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Diabetes mellitus (DM) and obesity have become two of the most prevalent and challenging diseases worldwide, with increasing incidence and serious complications. Recent studies have shown that noncoding RNA (ncRNA) and epigenetic regulation play crucial roles in the pathogenesis of DM complicated by obesity. Identification of the involvement of ncRNA and epigenetic regulation in the pathogenesis of diabetes with obesity has opened new avenues of investigation. Targeting these mechanisms with small molecules or RNA-based therapies may provide a more precise and effective approach to diabetes treatment than traditional therapies. In this review, we discuss the molecular mechanisms of ncRNA and epigenetic regulation and their potential therapeutic targets, and the research prospects for DM complicated with obesity.
RESUMEN
BACKGROUND: Progressive pancreatic ß cell dysfunction is a fundamental aspect of the pathology underlying type 2 diabetes mellitus (T2DM). Recently, mesenchymal stem cell (MSC) transplantation has emerged as a new therapeutic method due to its ability to promote the regeneration of pancreatic ß cells. However, current studies have focused on its efficacy, and there are few clinical studies on its safety. AIM: To evaluate the safety of human umbilical cord (hUC)-MSC infusion in T2DM treatment. METHODS: An open-label and randomized phase 2 clinical trial was designed to evaluate the safety of hUC-MSC transplantation in T2DM in a Class A hospital. Ten patients in the placebo group received acellular saline intravenously once per week for 3 wk. Twenty-four patients in the hUC-MSC group received hUC-MSCs (1 × 106 cells/kg) intravenously once per week for 3 wk. Diabetic clinical symptoms and signs, laboratory findings, and imaging findings were evaluated weekly for the 1st mo and then at weeks 12 and 24 post-treatment. RESULTS: No serious adverse events were observed during the 24-wk follow-up. Four patients (16.7%) in the hUC-MSC group experienced transient fever, which occurred within 24 h after the second or third infusion; this did not occur in any patients in the placebo group. One patient from the hUC-MSC group experienced hypoglycemic attacks within 1 mo after transplantation. Significantly lower lymphocyte levels (weeks 2 and 3) and thrombin coagulation time (week 2) were observed in the hUC-MSC group compared to those in the placebo group (all P < 0.05). Significantly higher platelet levels (week 3), immunoglobulin levels (weeks 1, 2, 3, and 4), fibrinogen levels (weeks 2 and 3), D-dimer levels (weeks 1, 2, 3, 4, 12, and 24), and neutrophil-to-lymphocyte ratios (weeks 2 and 3) were observed in the hUC-MSC group compared to those in the placebo group (all P < 0.05). There were no significant differences between the two groups for tumor markers (alpha-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen 199) or blood fat. No liver damage or other side effects were observed on chest X-ray. CONCLUSION: Our study suggested that hUC-MSC transplantation has good tolerance and high safety in the treatment of T2DM. It can improve human immunity and inhibit lymphocytes. Coagulation function should be monitored vigilantly for abnormalities.
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BACKGROUND: Progressive pancreatic ß-cell dysfunction is a fundamental part of the pathology of type 2 diabetes mellitus (T2DM). Cellular therapies offer novel opportunities for the treatment of T2DM to improve the function of islet ß-cells. AIM: To evaluate the effectiveness and safety of human umbilical cord-mesenchymal stem cell (hUC-MSC) infusion in T2DM treatment. METHODS: Sixteen patients were enrolled and received 1 × 106 cells/kg per week for 3 wk as intravenous hUC-MSC infusion. The effectiveness was evaluated by assessing fasting blood glucose, C-peptide, normal glycosylated hemoglobin A1c (HbA1c), insulin resistance index (homeostatic model assessment for insulin resistance), and islet ß-cell function (homeostasis model assessment of ß-cell function). The dosage of hypoglycemic agents and safety were evaluated by monitoring the occurrence of any adverse events (AEs). RESULTS: During the entire intervention period, the fasting plasma glucose level was significantly reduced [baseline: 9.3400 (8.3575, 11.7725), day 14 ± 3: 6.5200 (5.2200, 8.6900); P < 0.01]. The HbA1c level was significantly reduced on day 84 ± 3 [baseline: 7.8000 (7.5250, 8.6750), day 84 ± 3: 7.150 (6.600, 7.925); P < 0.01]. The patients' islet ß-cell function was significantly improved on day 28 ± 3 of intervention [baseline: 29.90 (16.43, 37.40), day 28 ± 3: 40.97 (19.27, 56.36); P < 0.01]. The dosage of hypoglycemic agents was reduced in all patients, of whom 6 (50%) had a decrement of more than 50% and 1 (6.25%) discontinued the hypoglycemic agents. Four patients had transient fever, which occurred within 24 h after the second or third infusion. One patient (2.08%) had asymptomatic nocturnal hypoglycemia after infusion on day 28 ± 3. No liver damage or other side effects were reported. CONCLUSION: The results of this study suggest that hUC-MSC infusion can improve glycemia, restore islet ß-cell function, and reduce the dosage of hypoglycemic agents without serious AEs. Thus, hUC-MSC infusion may be a novel option for the treatment of T2DM.
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The aim of this study is to investigate the effect of mesenchymal stem cell (MSC)-derived exosomes on diabetes mellitus-induced myocardial injury, and the underlying mechanism. Thirty adult male Sprague Dawley rats were randomly assigned to three groups of ten rats each: normal control group, diabetic control group and MSC exosomes group. Exosomes were isolated from MSCs through gradient ultracentrifugation. With the exception of normal control, diabetes mellitus (DM) was induced in the rats with a single intraperitoneal injection of 30 mg/kg body weight streptozotocin (STZ) in 0.1 mol/L sodium citrate buffer. Rats in MSC exosomes group were intravenously injected with MSC-derived exosomes once a week for 12 weeks. Left ventricular collagen (LVC) level was measured using acid hydrolysis method. Fatty acid transporters (FATPs) and fatty acid beta oxidase (FA-ß-oxidase) were determined using enzyme-linked immunosorbent assay (ELISA). Gene and protein expressions of TGF-ß and Smad2 were determined using real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting. Flow cytometric analysis and Western blotting revealed positive expression of exosomal specific marker, CD63. The level of LVC was significantly higher in diabetic control group than in normal control group, but was significantly reduced after treatment with MSC-derived exosomes (p < 0.05). The levels of FATPs and FA-ß-oxidase were significantly lower in diabetic control group than in normal control group (p < 0.05). However, treatment with MSC-derived exosomes significantly increased the levels of these proteins (p < 0.05). The levels of expression of TGF-ß1 and Smad2 mRNAs were significantly higher in the diabetic control group than in normal control group, but were significantly reduced after treatment with MSC-derived exosomes (p < 0.05). The expressions of TGF-ß1 and Smad2 proteins were also significantly upregulated in diabetic control group, when compared with normal control group (p < 0.05). However, treatment with MSC-derived exosomes significantly down-regulated the expression of these proteins (p < 0.05). The results obtained in this study indicate that MSC-derived exosomes improve DM-induced myocardial injury and fibrosis via inhibition of TGF-ß1/Smad2 signaling pathway.
