1DM independent of conventional cardiovascular disease risk factors.
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http://dx.doi.org/10.1038/srep26805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880892PMC
May 2016

Prevalence of chronic kidney disease and associated factors in Chinese individuals with type 2 diabetes: Cross-sectional study.

J Diabetes Complications 2016 07 17;30(5):803-10. Epub 2016 Mar 17.

Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address:

Aims: This cross-sectional study aimed to determine the prevalence and associated risk factors of chronic kidney disease (CKD) in Chinese type 2 diabetic patients.

Methods: A total of 3301 patients with type 2 diabetes were included in this study. Anthropometric parameters and biochemical indices were measured. The main outcome measures were detection of CKD, albuminuria and estimated glomerular filtration rate (eGFR).

Results: The prevalence of CKD and albuminuria in Shanghai Chinese type 2 diabetic patients was 27.1% and 25.2%. The prevalence of mildly decreased renal function or worse (eGFR<60/mL/min/1.73m(2)) was 6%. The prevalence of glomerular hyperfiltration was 12.2%. The prevalence of diabetic kidney disease (DKD) according to the newest NKF's KDOQI classification was 12.03%. Risk factors associated with DKD were SBP, retinopathy, neuropathy, TG, LDL, anemia and HbA1c. Clinical factors associated with both albuminuria and low eGFR (≥60/<60) were SBP, retinopathy, TC, TG and anemia.

Conclusion: In conclusion, CKD and DKD were common in the Shanghai Chinese patients with T2DM and were similar to that in Western patients. Prevention and control of diabetes should be a high priority in reducing the CKD burden in China.
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http://dx.doi.org/10.1016/j.jdiacomp.2016.03.020DOI Listing
July 2016

A causal relationship between uric acid and diabetic macrovascular disease in Chinese type 2 diabetes patients: A Mendelian randomization analysis.

Int J Cardiol 2016 Jul 31;214:194-9. Epub 2016 Mar 31.

Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.

Background: As the association between uric acid and macrovascular disease has been heavily debated, we aimed to confirm whether there is a causal relationship between uric acid and diabetic macrovascular disease through Mendelian randomization analysis.

Methods: In 3207 type 2 diabetes patients, seventeen SNPs (single nucleotide polymorphisms) related to uric acid were genotyped. A weighted GRS (genetic risk score) was calculated using selected SNPs and the strength of their effects on uric acid levels. Diabetic macrovascular disease was diagnosed through vascular ultrasound, magnetic resonance imaging or other clinical evidence. Associations of diabetic macrovascular disease with uric acid and weighted GRS were evaluated separately.

Results: In total participants and among females, the prevalence of diabetic macrovascular disease was significantly higher in hyperuricemic group than in normouricemic group, and uric acid was associated with diabetic macrovascular disease (OR=1.068, p=0.0349; OR=1.122, p=0.0158). The prevalence of diabetic macrovascular disease increased with the weighted GRS in a J-shaped manner for the females. The weighted GRS was positively correlated with uric acid in total population, male patients and female patients (β=0.203, p<0.0001; β=0.255, p<0.0001; β=0.142, p<0.0001, respectively). The weighted GRS was significantly associated with diabetic macrovascular disease in female patients (OR=1.184, p=0.0039). Among females, the observed association between weighted GRS and diabetic macrovascular disease was greater than predicted.

Conclusions: Using the uric acid-related weighted GRS as an instrumental variable for Mendelian randomization analysis, our study provided an evidence for causal relationship between uric acid and diabetic macrovascular disease in Chinese females with type 2 diabetes mellitus.
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http://dx.doi.org/10.1016/j.ijcard.2016.03.206DOI Listing
July 2016

The Chronic Kidney Disease Epidemiology Collaboration equation improves the detection of hyperfiltration in Chinese diabetic patients.

Int J Clin Exp Med 2015 15;8(12):22084-97. Epub 2015 Dec 15.

Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiaotong University Affiliated Sixth People's Hospital Shanghai 200233, China.

Objective: Hyperfiltration confers an increased risk of diabetic nephropathy. Early detection can ensure timely intervention and improved treatment outcomes. Because GFR is known to be affected by hyperglycemia, the aim of this study was to compare the influence of hyperglycemia on GFR estimations calculated by the CKD-EPI equation, the CG equation, and the MDRD equations in estimating hyperfiltration in Chinese diabetic patients.

Materials And Methods: The performance of the equations, compared with the measured (99)mTc-DTPA glomerular filtration rate was analyzed in 3492 diabetic patients. Bias, precision, and accuracies were compared with respect to HbA1c status. The Bland-Altman method was used to evaluate the agreement among the equations with respect to the mGFR, and the receiver-operating characteristic curve method was used to evaluate diagnostic value of the three equations with respect to the detection of moderate renal failure and hyperfiltration.

Results: The mean absolute bias was the smallest for the CKD-EPI equation in the HbA1c < 7.2% cohort, and the highest accuracy within ± 15% and ± 30% was also reached with the CKD-EPI equation in both cohorts. For the detection of hyperfiltration, the CKD-EPI equation exhibited the best performance with the greatest combination of sensitivity and specificity. The biases of the three equations were significantly higher in the HbA1c ≥ 10.5% subgroup compared with the HbA1c < 7.2% cohort.

Conclusion: The CKD-EPI equation can be used as a screening tool for hyperfiltration and appears to be a more generalizable and accurate equation for estimating GFR in Chinese diabetic patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729969PMC
February 2016

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway.

Diabetologia 2016 Mar 19;59(3):644-54. Epub 2015 Dec 19.

Department of Ophthalmology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Haining Road 100, Shanghai, 200080, People's Republic of China.

Aims/hypothesis: The mechanisms underlying the cellular metabolic memory induced by high glucose remain unclear. Here, we sought to determine the effects of microRNAs (miRNAs) on metabolic memory in diabetic retinopathy.

Methods: The miRNA microarray was used to examine human retinal endothelial cells (HRECs) following exposure to normal glucose (N) or high glucose (H) for 1 week or transient H for 2 days followed by N for another 5 days (H→N). Levels of sirtuin 1 (SIRT1) and acetylated-nuclear factor κB (Ac-NF-κB) were examined following transfection with miR-23b-3p inhibitor or with SIRT1 small interfering (si)RNA in the H→N group, and the apoptotic HRECs were determined by flow cytometry. Retinal tissues from diabetic rats were similarly studied following intravitreal injection of miR-23b-3p inhibitor. Chromatin immunoprecipitation (ChIP) analysis was performed to detect binding of NF-κB p65 to the potential binding site of the miR-23b-27b-24-1 gene promoter in HRECs.

Results: High glucose increased miR-23b-3p expression, even after the return to normal glucose. Luciferase assays identified SIRT1 as a target mRNA of miR-23b-3p. Reduced miR-23b-3p expression inhibited Ac-NF-κB expression by rescuing SIRT1 expression and also relieved the effect of metabolic memory induced by high glucose in HRECs. The results were confirmed in the retina using a diabetic rat model of metabolic memory. High glucose facilitated the recruitment of NF-κB p65 and promoted transcription of the miR-23b-27b-24-1 gene, which can be suppressed by decreasing miR-23b-3p expression.

Conclusions/interpretation: These studies identify a novel mechanism whereby miR-23b-3p regulates high-glucose-induced cellular metabolic memory in diabetic retinopathy through a SIRT1-dependent signalling pathway.
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http://dx.doi.org/10.1007/s00125-015-3832-0DOI Listing
March 2016