Aim or purpose: To investigate the systemic role of IGSF10 in regulating bone homeostasis and remodeling, focusing on its molecular interplay with osteogenic networks. Materials and methods: Osteoblast-specific IGSF10-knockout mice (Oc-Cre;Igsf10flox/flox, 8-week-old females) and Igsf10flox controls were analyzed. Bone microarchitecture was assessed by micro-CT. Osteoclast activity was evaluated via TRAP staining. Bone marrow stromal cells (BMSCs) from knockout and control mice were subjected to osteogenic induction in vitro, with or without IGSF10 treatment. Primary human PDLCs were cultured in basal medium or osteogenic induction medium (OIM) ± recombinant IGSF10. Osteogenic markers (Runx2, ALP, Bsp) were analyzed by qPCR and Western blot. Mineralization was assessed via ALP staining (day 7) and Alizarin Red S quantification (day 14). RNA-seq and pathway enrichment analysis were performed on IGSF10-treated PDLCs to identify regulatory networks. Statistical analysis was performed using unpaired t-test and one-way ANOVA. Results: Osteoblast-specific IGSF10 knockout mice demonstrated reduced trabecular bone density and thickness in femurs and mandibles under basal conditions, independent of osteoclast activity. BMSCs from knockout mice exhibited impaired osteogenic differentiation (reduced Runx2, ALP, and mineralization), which was partially restored by exogenous IGSF10, while IGSF10 synergized with osteogenic signals to enhance mineralization in human periodontal fibroblasts. RNA-seq revealed that IGSF10 activated interferon-associated transcriptional networks during osteogenic programming, suggesting a novel regulatory axis in bone formation. Conclusions: IGSF10 regulates bone formation by enhancing differentiation and mineralization through activation of interferon-associated transcriptional networks, providing a potential therapeutic target for bone regeneration.

Background: Retarded gingival healing is the hallmark of bisphosphonate-related osteonecrosis of the jaw (BRONJ) and poses a great challenge to maxillofacial surgeons. Although previous studies have showed that bisphosphonates (BPs) are highly toxic to healthy gingival mesenchymal stem cells (GMSCs) in vitro, there is overall lack of direct evidence demonstrating the regeneration capacity of oral mucosa in BRONJ patients. In present study, we aim to isolate GMSCs from BRONJ patients’ gingiva and assessed their phenotypes and functions in vitro, as well as their therapeutic effects for wound healing in a mice excisional skin model. Methods: BRONJ patients’ gingival samples were used for microarray analysis, histological detection and cell culture. The stem cells isolated from the central gingiva (center-BRONJ GMSCs) and the peripheral lesions (peri-BRONJ GMSCs) were analyzed by Cell Counting Kit-8 (CCK-8), cell adhesion, scratch and flow cytometry. Luciferase/GFP (Green Fluorescent Proteins)-labeled GMSCs combined with Hydrogel were transplanted in a mice excisional skin model, and mice were divided into a hydrogel alone group, a hydrogel/control GMSCs group, a hydrogel/center-BRONJ GMSCs group and a hydrogel/peri-BRONJ GMSCs group. Bioluminescence imaging trace cell survival in vivo. Healing effects were evaluated by wound area measurement, histology, immunohistochemistry (IH) and immunofluorescence (IF). Results: Center-BRONJ GMSCs and peri-BRONJ GMSCs were all fibroblast-like cells, but they became slender and more wrinkled compared control GMSCs. Notably, they exhibited decreased proliferation, adhesion, migration capacities and underwent early apoptosis in vitro. In animal model, BRONJ GMSCs transplantation also displayed lower cell survival rate and poor healing effects than that of control group. Mechanistically, we found that the expression of TGF-β1 signaling pathway was suppressed not only in BRONJ patients’ gingival lesions but also in BRONJ GMSCs transplantation animal model. Conclusions: In BRONJ patients’ microenvironment, the regeneration ability of oral mucosa was dramatically decreased. Our mice skin model demonstrated for the first time that BRONJ GMSCs transplantation displayed poor effects on wound healing mainly via suppressing TGF-β1 signaling pathway. This study provides new insights into the prevention for BRONJ by improving the functions of GMSCs in accelerating gingival wound healing.

This phase II clinical trial investigated the efficacy and safety of intramuscular injection of plasmid pUDK-HGF, which encodes the human hepatocyte growth factor gene in patients with critical limb ischemia. Resting pain patients (n = 119) and patients with leg ulcers (n = 121) were enrolled as two cohorts and randomized to receive pUDK-HGF treatment on days 0, 14, and 28. In the resting pain cohort, the proportion of patients with complete pain relief on day 180 after receiving pUDK-HGF injection, as the primary outcome, was significantly higher than that of the placebo group on the same day (p = 0.0148). More responders with >50% pain reduction were also observed in the pUDK-HGF groups than in the placebo groups (p = 0.0168). In the ulcer cohort of patients, pUDK-HGF treatment tended to be superior to the placebo in the percentage of patients with both complete ulcer healing and >50% ulcer healing. No significant differences in the incidence of adverse events (AEs) or serious AEs were observed among the groups. The mid-dose pUDK-HGF (6 mg) was the most efficacious, and is therefore an appropriate dose for use in a phase III clinical trial. This study was approved by the China Food and Drug Administration (2013L00637), China Clinical Trial Registry URL: www.chinadrugtrials.org.cn. Unique Identifier: 20130378.

Polycystic ovary syndrome (PCOS) is an endocrine-related disease and global cause of infertility that is associated with abnormal folliculogenesis. Inhibited granulosa cell (GC) proliferation is recognized as a key factor that underlies aberrant follicle maturation. Many epigenetic landscape modifications have been characterized in PCOS patients. However, the epigenetic regulation pathways in follicular dysplasia are not completely understood. In this study, we reported a novel mechanism of DNA hypomethylation induced by long non-coding RNAs (lncRNAs) and its function in cell cycle progression. We observed that lnc-MAP3K13-7:1 was highly expressed in GCs from patients with PCOS, with concomitant global DNA hypomethylation, decreased DNA methyltransferase 1 (DNMT1) expression, and increased cyclin-dependent kinase inhibitor 1A (CDKN1A, p21) expression. In KGN cells, lnc-MAP3K13-7:1 overexpression resulted in cell cycle arrest in the G0/G1 phase, as well as the molecular inhibition and genetic silencing of DNMT1. Mechanistically, lnc-MAP3K13-7:1 inhibited DNMT1 expression by acting as a protein-binding scaffold and inducing ubiquitin-mediated DNMT1 protein degradation. Moreover, DNMT1-dependent CDKN1A promoter hypomethylation increased CDKN1A transcription, resulting in attenuated GC growth. Our work uncovered a novel and essential mechanism through which lnc-MAP3K13-7:1-dependent DNMT1 inhibition regulates CDKN1A/p21 expression and inhibits GC proliferation.

Background It is generally believed that gait characteristics of diabetic neuropathic patients differ from non-diabetic ones. However, it is still unclear whether these changes during walking could also be extended for different conditions of type 2 diabetes mellitus (T2DM), especially diabetic individuals with lower extremity complications. Methods In this investigation, gait was examined among 1861 participants with or without T2DM from three study centers. Subjects with NGT(normal glucose tolerance) and IGT (impaired glucose tolerance) were taken as control groups, patients with T2DM were divided into 4 groups: DM (no chronic complications), DPN (DM complicated with diabetic peripheral neuropathy), LEAD (DM complicated with lower extremity artery disease) and DPN + LEAD. Analyses of variance were employed to verify possible differences of gait parameters between these groups. Results Results showed lowered cadence, increased step time and decreased walking speed in diabetes with lower extremity neural and/or vascular complications (all p < 0.05). Increased duty factor_double stance was displayed in participants with LEAD alone (32.51%, p < 0.05). And the results displayed lower SDA (1.32 vs. 1.57, p < 0.01) and SDB (0.38 vs. 0.51, p < 0.01) of subjects with both DPN and LEAD. All these indicated the subjects with diabetic lower extremity complications showed much more conservative gait pattern. Stepwise multivariate regression models showed that independent variables were sex, age and leg length (p < 0.01). While, VPT was listed as significant independent predictor of cadence, step time, SDA and SDB (p < 0.05). And ABI was documented as significant independent predictor of stride length, duty-factor_Double stance, SDA and SDB (p < 0.05). Binary logistic regression analysis revealed a significant positive association between decreased stride length and the lowest ABI group (OR = 112.19, 95% CI: 3.11- 4040.13, p = 0.01). ROC analysis showed a significant discriminatory power of step time for occurrence of DPN. The AUC value was 0.752 (95% CI: 0.721–0.782, p < 0.01) . Conclusions In total, the cut-off point was 526.13 ms for predicting DPN. Maybe, this non-invasive and non-irritating gait examination could be an alternative measurement that could help distinguish diabetic neuropathy conveniently.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disease in premenopausal women. Long non-coding RNAs (lncRNAs) constitute important factors in numerous biological processes. However, their roles in PCOS pathogenesis require further clarification. Our study aims to elucidate the roles of lncRNA lnc-CCNL1-3:1 (CCNL) in PCOS. CCNL expression in human luteinized granulosa cells (hLGCs) derived from women with and without PCOS was detected. The full length of CCNL was obtained by 5' and 3' rapid amplification of cDNA ends. CCNL roles in granulosa cell apoptosis, mitochondrial function, and glucose uptake were evaluated. The binding relationship between CCNL and forkhead box O1 (FOXO1) was determined by RPISeq, RNA immunoprecipitation, subcellular fractionation, and immunofluorescence. In KGN cells and hLGCs, CCNL overexpression upregulated FOXO1 expression, promoted cell apoptosis, reduced glucose transport capability, and impaired mitochondrial function, and these effects were partially abolished by silencing FOXO1. The interaction of CCNL with FOXO1 might prevents FOXO1 exclusion from the nucleus and subsequent degradation in the cytosol. We determined that CCNL serve as a facilitator in the processes of PCOS. CCNL might participate in PCOS pathologies such as follicular atresia and insulin resistance.

Polycystic ovary syndrome (PCOS) is a common metabolic and reproductive disorder with an increasing risk for type 2 diabetes. Insulin resistance is a common feature of women with PCOS, but the underlying molecular mechanism remains unclear. This study aimed to screen critical long non-coding RNAs (lncRNAs) that might play pivotal roles in insulin resistance, which could provide candidate biomarkers and potential therapeutic targets for PCOS. Gene expression profiles of the skeletal muscle in patients with PCOS accompanied by insulin resistance and healthy patients were obtained from the publicly available Gene Expression Omnibus (GEO) database. A global triple network including RNA-binding protein, mRNA, and lncRNAs was constructed based on the data from starBase. Then, we extracted an insulin resistance-associated lncRNA-mRNA network (IRLMN) by integrating the data from starBase and GEO. We also performed a weighted gene co-expression network analysis (WGCNA) on the differentially expressed genes between the women with and without PCOS, to identify hub lncRNAs. Additionally, the findings of key lncRNAs were examined in an independent GEO dataset. The expression level of lncRNA RP11-151A6.4 in ovarian granulosa cells was increased in patients with PCOS compared with that in control women. Levels were also increased in PCOS patients with higher BMI, hyperinsulinemia, and higher HOMA-IR values. As a result, RP11-151A6.4 was identified as a hub lncRNA based on IRLMN and WGCNA and was highly expressed in ovarian granulosa cells, skeletal muscle, and subcutaneous and omental adipose tissues of patients with insulin resistance. This study showed the differences between lncRNA and mRNA profiles from healthy women and women with PCOS and insulin resistance. Here, we demonstrated that RP11-151A6.4 might play a vital role in insulin resistance, androgen excess, and adipose dysfunction in patients with PCOS. Further study concerning RP11-151A6.4 could elucidate the underlying mechanisms of insulin resistance.

The underlying mechanism of the chemokine-C receptor 7 (CCR7) that leads to aberrant trophoblast migration and invasion in recurrent spontaneous abortion (RSA) remains unknown. CCR7 is considered crucial for migration and invasion and has been associated with the risk of miscarriage. However, the functional role of CCR7 in RSA is not fully understood. Our study found that CCR7 mRNA and protein abundance were significantly decreased in the villous from RSA patients compared with healthy controls. Knockdown of CCR7 caused a significant reduction of migration and invasion in JAR and JEG-3 cells. Meanwhile, CCR7 functioned as a positive upstream factor of the AKT pathway contributing to the expression of GATA2, promoting trophoblast migration, and invasion via MMP2. Notably, a decreased abundance of CCR7 was positively correlated with the phosphorylation of AKT and with an abundance of GATA2 and MMP2 in human villous specimens of RSA compared with the control group. CCL19, a ligand of CCR7, could promote trophoblast migration and invasion by activating the deregulation of the CCR7-mediated pathway in RSA. We are convinced that CCR7 and its downstream factors may be possible mechanisms for the pathogenesis of RSA.

INTRODUCTION:Embryo implantation depends on trophoblast cells migration and invasion. Abnormal function of trophoblast cells could result in many pregnancy complications. Secreted protein acidic and rich in cysteine like-1 (SPARCL1) has been reported to inhibit cell migration and tumor invasion. This study aimed to explore the role of SPARCL1 in trophoblast functions.METHODS:Villous specimens were obtained from 31 women with spontaneous abortion and 31 women with normal early pregnancy to determine the expression of SPARCL1. HTR8/SVneo cells and JAR cells were transfected with pIRES2-EGFP-SPARCL1 vectors and control vectors. The proliferation assay and scratch-wound assay were performed. Quantitative polymerase chain reaction (qPCR) and western blotting were performed to assess epithelial mesenchymal transition (EMT)-related molecules including MMP2, MMP3, N-cadherin, E-cadherin and vimentin. Extracellular signal-regulated kinase (ERK) phosphorylation activity and AP-1 expression in HTR8/SVneo cells following multi-scratching were detected using above assays.RESULTS:The mRNA and protein levels of SPARCL1 were significantly higher in the abortion group than in the normal pregnancy group. After transfection, there was no difference of cell viability between the SPARCL1-overexpression group and control vector group. However, the migration distance and area were reduced and the abundances of EMT related molecules were changed by SPARCL1 overexpression when compared with controls. Lower ERK phosphorylation activity and decreased Fos and Jun expressions were noted at high level of SPARCL1.CONCLUSION:Restrained migration and invasion were noted in trophoblast cells with SPARCL1 overexpression, which might affect embryo implantation and placenta development. It could be involved in the pathogenesis of spontaneous abortion.

The authors wish to point out that the source of two cell lines have been elaborated in the Materials and methods section, and contribution from additional partners have been fully acknowledged.1In Materials and Methods Section 2.2, the sentence “SVOG and KGN cells were obtained from Shandong University” should be replaced with: “SVOG cells were gifted from Prof. Peter C.K. Leung of University of British Columbia to The Chinese University of Hong Kong – Shandong University (CUHK-SDU) Joint Laboratory on Reproductive Genetics. KGN cells were gifted from Prof. Toshihiko Yanase of Fukuoka University in Japan to Center for Reproductive Medicine, Shandong Provincial Hospital, Shandong University.”2The correct Acknowledgements section should read as follows: We thank Prof. Chan Wai-Yee from CUHK-SDU Joint Laboratory on Reproductive Genetics for his valuable comments. We also thank Prof. Peter C.K. Leung and Prof. T. Yanase for their generous gifts of cell lines. Long non-coding RNA LINC-01572:28 inhibits granulosa cell growth via a decrease in p27 (Kip1) degradation in patients with polycystic ovary syndromeOur findings, therefore, suggest that LINC-01572:28 suppresses cell proliferation and cell cycle progression by reducing the degradation of p27 protein via SKP2 binding. Full-Text PDF Open Access

BACKGROUND:Disordered folliculogenesis is a key feature of polycystic ovary syndrome (PCOS), but the underlying molecular mechanism remains unclear. METHODS:Long non-coding RNA (lncRNA) expression in luteinized granulosa cells (hLGCs) derived from women with and without PCOS were analyzed using microarray and qRT-PCR. Immortalized human granulosa cell lines were cultured for proliferation assays after transfection with the LINC-01572:28 over-expression vector in the presence or absence of p27 siRNA. Protein expression analysis, rescue assays, and RNA immunoprecipitation (RIP) were used to confirm the LINC-01572:28 substrate. FINDINGS:LINC-01572:28 and p27 protein were elevated whereas proliferating cell nuclear antigen protein was decreased in the hLGCs of women with PCOS. LINC-01572:28 expression was positively correlated with basal testosterone levels. Over-expression of LINC-01572:28 inhibited cell proliferation and impeded G1/S transition, which were partially reversed by siRNA-mediated p27 knockdown. INTERPRETATION:Our findings, therefore, suggest that LINC-01572:28 suppresses cell proliferation and cell cycle progression by reducing the degradation of p27 protein via SKP2 binding.

OBJECTIVE:To investigate the relationship between ankle-branchial index (ABI) and cardiovascular disease in type 2 diabetes patients. METHODS:A total of 634 inpatients with type 2 diabetes were recruited in this cross-sectional study. All patients were measured with ABI and computed tomography angiography (CTA) scan for coronary artery disease (CAD). According to ABI values, patients were divided into three groups: low-ABI group (ABI < 0.9, n = 259), normal-ABI group (ABI = 0.9-1.3, n = 272), and high-ABI group (ABI > 1.3, n = 103). According to the manifestation of coronary CTA, the patients were divided into CAD group (n = 348) and non-CAD group (n = 286). Their clinical data and biochemical parameters were compared and analysed. RESULTS:The prevalence of CAD in low-ABI group (90%) was significantly higher than that of normal-ABI group (33%) and high-ABI group (25%) (both P < 0.01). Spearman correlation analysis showed that age, sex, duration, spontaneous bacterial peritonitis, total cholesterol (TC), triglyceride, low-density lipoprotein cholesterol (LDL-C), serum creatinine, and glycosylated haemoglobin (HbA1c ) were positively correlated with CAD, and high-density lipoprotein cholesterol (HDL-C), glomerular filtration rate, and ABI were negatively correlated with CAD. Logistic regression analysis further revealed that age, sex, duration, TC, HDL-C, LDL-C, HbA1c , and ABI were independent risk factors of CAD. After all potential confounders is adjusted, the risk of CAD in low-ABI group still increased over four times than the normal-ABI group (odds ratio [OR], 5.32; 95% CI, 1.973-16.5; P < 0.001). In female patients, this risk increased more than nine times (OR, 10.63; 95% CI, 3.416-17.8; P < 0.001). Receiver-operating characteristic analysis indicated that ABI < 1.045 predicted the occurrence of CAD (sensitivity, 79.7%; specificity, 71.5%; P < 0.01). CONCLUSIONS:ABI is an independent risk factor for CAD and may be a potential simple screening instrument for CAD in Chinese type 2 diabetic patients, especially in elder women.

BACKGROUND:Vitamin D deficiency was reported to be associated with diabetic peripheral neuropathy. But the association in Chinese population and the screening value of vitamin D deficiency for diabetic peripheral neuropathy were unknown.METHODS:A total of 861 patients with type 2 diabetes were recruited in this cross-sectional study. Vitamin D deficiency was defined as serum circulating 25-hydroxyvitamin D(25(OH)D) level < 20 ng/mL. Peripheral neuropathy was evaluated by neurological symptoms, neurological signs, neurothesiometer and electromyogram.RESULTS:The patients with diabetic peripheral neuropathy had significantly lower serum 25(OH)D concentration (15.59 ± 7.68 ng/mL) and higher prevalence of vitamin D deficiency (80%) than patients with signs of diabetic peripheral neuropathy (17.66 ± 7.50 ng/mL; 64.5%) and non-DPN patients (18.35 ± 6.60; 61.7%) (all p < 0.01). Spearman's correlation analysis showed that serum circulating 25(OH)D level was closely associated with DPN (r = 0.121) and signs of DPN (r = 0.111) (both p < 0.01). After adjusting for all potential confounders, VDD was still linked with increased risk of DPN [odds ratio 2.59 (1.48-4.53)] (p < 0.01). Logistical regression analysis further revealed that VDD was an independent risk factor for DPN (β = 0.88) (p < 0.01). Receiver operating characteristic analysis indicated that serum 25(OH)D < 17.22 ng/mL hinted the signs of DPN and serum 25(OH)D < 16.01 ng/mL predicted the occurrence of DPN (both p < 0.01).CONCLUSIONS:Vitamin D deficiency is an independent risk factor for diabetic peripheral neuropathy and may be a potential biomarker for peripheral neuropathy in Chinese patients with type 2 diabetes. Copyright © 2016 John Wiley & Sons, Ltd.

目的 探讨血清高胱抑素-C水平与糖尿病足溃疡(DFU)严重程度是否存在联系.方法 本研究为横断面研究,纳入上海市糖尿病临床医学中心2014年1月～2015年2月就医的975例2型糖尿病(T2DM)患者,其中足溃疡(DFU)患者110例,865例无足病者(NDF)作为对照组.收录患者血清、一般临床数据、糖代谢指标、血脂、肝肾功能、胱抑素C、C反应蛋白、血常规等生化指标检测结果.采取t检验、方差分析、卡方检验、Spearman相关分析、多元Logistic回归分析等统计学方法研究Cys C与DFU严重程度的关系.结果 DF组年龄、病程、吸烟比例、空腹血糖、血肌酐、血清CysC、糖化血红蛋白水平均明显高于非足病组(NDF),差异有统计学意义(P均＜0.01).DFU患者不同Wagner水平间单因素方差分析显示,DFU患者的Wagner分级越高,Cys C升高越明显(F=11.27,P＜0.01);且血肌酐、尿素氮、糖化血红蛋白水平越高(F=4.9、4.9、3.18,P均＜0.05).Spearman相关分析表明,ABI水平与DFU的Wagner分级呈负相关(r=-0.241,P＜0.05),吸烟史、Cys C、肌酐、尿酸、糖化血红蛋白水平与DFU患者的Wagner分级呈正相关(r=0.205、0.344、0.237、0.231、0.053,P均＜0.05).Logistic回归分析显示,排除其他DFU严重程度的传统影响因子后,Cys C升高仍是DFU Wagner分级级别的独立影响因素(β=1.381,95％CI:1.039～15.228,P＜0.01).结论 血清胱抑素-C水平与糖尿病足溃疡密切相关,高胱抑素-C水平提示糖尿病足溃疡更严重.

We investigated the relationship between serum cystatin C levels and the prognosis of diabetic foot ulcerations (DFU). A population‐based cohort study involving 1018 patients with type 2 diabetes was conducted. These patients recruited and divided into two groups: nondiabetic foot ulcer group (NDF, n = 865, 85.5%) and diabetic foot ulcer group (DFU, n = 147, 14.5%).After a 1‐year‐follow‐up, DFUs were grouped into healing ( n = 110, 74.8%) and nonhealing ( n = 37, 25.2%) group based on the clinical prognosis. Compared with the healing group, the nonhealing group were older, had long diabetic duration and had significantly increased serum cystatin C concentrations in DFU ( p < 0.01). After adjustments for age, diabetes duration, renal function and infection control, multiple logistical regression analysis revealed that cystatin C remained associated increased risk of undesirable DFU outcome (OR = 7.279, 95% CI: 1.299–40.784, p < 0.05). When divided into quartiles according to cystatin C levels, the healing rate of Quartile 4 was significantly lower (57.9%) compared with other groups ( p < 0.01). The odd is ratio (OR) analysis showed that the risk of undesirable DFU outcome in Quartile 4 was significantly higher (OR = 4.554, 95% CI: 3.14–5.12, p < 0.05) compared with that in Quartile 1. We concluded that there was a strong and independent association between serum cystatin C and diabetic foot ulceration prognosis, cystatin C > 1.35 mg/L predicts more than sixfold increased risk of incurable foot ulceration.

Aim The association between thyroid stimulating hormone (TSH) and type 2 diabetes mellitus (T2DM) is well known. However, whether TSH is related to diabetic peripheral neuropathy (DPN) has not been studied. The aim of this study was to explore the relationship between TSH and DPN in Chinese patients with T2DM. Methods In this cross-sectional study, 605 patients with T2DM were enrolled. Subclinical hypothyroidism (SCH) was defined as an elevated TSH level (>4.0 mIU/L) and a normal free thyroxine level. DPN was evaluated by neurological symptoms, neurological signs, and electromyogram. Results Serum TSH levels were significantly higher in DPN and signs of DPN compared with non-DPN T2DM patients (both P < 0.01).The prevalence of DPN and signs of DPN in SCH subjects was higher than that in euthyroid subjects (both P < 0.01). Spearman's correlation analysis showed that the serum TSH level was positively associated with DPN (r = 0.172, P < 0.01). A significant independent association between TSH and DPN was found by multiple logistic regression analysis after adjusting for potential confounding variables [odds ratio (OR) = 1.365, P < 0.01]. The patients were sequentially assigned to quartiles according to TSH level. Compared with quartile 1, patients in quartile 2 (P < 0.01), quartile 3 (P = 0.01), and quartile 4 (P < 0.01) had a higher risk of DPN. Receiver-operating characteristic curve analysis revealed that the optimal cutoff point of TSH to indicate DPN was 3.045 mIU/L in men and 2.94 mIU/L in women. Conclusion TSH level is independently associated with DPN in Chinese population with T2DM. A high serum TSH level may be a potential risk factor for DPN.

We assessed the association between high ankle–brachial index (ABI) and cardiovascular disease (CVD) and peripheral arterial disease (PAD) in Chinese patients with type 2 diabetes mellitus (T2DM). The ABI was measured, and foot inspection was performed in 2080 outpatients with T2DM. The clinical characters in different ABI levels were analyzed, and the diagnostic value of high ABI to CVD and PAD was determined. Compared with the normal ABI group, the high ABI (>1.3) group had a higher prevalence of CVD and PAD but less than the low ABI (≤0.9) group. High ABI was an independent risk factor for the development of CVD and PAD. Receiver–operating characteristic curve analysis showed that the optimal cutoff of high ABI to predict CVD and PAD was 1.43 and 1.45, respectively. The odds ratio of high ABI for CVD and PAD was 2.25 and 6.97, respectively, after adjusting for other confounding risk factors. In conclusion, high ABI indicated the risk of CVD and PAD in Chinese populations with T2DM.

Fibroblast growth factor 21 (FGF21) is an emerging metabolic regulator associated with glucose and lipid metabolism, and it is still unclear whether FGF21 is related to atherosclerosis. Here, we explored the potential link between FGF21 and lower extremity atherosclerotic disease (LEAD) in type 2 diabetic patients.