Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes (original) (raw)
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Molecular and Cellular Endocrinology, 2019
The delayed diagnosis and the inadequate treatment of diabetes increase the risk of chronic complications. The study of regulatory molecules such as miRNAs can provide expression profiles of diabetes and diabetes complications. We evaluated the lymphomononuclear cell miRNA profiles of 63 Type 1 and Type 2 diabetes patients presenting or not microvascular complications, and 40 healthy controls, using massive parallel sequencing. Gene targets, enriched pathways, dendograms and miRNA-mRNA networks were performed for the differentially expressed miRNAs. Six more relevant miRNAs were validated by RT-qPCR and data mining analysis. MiRNAs associated with specific complications included: i) neuropathy (miR-873-5p, miR-125a-5p, miR-145-3p and miR-99b-5p); ii) nephropathy (miR-1249-3p, miR-193a-5p, miR-409-5p, miR-1271-5p, miR-501-3p, miR-148b-3p and miR-9-5p); and iii) retinopathy (miR-143-3p, miR-1271-5p, miR-409-5p and miR-199a-5p). These miRNAs mainly targeted gene families and specific genes associated with advanced glycation end products and
The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes
Nature medicine, 2015
Pancreatic beta cell death is a hallmark of type 1 (T1D) and type 2 (T2D) diabetes, but the molecular mechanisms underlying this aspect of diabetic pathology are poorly understood. Here we report that expression of the microRNA (miR)-200 family is strongly induced in islets of diabetic mice and that beta cell-specific overexpression of miR-200 in mice is sufficient to induce beta cell apoptosis and lethal T2D. Conversely, mir-200 ablation in mice reduces beta cell apoptosis and ameliorates T2D. We show that miR-200 negatively regulates a conserved anti-apoptotic and stress-resistance network that includes the essential beta cell chaperone Dnajc3 (also known as p58IPK) and the caspase inhibitor Xiap. We also observed that mir-200 dosage positively controls activation of the tumor suppressor Trp53 and thereby creates a pro-apoptotic gene-expression signature found in islets of diabetic mice. Consequently, miR-200-induced T2D is suppressed by interfering with the signaling of Trp53 and...
Mutat Res, 2015
The development of type 2 diabetes mellitus (T2D) is associated with a number of genetic and environmental factors. Hyperglycemia, a T2D hallmark, is related to several metabolic complications, comorbidities and increased DNA damage. However, the molecular alterations of a proper glucose control are still unclarified. In this study, we aimed to evaluate DNA damage (comet assay), as well as to compare the transcriptional expression (mRNA and miRNA analyzed by the microarray technique) displayed by peripheral blood mononuclear cells (PBMCs) from three distinct groups: hyperglycemic T2D patients (T2D-H, n = 14), non-hyperglycemic T2D patients (T2D-N, n = 15), and healthy non-diabetic individuals (n = 16). The comet assay revealed significantly (p < 0.05) higher levels of DNA damage in T2D-H group compared to both T2D-N and control groups, while a significant difference was not observed between the control and T2D-N groups. After bioinformatics analysis, the differentially expressed mRNAs were subjected to functional enrichment analysis (DAVID) and inflammatory response was among the enriched terms found when comparing T2D-N with controls and T2D-H with T2D-N. Concerning the gene set enrichment and gene set analyses, among the differentially expressed gene sets, three were of interest: regulation of DNA repair (T2D-H versus T2D-N), superoxide response (T2D-H versus control group), and response to endoplasmic reticulum stress (T2D-H versus control group). We also identified miRNAs related with T2D and hyperglycemia not yet associated with these conditions in the literature. Some of the differentially expressed mRNAs were among the predicted targets of the differentially expressed miRNAs. Our results showed the association of hyperglycemia with increased DNA damage and aberrant expression of miRNAs and genes related to several biological processes, such as inflammation, DNA repair, ROS production and antioxidant defense, highlighting the importance of proper glycemic control. Moreover, the transcriptional expression of miRNAs provided novel information for understanding the regulatory mechanisms involved in the T2D progression.
Non-Coding RNA
The partial remission (PR) phase of type 1 diabetes (T1D) is an underexplored period characterized by endogenous insulin production and downmodulated autoimmunity. To comprehend the mechanisms behind this transitory phase and develop precision medicine strategies, biomarker discovery and patient stratification are unmet needs. MicroRNAs (miRNAs) are small RNA molecules that negatively regulate gene expression and modulate several biological processes, functioning as biomarkers for many diseases. Here, we identify and validate a unique miRNA signature during PR in pediatric patients with T1D by employing small RNA sequencing and RT-qPCR. These miRNAs were mainly related to the immune system, metabolism, stress, and apoptosis pathways. The implication in autoimmunity of the most dysregulated miRNA, miR-30d-5p, was evaluated in vivo in the non-obese diabetic mouse. MiR-30d-5p inhibition resulted in increased regulatory T cell percentages in the pancreatic lymph nodes together with a hi...
miR-25 and miR-92b Regulate Insulin Biosynthesis and Pancreatic β-Cell Apoptosis
2021
Purpose. - Pancreatic β-cell failure is a central hallmark of the pathogenesis of diabetes mellitus; however, the molecular basis underlying chronic inflammation-caused β-cell failure remains unclear. This study reported here specifically assessed the association between miR-25/miR-92b family and β-cell failure in diabetes.Methods. - IL-1β and two additional ER stress activators, palmitate and tunicamycin were applied to evaluate the expression level miR-25 by Taqman® RT-PCR. Glucose- and potassium-stimulated insulin secretion assays were performed to assess β-cell function. Dual luciferase activity, and western blotting assays were utilized for miR-25 target gene verification. CCK-8 and TUNEL staining were used to evaluate β-cell viability and apoptosis.Results. – miRNA ChIP identified the increased level of miR-25 in INS-1 cells by IL-1β treatment. Expression levels of miR-25 were significantly upregulated with the treatment of IL-1β, palmitate or tunicamycin in both INS-1 cells a...
Science translational medicine, 2017
Immunologically based clinical trials performed thus far have failed to cure type 1 diabetes (T1D), in part because these approaches were nonspecific. Because the disease is driven by autoreactive CD4 T cells, which destroy β cells, transplantation of hematopoietic stem and progenitor cells (HSPCs) has been recently offered as a therapy for T1D. Our transcriptomic profiling of HSPCs revealed that these cells are deficient in programmed death ligand 1 (PD-L1), an important immune checkpoint, in the T1D nonobese diabetic (NOD) mouse model. Notably, the immunoregulatory molecule PD-L1 plays a determinant role in controlling/inhibiting activated T cells and thus maintains immune tolerance. Furthermore, our genome-wide and bioinformatic analysis revealed the existence of a network of microRNAs (miRNAs) controlling PD-L1 expression, and silencing one of key altered miRNAs restored PD-L1 expression in HSPCs. We therefore sought to determine whether restoration of this defect would cure T1D...
Frontiers in Endocrinology, 2022
Background: Considering the potential role of miRNAs as biomarkers and their interaction with both nuclear and mitochondrial genes, we investigated the miRNA expression profile in type 1 diabetes (T1DM) patients, including the pathways in which they are involved considering both nuclear and mitochondrial functions. Methods: We analyzed samples of T1DM patients and control individuals (normal glucose tolerance) by high throughput miRNA sequencing (miRNome). Next, five miRNAshsa-miR-26b-5p, hsa-let-7i-5p, hsa-miR-143-3p, hsa-miR-501-3p and hsa-miR-100-5pwere validated by RT-qPCR. The identification of target genes was extracted from miRTarBase and mitoXplorer database. We also performed receiver operating characteristic (ROC) curves and miRNAs that had an AUC > 0.85 were considered potential biomarkers. Results: Overall, 41 miRNAs were differentially expressed in T1DM patients compared to control. Hsa-miR-21-5p had the highest number of predicted target genes and was Frontiers in Endocrinology frontiersin.org 01
Immunobiology, 2013
Introduction: It is well established that type 1 diabetes (T1D) is an autoimmune disease. Controversial data exists regarding the differential control of the immune system in T1D patients compared to unaffected individuals. MicroRNAs (miRNAs) are involved in the control of gene expression (by negative regulation of gene expression at post-transcriptional level, by mediating translational repression or degradation of the mRNA targets). Their potential role in T cell activation and autoimmunity is controversial. Aim: We investigated the expression profile of miR-21a and miR-93 in PMC samples of 20 T1D patients and 20 healthy controls by means of qPCR in different glucose concentrations (basal, 11 nM and 25 mM), and we analyzed the possible relationship of this expression pattern with autoimmunity. Results: MiR-21a was significantly underexpressed in T1D samples (media values expression 0.23 ± 0.05, p < 0.01) compared to controls (values less than 1 indicate a decrease in gene expression). When the PMCs were incubated with glucose 11 mM and 25 mM, miR-21a expression decreased in controls and increased in T1D samples (0.506 ± 0.05, p < 0.04). MiR-93 was underexpressed in T1D patients (0.331 ± 0.05, p < 0.02) compared to control samples. However, when the PBMCs were incubated with glucose, no changes were observed. No association with autoimmunity was observed. Conclusion: We demonstrated that miRNAs have a differential expression in PBMCs from T1D patients compared to controls, suggesting that these miRNAs or others could be involved in T cell regulation.
International Journal of Molecular Sciences, 2020
Diabetes mellitus (DM) is one of the main causes of morbidity and mortality, with an increasing incidence worldwide. The impact of DM on public health in developing countries has triggered alarm due to the exaggerated costs of the treatment and monitoring of patients with this disease. Considerable efforts have been made to try to prevent the onset and reduce the complications of DM. However, because insulin-producing pancreatic β-cells progressively deteriorate, many people must receive insulin through subcutaneous injection. Additionally, current therapies do not have consistent results regarding the prevention of chronic complications. Leveraging the approval of real-time continuous glucose monitors and sophisticated algorithms that partially automate insulin infusion pumps has improved glycemic control, decreasing the burden of diabetes management. However, these advances are facing physiologic barriers. New findings in molecular and cellular biology have produced an extraordina...