Introduction:Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduced the risk of heart and kidney outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in FIDELITY, a prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD trials. This subanalysis explored the efficacy and safety of finerenone vs. placebo in Chinese patients. Methods:Patients with CKD (urine albumin-to-creatinine ratio 30-5,000 mg/g, estimated glomerular filtration rate [eGFR] ≥25 mL/min/1.73 m2) and T2D, on optimized renin-angiotensin system inhibitors, were randomized 1:1 to finerenone or placebo. Key outcomes included a kidney composite (kidney failure, sustained ≥57% eGFR decrease from baseline over ≥4 weeks, or kidney-related death) and a cardiovascular (CV) composite (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). An additional kidney composite outcome was kidney failure, sustained ≥40% eGFR decrease from baseline over ≥4 weeks, or kidney-related death. Treatment-emergent adverse events were also assessed. Results:In this Chinese patient subanalysis (n = 697), finerenone reduced the risk of the ≥57% and ≥40% kidney composite outcomes (hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.38-0.86; p = 0.0066 and HR: 0.54; 95% CI: 0.40-0.74; p < 0.0001, respectively) and CV composite outcome risk vs. placebo (HR: 0.82; 95% CI: 0.52-1.29; p = 0.3866). Safety outcomes were similar between treatment arms. Hyperkalemia leading to treatment discontinuation was low for finerenone (2.6%) and placebo (0.9%). Conclusion:Finerenone demonstrated kidney benefits, favorable trends on CV outcome, and a manageable safety profile in the FIDELITY Chinese subpopulation.

BACKGROUND:Xenotransplantation of porcine cells, tissues or organs offers a promising strategy to address the critical shortage of human donor organs. However, cross-species pathogen transmission, instant blood-mediated inflammatory reaction (IBMIR)-related liver injury, chronic over-immunosuppression, and long-term safety remain major challenges in porcine islet xenotransplantation. In this study, we performed a clinical trial aimed to evaluate the biosafety of neonatal porcine islet xenotransplantation in patients with type 1 diabetes. METHODS:Ten recipients were assigned to two groups receiving non-encapsulated neonatal islet cell clusters via the jugular-hepatic-portal vein at mean doses of 6354 ± 835 IEQ/kg and 11 600 ± 1100 IEQ/kg, respectively. Donor pigs originated from a highly inbred, PERV-C-negative colony reared in designated pathogen-free (DPF) conditions, with rigorous pathogen and PERV screening. Immunosuppression included mycophenolate mofetil, tacrolimus, belatacept, and autologous regulatory T-cell therapy, combined with tocilizumab. Continuous low-dose heparin was infused via a portal vein catheter was used for 7 days as anticoagulation therapy. Recipients and spouses were monitored for over 5 years, with 7 followed for more than 10 years. RESULTS:No PERV transmission or transplant-related infections were detected in any recipient or contact during long-term follow-up. The procedure was safe and well-tolerated, with only transient liver function and coagulation changes and mild adverse events. Both groups showed reduced exogenous insulin requirements and markedly lower hypoglycemia incidence, with better glucose control in the higher-dose group. CONCLUSION:This study demonstrates that DPF PERV-C-free neonatal porcine islet xenotransplantation is biologically safe and partially effective, supporting its value as a reliable donor source and foundational platform for advancing clinical islet xenotransplantation. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT03162237.

Oxidative stress is a key driving factor for the progression of vascular disease in diabetes, and is closely related to endothelial dysfunction. The exact mechanism by which glucagon-like peptide-1 (GLP-1) directly protects vascular endothelium by reducing oxidative stress is not yet fully understood. In this study, we investigated the protective effect of GLP-1 on endothelial cells exposed to palmitic acid (PA)/high glucose-induced oxidative stress and further explored the potential mechanisms involved in microRNA-139-5p (miR-139-5p) regulation. We found that miR-139-5p expression was exhibited significantly elevated in HUVECs that were exposed to PA/high glucose or H2O2, which were reversed by glutathione. Interestingly, this expression was significantly attenuated after GLP-1 pretreatment, with reduced reactive oxygen species (ROS), increased GSH/GSSG ratio and amelioration of cell dysfunction. Overexpression of miR-139-5p resulted in increased ROS and apoptosis, decreased GSH/GSSG ratio, damaged migration and proliferation of HUVECs, while inhibition of miR-139-5p significantly restored PA-induced HUVECs impairments. Further investigation revealed that miR-139-5p directly targets superoxide dismutase 1 (SOD1)/glutamate–cysteine ligase catalytic (GCLc) subunit. The upregulation of miR-139-5p abrogated the protective effects of GLP-1 on cells exposed to PA, and GLP-1-induced downregulation of miR-139-5p was counteracted by the GLP-1 receptor antagonist exendin(9–39). These findings demonstrated that GLP-1 ameliorates oxidative stress-induced endothelial dysfunction, at least in part, by suppressing miR-139-5p, which targets SOD1 and GCLc. This provides further evidence for the vascular protective effects of GLP-1 intervention in diabetes.

Oxidative stress is a key driving factor for the progression of vascular disease in diabetes, and is closely related to endothelial dysfunction. The exact mechanism by which glucagon-like peptide-1 (GLP-1) directly protects vascular endothelium by reducing oxidative stress is not yet fully understood. In this study, we investigated the protective effect of GLP-1 on endothelial cells exposed to palmitate/high glucose-induced oxidative stress and further explored the potential mechanisms involved in microRNA-139-5p (miR-139-5p) regulation. We found that miR-139-5p expression was exhibited significantly elevated in HUVECs that were exposed to palmitate/high glucose or H2O2, which were reversed by glutathione. Interestingly, this expression was significantly attenuated after GLP-1 pretreatment, with reduced ROS, increased GSH/GSSG ratio and amelioration of cell dysfunction. Overexpression of miR-139-5p resulted in increased ROS and apoptosis, decreased GSH/GSSG ratio, damaged migration and proliferation of HUVECs, while inhibition of miR-139-5p significantly restored palmitate-induced HUVECs impairments. Further investigation revealed that miR-139-5p directly targets superoxide dismutase 1(SOD1)/ glutamate-cysteine ligase catalytic subunit(GCLc). The upregulation of miR-139-5p abrogated the protective effects of GLP-1 on cells exposed to palmitate, and GLP-1-induced downregulation of miR-139-5p was counteracted by the GLP-1 receptor antagonist Exendin(9-39). These findings demonstrated that GLP-1 ameliorates oxidative stress-induced endothelial dysfunction, at least in part, by suppressing miR-139-5p, which targets SOD1 and GCLc. This provides further evidence for the vascular protective effects of GLP-1 intervention in diabetes.

Epigenetics is increasingly recognized as a crucial factor in angiogenesis. Ubiquitin-like with PHD and RING Finger Domains 1 (UHRF1) is an important epigenetic regulatory protein involved in regulating cellular life processes, developing many diseases. However, its potential role in regulating embryonic vascular development and postnatal angiogenesis is unclear. Our study found that endothelial cell-specific UHRF1 knockout mice showed obvious developmental disorders at the embryonic stage (E11.5-15.5), including impaired development of the individual embryo size and organs, sparse vascularity in the yolk sac, or even death. In the lower limb ischemia model, UHRF1 expression in ischemic muscle tissues of mice is proportionate to the regeneration of blood vessels. To confirm the specific inhibition of UHRF1, we transfected an adeno-associated virus serotype 9 which inserted a TIE-2 promoter and mediated the delivery of short hairpin RNA (AAV9-TIE-2-shUHRF1) into mouse vascular endothelial cells to knock down UHRF1 specifically. We observed that the knockdown of UHRF1 in endothelial cells results in poorer lower limb perfusion in mice. Mechanically, UHRF1 knockdown decreased the tube-forming capacity of ECFCs, whereas overexpression of UHRF1 by diabetic ECFCs where UHRF1 expression is typically downregulated significantly increased the tube-forming capacity of the cells. RNAseq and related bioinformatics analyses showed that differentially expressed genes (DEGs) were mainly involved in angiogenesis-related pathways. The results of qPCR and western blot showed that the protein and mRNA levels of angiogenesis-related factors (VEGF, PDGF, and ANGPT1), as well as vascular endothelial surface marker molecules (VEGFR2, CD31, and c-Kit), were down-regulated accordingly. Furthermore, ChIP experiments showed that UHRF1 was able to bind the promoters of VEGFR2 and CD31, affecting the levels of histone-methylated protein (H3K4me3 and H3K27me3) enriched in the promoter region. However, the expression of CD31 and VEGFR2 can be reversed separately after the transformation of different histone-methylated protein levels (H3K4me3 and H3K27me3). Taken together, UHRF1 may regulate angiogenic gene expression and vascular endothelial cell differentiation through epigenetic mechanisms and is essential for angiogenesis.

O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant genetic disorder caused by mutations in the KMT2E (lysine methyltransferase 2E) gene. The Third Xiangya Hospital of Central South University admitted a 12-year and 9-month-old male patient who presented with growth retardation, intellectual disability, and distinctive facial features. Peripheral blood was collected from the patient, and DNA was extracted for genetic testing. Chromosome karyotyping showed 46XY. Whole-exome sequencing and low-coverage massively parallel copy number variation sequencing (CNV-seq) revealed a 506 kb heterozygous deletion in the 7q22.3 region, which includes 6 genes, including KMT2E. The patient was diagnosed with ODLURO syndrome. Both the patient's parents and younger brother had normal clinical phenotypes and genetic test results, indicating that this deletion was a de novo mutation. The clinical and genetic characteristics of this case can help increase clinicians' awareness of ODLURO syndrome.

Background Type 2 diabetes (T2DM) remains a challenge to treat despite the expansion of various therapeutic classes. Visepegenatide (PB-119) is a once a week, subcutaneous, glucagon-like peptide-1 receptor agonist (GLP-1 RA) injection without the requirement of dose titration that has shown glycaemic control and safety profile in two phase 2 studies conducted in China and the United States, respectively. The aim of this study was to evaluate the efficacy and safety of visepegenatide as a monotherapy in treatment-naive patients with T2DM. Methods This was a multicentre, double-blind, parallel, placebo-controlled, phase 3 trial conducted in 30 centres in China. Adult participants (aged 18-75 years) with T2DM, glycated haemoglobin (HbA1c) of 7.5%-11.0% [58.47-96.73 mmol/mol], body mass index (BMI) of 18-40 kg/m(2), and who had been treated with diet and exercise alone for at least 8 weeks before the screening visit were eligible for enrolment. After a 4-week placebo injection run-in period, participants with HbA1c of 7.0%-10.5% [53.0-91.3 mmol/mol] and fasting plasma glucose (FPG) < 15 mmol/L were randomised in a ratio of 1:1 to receive visepegenatide (150 mu g) or placebo subcutaneous injections once a week for 24 weeks. The treatment was extended to another 28 weeks during which all participants received visepegenatide. The primary outcome was a change in HbA1c from baseline to week 24. This study was registered with ClinicalTrials.gov, as NCT04504370. Findings Between November 2, 2020, and November 2, 2022, we randomly assigned 273 adult participants to the visepegenatide (n = 137) and placebo (n = 136) groups. In total, 257 (94.12%) participants, 131 (95.6%) on visepegenatide, and 126 (92.6%) on placebo, completed the double-blinded treatment period. At baseline, the mean (SD) HbA1c was 8.47% (0.81) [69.07 [8.81] mmol/mol], which rapidly decreased to 7.63% (0.80) [59.94 [8.70] mmol/mol] with visepegenatide by week 4 of treatment, and the change from baseline was significantly greater than that in the placebo group (-0.82% [-0.90 to -0.74]; [-8.99 [- 9.89 to -8.10] mmol/mol] vs -0.30% [-0.41 to -0.19]; [-3.30 [-4.50 to -2.09] mmol/mol]). At week 24, when evaluating the effects of treatment with treatment policy estimand, the least square mean (LSM change in HbA1c from baseline was -1.36 (95% confidence interval [CI] -1.52 to -1.20) [-14.84 [-16.60 to -13.08] mmol/mol] in the visepegenatide group vs -0.63 (-0.79 to -0.46) [-6.84 [-8.61 to -5.07] mmol/mol] in the placebo group. The reduction in HbA1c was significantly greater with visepegenatide than placebo (LSM difference -0.73, 95% CI -0.96 to -0.50; p < 0.001). When evaluating the treatment estimand with hypothetic policy, the LSM change in HbA1c from baseline in the visepegenatide group (-1.37 [-1.53 to -1.20]) [-14.95 [-16.76 to -13.14] mmol/mol] was significantly greater than the placebo group (-0.63 [-0.81 to -0.45]) [6.90 (-8.89 to -4.90) mmol/mol]. The LSM difference was (-0.74, 95% CI -0.98 to -0.49; [-8.00 [-10.50 to -5.50] mmol/mol]; p < 0.001]. A significantly greater proportion of the visepegenatide group achieved a target HbA1c level of <7% (<53 mmol/mol) than the placebo (50.4% vs 14.2%; p < 0.05) and stringent HbA1c level of <= 6.5% (<= 48 mmol/mol) (26.7% vs 7.9%), respectively. There was also a significantly greater improvement in FPG, 2-h postprandial glucose, homeostasis model assessment (HOMA) of beta cell function, post-prandial insulin, fasting, and post-prandial C-peptide level (p < 0.05) with visepegenatide treatment. The number (3 [2.2%]) of participants who received rescue therapy in the visepegenatide group was remarkably lower compared with those (17 [12.5%]) in the placebo group (p < 0.05). During the extended treatment period, visepegenatide consistently maintained the efficacy till week 52 confirmed by all the above endpoints. The reduction in HbA1c at week 52 was -1.39% (-1.58 to -1.19) [-15.14 [-17.28 to -13.01] mmol/mol], which was even greater than that at week 24. There was also a significant improvement in HOMA-insulin resistance (p = 0.004) at week 52 compared with the baseline value. For the placebo.visepegenatide group, which received visepegenatide in the extended treatment period, a notable decrease in HbA1c at week 52 compared to baseline was observed. The change from baseline in HbA1c was -1.49% (-1.68 to -1.30) [-16.27 [-18.37 to -14.16] mmol/mol]. The outcome was in the same direction as the visepegenatide group from the double-blind treatment period. Comprehensive benefits of visepegenatide including weight loss, improvement in lipid profile, and reduction in blood pressure have been demonstrated in this study. Visepegenatide reduced the body weight in a BMI-dependent manner that was prominent in BMI.32 kg/m(2) with a mean (SD) reduction of -4.77 (13.94) kg at week 52 (p < 0.05). Incidences of gastrointestinal adverse events were less common than other weekly GLP-1 RA in the market, and most of the adverse events were mild and moderate in nature, occurring in the first weeks of the treatment, and were transient. No serious hypoglycaemia or grade 2 hypoglycaemia (blood glucose: <= 3 mmol/L) was reported during the study. Interpretation As a monotherapy, visepegenatide provided rapid without the risk of hypoglycaemia, significant, and sustainable glycaemic control by improving islet beta-cell function and insulin resistance. Treatment with visepegenatide induced early treatment response in reducing HbA1c and maintaining glycaemic control for 52 weeks. Meanwhile, visepegenatide provided a comprehensive benefit in body weight loss, lipids, and blood pressure reduction. Visepegenatide had a better safety profile than other weekly GLP-1 RA in participants with T2DM even without the requirement of dose titration. Visepegenatide would provide an optimal treatment approach with its high benefit and low-risk balance. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).

IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disorder that can affect multiple organs throughout the body, predominantly in middle-aged and elderly males, with a male-to-female ratio of 2꞉1 to 3꞉1. IgG4-related retroperitoneal fibrosis (IgG4-RPF), a rare subtype of IgG4-RD, has an unclear etiology, and its comorbidity with type 2 diabetes mellitus is also uncommon. A lack of awareness of this condition in clinical practice can easily lead to misdiagnosis. On July 14, 2016, the Third Xiangya Hospital of Central South University admitted a patient with type 2 diabetes mellitus complicated by IgG4-RPF. Following comprehensive treatment, including blood glucose and blood pressure control, kidney protection, circulation improvement, and the use of prednisone, the patient's condition significantly improved. The retroperitoneal fibrotic mass decreased in size, renal function improved, and serum IgG4 levels decreased. After 8 years of follow-up, the condition did not recur. Analyzing this case in conjunction with a literature review suggests that the development of IgG4-RPF in diabetic patients may be related to chronic inflammation from metabolic syndrome and atherosclerotic plaques associated with long-standing diabetes. This provides valuable clinical ideas for clinicians in diagnosing and treating this rare comorbidity.

O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant genetic disorder caused by mutations in the

Finerenone significantly reduced the risk of kidney and heart outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the FIDELITY prespecified pooled analysis of the phase III FIDELIO-DKD and FIGARO-DKD trials. This FIDELITY subanalysis explored the efficacy and safety of finerenone in Chinese patients.

Background: This prespecified subgroup analysis of the FIDELIO-DKD trial aimed to evaluate the efficacy and safety of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) in China. Methods: 372 participants were recruited from 67 centers in China and randomized 1:1 to oral finerenone or placebo with standard therapy for T2DM. The primary composite outcome included kidney failure, sustained decrease of estimated glomerular filtration rate ≥40% from baseline over at least 4 weeks, or renal death. The key secondary composite outcome included death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Results: After a median follow-up of 30 months, the finerenone group showed a relative risk reduction (RRR) of 41% (hazard ratio [HR] = 0.59, 95% confidence interval [CI], 0.39–0.88; p = 0.009) for the primary composite outcome compared with placebo, consistent across its components with treatment benefits with finerenone. Based on an absolute between-group difference of 12.2% after 30 months, the number of patients who needed to be treated with finerenone to prevent one primary outcome event was eight (95% CI: 4–84). For the key secondary composite outcome, the finerenone group showed a RRR of 25% (HR = 0.75, 95% CI, 0.38–1.48; p = 0.408). Adverse events were similar between the two groups. The effects of finerenone on blood pressure were modest. No gynecomastia events were reported in the study. Hyperkalemia leading to discontinuation occurred in eight (4.3%) and two (1.1%) participants in the finerenone and control groups, respectively. The incidence of acute kidney injury was comparable between the two groups (1.6% vs. 1.6%). Conclusions: Finerenone resulted in lower risks of CKD progression than placebo and a balanced safety profile in Chinese patients with CKD and T2DM.

Diabetic foot ulcers are a serious complication of diabetes, with high mortality and a lack of effective clinical treatment, which leads to a considerable financial burden. Pien-Tze-Huang (PZH) is a Chinese traditional medicine with a long history that has been found to be an effective and convenient treatment for inflammatory diseases such as skin abscesses and ulcers. In this study, we assessed the effects of PZH on diabetic wounds and the underlying mechanisms. The wounds were established on the backs of streptozotocin-induced type 1 diabetic rats and type 2 diabetic mouse models. We found that PZH treatment used locally or by gavage significantly promoted wound healing, accelerated re-epithelialization and vasculature in the wound tissue, upregulated the expression of the growth factors VEGF-A, PDGF, and EGF, and activated the Nrf2/ARE pathway in the wound tissue. In vitro assays showed that PZH improved the proliferation, migration and angiogenic function of human umbilical vein endothelial cells (HUVECs) cultured in palmitic acid, reduced the expression of the apoptotic proteins p53, Bax, and cleaved-caspase3, and activated Nrf2/ARE signaling; however, these protective effects were abrogated after Nrf2 was knocked down by specific siRNA. In addition, the levels of the serum inflammatory cytokines IL-1β, TNF-α, and IL-6 were reduced after PZH gavage treatment. In conclusion, the positive role of PZH in diabetic wound healing might be related to the activation of the Nrf2/ARE pathway to regulate the level of oxidative stress in vivo and increase the expression of growth factors to improve angiogenesis.

Background: Oxidative stress is recognized as a key factor in the induction of endothelial dysfunction in diabetes. However, the specific mechanisms have not been fully elucidated. We herein hypothesized that ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) might have a role in oxidative stress-induced endothelial cell (EC) apoptosis in diabetes. Methods: Western blot, qPCR, wound healing assay, apoptosis assay, reactive oxygen species (ROS) detection, dual-luciferase reporter assay, methylation-specific PCR, bisulfite sequencing PCR and chromatin immunoprecipitation assay were performed. Results: UHRF1 expression levels were significantly decreased in endothelial colony-forming cells derived from peripheral blood of participants with type 2 diabetes compared with individuals without diabetes. ECs treated with high glucose, palmitate or hydrogen peroxide in vitro also exhibited decreased UHRF1 protein levels. Silencing of UHRF1 led to decreased migration ability and increased apoptosis and ROS production in ECs, which might be related to impaired Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2)/haeme oxygenase-1 pathway. Mechanistically, UHRF1 is closely implicated in epigenetic regulation of chromatin modification status at KEAP1 genomic locus via histone acetylation. NRF2 down-regulation in turn inhibits UHRF1 protein level, which might be due to increased ROS generation. Conclusion: Diabetes-induced oxidative stress can mediate down-regulation of UHRF1, which enhances ROS production by regulating KEAP1/p-NRF2 pathway through histone acetylation and might also form a self-perpetuating feedback loop with KEAP1/p-NRF2 to further promote oxidative stress-induced apoptosis of ECs in diabetes.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which tumor-induced osteochondrosis is a metabolic bone disease caused by increased renal excretion of phosphorus due to excessive secretion of fibroblast growth factor 23 (FGF23) by tumor tissue. We report here a rare case of TIO in which the tumor was found in the hyoid body and the patient had tertiary hyperparathyroidism. The patient's symptoms did not improve after removal of the tumor from the hyoid body, and the patient's hypophosphatemia was gradually improved after subsequent removal of the left parathyroid gland. TIO derived from the tongue tumor is very rare, and also subsequent tertiary hyperparathyroidism is even rarer. This report helps to improve the understanding of TIO and provides reference in the diagnosis and treatment of TIO.

The properties and functions of BMSCs were altered by the diabetic microenvironment, and its mechanism was not very clear. In recent years, the regulation of the function of BMSCs by microRNA has become a research hotspot, meanwhile, HOX genes also have been focused on and involved in multiple functions of stem cells. In this study, we investigated the role of miR-139-5p in diabetes-induced BMSC impairment. Since HOXA9 may be a target gene of miR-139-5p, we speculated that miR-139-5p/HOXA9 might be involved in regulating the biological characteristics and the function of BMSCs in diabetes. We demonstrated that the miR-139-5p expression was increased in BMSCs derived from STZ-induced diabetic rats. MiR-139-5p mimics were able to inhibit cell proliferation, and migration and promoted senescence and apoptosis in vitro. MiR-139-5p induced the down-regulated expression of HOXA9 and c-Fos in BMSCs derived from normal rats. Moreover, miR-139-5p inhibitors reversed the tendency in diabetic-derived BMSCs. Further, gain-and-loss function experiments indicated that miR-139-5p regulated the functions of BMSCs by targeting HOXA9 and c-Fos. In vivo wound model experiments showed that the downregulation of miR-139-5p further promoted the epithelialization and angiogenesis of diabetic BMSC-mediated skin. In conclusion, induction of miR-139-5p upregulation mediated the impairment of BMSCs through the HOXA9/c-Fos pathway in diabetic rats. Therefore, miR-139-5p/HOXA9 might be an important therapeutic target in treating diabetic BMSCs and diabetic complications in the future.

Werner syndrome（WS）is an autosomal recessive disease. It is an adult onset early aging syndrome with a total incidence rate of 1:1 million to 1:10 million. In this report,we described the clinical features,laboratory and imaging examinations of 3 cases of WS complicated with diabetes mellitus,foot ulcer and hypogonadism,and also the relevant gene testing.

OBJECTIVE:This phase 3 confirmatory diabetes mellitus treatment study compared the safety and efficacy of Rapilin and NovoRapid insulin asparts in combination with metformin. METHODS:This 24-week, open-label, randomized, active-controlled, noninferiority phase 3 confirmatory study conducted across centers in China aimed to enroll patients with type 2 diabetes mellitus and blood sugar glucose inadequately controlled by oral antidiabetic drugs. Randomized patients received subcutaneous mealtime Rapilin or NovoRapid (3:1) injections, with metformin. The primary objectives were to demonstrate noninferiority (margin of 0.4%) in HbA1c change from baseline and compare safety profiles of Rapilin versus NovoRapid after 24 weeks. Secondary outcomes included 2-h postprandial plasma glucose (PPG), fasting plasma glucose (FPG), and patients achieving HbA1c <7.0% and ≤6.5%. RESULTS:590 patients with type 2 diabetes mellitus were randomized to Rapilin (n = 441) and NovoRapid (n = 149) groups. After 24 weeks, the mean HbA1c change from baseline was -2.20% (Rapilin) and -2.32% (NovoRapid); the estimated treatment difference based on least-square means was 0.04% (95% CI: -0.17, 0.26), meeting the noninferiority criteria for Rapilin versus NovoRapid. Comparable improvements were reported for mean 2-hour PPG (6.14 and 6.29 mmol/L), FPG (2.02 and 1.70 mmol/L), and patients with HbA1c <7.0% (52.6% and 51.0%) and ≤6.5% (34.2% and 30.9%), in the Rapilin and NovoRapid groups, respectively, with no significant safety or immunogenicity outcome differences. CONCLUSIONS:Rapilin demonstrated non-inferior glycemic control, and matching safety and immunogenicity to NovoRapid in patients with type 2 diabetes mellitus also receiving metformin over 24 weeks. TRIAL REGISTRATION:ChiCTR20003129041.

Stem cells and progenitor cells have been identified as potential new therapeutic options for severe limb ischemia to induce angiogenesis, and hyaluronic acid (HA) is commonly applied as a biomaterial in tissue engineering. However, the efficiency of HA combined with human umbilical cord blood-derived endothelial colony forming cells (ECFCs) and human umbilical-derived mesenchymal stem cells (MSCs) on angiogenesis is unclear. In the present study, we showed that HA promoted angiogenesis induced by MSCs-ECFCs in Matrigel plugs and promoted blood perfusion of murine ischemic muscles. Laser confocal microscopy revealed that human-derived cells grew into the host vasculature and formed connections, as shown by mouse-specific CD31+/human-specific CD31+ double staining. In vitro assays revealed that HA supported cell proliferation and migration, enhanced CD44 expression and reduced microRNA (miR)-139-5p expression. Further analysis revealed that miR-139-5p expression was negatively regulated by CD44 in ECFCs. Flow cytometry assays showed that HA increased CD31 positive cells proportion in MSC-ECFC and could be reversed by miR-139-5p mimics transfection. Moreover, the improvement of MSC-ECFC proliferation and migration induced by HA could be blocked by upregulation of miR-139-5p expression. In conclusion, HA facilitates angiogenesis of MSCs-ECFCs, and this positive effect be associated with activation of the CD44/miR-139-5p pathway, providing a promising strategy for improving severe limb ischemia.