Статті в журналах: "MicroRNAs - biomarkers - type 1 diabetes"

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Martens, Geert A., Geert Stangé, Lorenzo Piemonti, Jasper Anckaert, Zhidong Ling, Daniel G. Pipeleers, Frans K. Gorus, et al. "The MicroRNA Landscape of Acute Beta Cell Destruction in Type 1 Diabetic Recipients of Intraportal Islet Grafts." Cells 10, no. 7 (July 4, 2021): 1693. http://dx.doi.org/10.3390/cells10071693.

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Ongoing beta cell death in type 1 diabetes (T1D) can be detected using biomarkers selectively discharged by dying beta cells into plasma. microRNA-375 (miR-375) ranks among the top biomarkers based on studies in animal models and human islet transplantation. Our objective was to identify additional microRNAs that are co-released with miR-375 proportionate to the amount of beta cell destruction. RT-PCR profiling of 733 microRNAs in a discovery cohort of T1D patients 1 h before/after islet transplantation indicated increased plasma levels of 22 microRNAs. Sub-selection for beta cell selectivity resulted in 15 microRNAs that were subjected to double-blinded multicenter analysis. This led to the identification of eight microRNAs that were consistently increased during early graft destruction: besides miR-375, these included miR-132/204/410/200a/429/125b, microRNAs with known function and enrichment in beta cells. Their potential clinical translation was investigated in a third independent cohort of 46 transplant patients by correlating post-transplant microRNA levels to C-peptide levels 2 months later. Only miR-375 and miR-132 had prognostic potential for graft outcome, and none of the newly identified microRNAs outperformed miR-375 in multiple regression. In conclusion, this study reveals multiple beta cell-enriched microRNAs that are co-released with miR-375 and can be used as complementary biomarkers of beta cell death.

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Garavelli, Silvia, Sara Bruzzaniti, Elena Tagliabue, Francesco Prattichizzo, Dario Di Silvestre, Francesco Perna, Lucia La Sala, et al. "Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity." International Journal of Molecular Sciences 21, no. 2 (January 11, 2020): 477. http://dx.doi.org/10.3390/ijms21020477.

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Immune cell subsets and microRNAs have been independently proposed as type 1 diabetes (T1D) diagnostic and/or prognostic biomarkers. Here, we aimed to analyze the relationships between peripheral blood circulating immune cell subsets, plasmatic microRNAs, and T1D. Blood samples were obtained from both children with T1D at diagnosis and age-sex matched healthy controls. Then, immunophenotype assessed by flow cytometry was coupled with the quantification of 60 plasmatic microRNAs by quantitative RT-PCR. The associations between immune cell frequency, plasmatic microRNAs, and the parameters of pancreatic loss, glycemic control, and diabetic ketoacidosis were assessed by logistic regression models and correlation analyses. We found that the increase in specific plasmatic microRNAs was associated with T1D disease onset (let-7c-5p, let-7d-5p, let-7f-5p, let-7i-5p, miR-146a-5p, miR-423-3p, and miR-423-5p), serum C-peptide concentration (miR-142-5p and miR-29c-3p), glycated hemoglobin (miR-26a-5p and miR-223-3p) and the presence of ketoacidosis (miR-29c-3p) more strongly than the evaluated immune cell subset frequency. Some of these plasmatic microRNAs were shown to positively correlate with numbers of blood circulating B lymphocytes (miR-142-5p) and CD4+CD45RO+ (miR-146a-5p and miR-223-3p) and CD4+CD25+ cells (miR-423-3p and miR-223-3p) in children with T1D but not in healthy controls, suggesting a disease-specific microRNA association with immune dysregulation in T1D. In conclusion, our results suggest that, while blood co-circulating extracellular microRNAs and immune cell subsets may be biologically linked, microRNAs may better provide powerful information about T1D onset and severity.

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Trukhina, Diana, Elizaveta Mamedova, Alexey Nikitin, Philipp Koshkin, Zhanna Belaya, and Galina Melnichenko. "RF25 | PMON147 Plasma MicroRNA Expression in Phenocopy of Multiple Endocrine Neoplasia Type 1 Compared to Patients with Acromegaly and Primary Hyperparathyroidism: Potential Biomarkers of Multiple Endocrine Tumor Growth." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A584—A585. http://dx.doi.org/10.1210/jendso/bvac150.1211.

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Abstract Introduction Changes in the expression of microRNA facilitate in the formation of various tumors. MEN1 is a rare disease caused by mutations in MEN1 gene encoding the menin protein and characterize by the occurrence of parathyroid, pituitary, gastroenteropancreatic and other tumors. If a patient with the MEN1 phenotype carry no mutations in the MEN1 gene, the condition considers a phenocopy of syndrome (phMEN1). We hypothesize that the pathogenic link among the above sporadic tumors might be represented by molecular pathways involving the MEN1 gene and epigenetic regulations — particularly microRNAs. Materials & methods Single-center, case-control study: assessment of plasma microRNA expression in patients with phMEN1, acromegaly (AM), primary hyperparathyroidism (PHPT) and healthy controls. Morning plasma samples were collected from fasting patients and age- and sex-matched controls and stored at –80°C. Total RNA isolation: miRNeasy Mini Kit with QIAcube. The libraries were prepared by the QIAseq miRNA Library Kit following the manufacturer. Circulating miRNA sequencing was done on Illumina NextSeq 500 (Illumina). Subsequent data processing was performed using the DESeq2 bioinformatics algorithm. Results We enrolled 36 consecutive patients (12 patients in each group) with phMEN1, AM, PHPT, along with 12 age and gender matched controls. Median age of phMEN1 group — 59 [52; 60.5]; AM — 59 [52; 63]; PHPT — 60.5 [54; 62.5]; control — 59 [51.5; 62.5]. The groups did not differ in age (p=0.88) and gender – in all groups were 11 women and 1 man (p=1.00). We divided all assessed microRNAs into 3 groups based on the significance of the results; the first group consisted of samples with the highest levels of detected microRNAs (>50), the second group — moderate (10–50), the third group — the lowest (<10). The microRNA expression pattern was almost the same between AM and phMEN1 groups (15 microRNAs upregulated, 10 — downregulated), we found slightly decreased hsa-miR-4301 (padj=0.038); it is interesting that phMEN group when compared to PHPT and control groups showed decline in hsa-miR-4301 too. PHPT and control groups had also quite similar expression profile (4 microRNAs upregulated, 19 — downregulated). 607 microRNA were differently expressed in groups phMEN1 and PHPT (473 upregulated microRNAs, 134 — downregulated). We found increased expression of some microRNAs that interferes with menin: hsa-miR-24-1-5p (padj=0.0008), hsa-miR-24-3p (padj=0.034), hsa-miR-26a-5p (padj=0.0005), hsa-miR-421 (padj=0.018), hsa-miR-762 (padj=0.027). In addition, we found decreased microRNAs with oncogene potential: miR-3182 (padj=0.007), hsa-miR-875-5p (padj<0.001), hsa-miR-6749-5p (padj<0.001). 173 microRNA differed in phMEN1 and control groups (11 microRNAs upregulated, 162 — downregulated). We detected several decreased microRNAs in phMEN1 that participate in tumor genesis: hsa-miR-625-3p (padj<0.005), hsa-miR-3168 (padj=0,028), hsa-miR-302b-3p (padj<0.001). Conclusion We found microRNAs, which could potentially become biomarkers in phMEN1 diagnosis. The results need to be validated using different measurement method with larger sample size. Likewise further assessment of plasma microRNA expression in genetically confirmed MEN1 patients is needed. Presentation: Monday, June 13, 2022 12:30 p.m. - 12:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

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Mi, Qing-Sheng, Metthew Weiland, Ruiqun Qi, and Li Zhou. "Global miRNA expression profiles uncover serum miRNAs as novel biomarkers for diabetes staging in NOD mice (P3267)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 192.19. http://dx.doi.org/10.4049/jimmunol.190.supp.192.19.

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Abstract Type 1 diabetes (T1D) is an autoimmune diseases resulting from T cell-mediated pancreatic beta cell destruction. New biomarkers are urgently needed for earlier T1D risk prediction and progression. MicroRNAs (miRNAs) regulate beta cell and immune cell development and function, and are involved in T1D development. Recently, it has been discovered that serum contains large amounts of stable miRNAs derived from immune cells and other tissues/cells, and that serum miRNAs might serve as biomarkers for disease prediction and progression. Yet little is known about serum miRNAs in T1D. We hypothesize that serum miRNAs could be a novel class of blood-based biomarker for diabetes staging. Serum RNAs were isolated from nonobese diabetic (NOD) mice at different stages (3-4, 7-8, 16-19 weeks, and newly diagnosed diabetes) during diabetes development. Serum miRNA expression profiles were performed by real-time RT-PCR MicroRNA Arrays. Twenty-three miRNAs appeared to have specific expression patterns during diabetes development. Single qRT-PCR further confirmed that serum miR-150, miR-146b, and miR-215 are significantly upregulated starting at the stage of insulitis, destructive insulitis and diabetes, respectively. Our data highly suggest that serum miRNAs are potential novel biomarkers for diabetes prediction and staging, and that miR-150, miR-146b and miR-215 could be used as serum biomarkers for diabetes staging or therapy response in the NOD mouse.

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Chen, Haiyong, Hui-Yao Lan, Dimitrios H. Roukos, and William C. Cho. "Application of microRNAs in diabetes mellitus." Journal of Endocrinology 222, no. 1 (April 29, 2014): R1—R10. http://dx.doi.org/10.1530/joe-13-0544.

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MicroRNAs (miRNAs) are small molecules negatively regulating gene expression by diminishing their target mRNAs. Emerging studies have shown that miRNAs play diverse roles in diabetes mellitus. Type 1 diabetes (T1D) and T2D are two major types of diabetes. T1D is characterized by a reduction in insulin release from the pancreatic β-cells, while T2D is caused by islet β-cell dysfunction in response to insulin resistance. This review describes the miRNAs that control insulin release and production by regulating cellular membrane electrical excitability (ATP:ADP ratio), insulin granule exocytosis, insulin synthesis in β-cells, and β-cell fate and islet mass formation. This review also examines miRNAs involved the insulin resistance of liver, fat, and skeletal muscle, which change insulin sensitivity pathways (insulin receptors, glucose transporter type 4, and protein kinase B pathways). This review discusses the potential application of miRNAs in diabetes, including the use of gene therapy and therapeutic compounds to recover miRNA function in diabetes, as well as the role of miRNAs as potential biomarkers for T1D and T2D.

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Earle, Angel, Madison Bessonny, Josh Benito, Kun Huang, Hannah Parker, Emily Tyler, Brittany Crawford, et al. "Urinary Exosomal MicroRNAs as Biomarkers for Obesity-Associated Chronic Kidney Disease." Journal of Clinical Medicine 11, no. 18 (September 7, 2022): 5271. http://dx.doi.org/10.3390/jcm11185271.

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The early detection of chronic kidney disease (CKD) is key to reducing the burden of disease and rising costs of care. This need has spurred interest in finding new biomarkers for CKD. Ideal bi-omarkers for CKD should be: easy to measure; stable; reliably detected, even when interfering substances are present; site-specific based on the type of injury (tubules vs. glomeruli); and its changes in concentration should correlate with disease risk or outcome. Currently, no single can-didate biomarker fulfills these criteria effectively, and the mechanisms underlying kidney fibrosis are not fully understood; however, there is growing evidence in support of microRNA-mediated pro-cesses. Specifically, urinary exosomal microRNAs may serve as biomarkers for kidney fibrosis. In-creasing incidences of obesity and the recognition of obesity-associated CKD have increased interest in the interplay of obesity and CKD. In this review, we provide: (1) an overview of the current scope of CKD biomarkers within obese individuals to elucidate the genetic pathways unique to obesi-ty-related CKD; (2) a review of microRNA expression in obese individuals with kidney fibrosis in the presence of comorbidities, such as diabetes mellitus and hypertension; (3) a review of thera-peutic processes, such as diet and exercise, that may influence miR-expression in obesity-associated CKD; (4) a review of the technical aspects of urinary exosome isolation; and (5) future areas of research.

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Gomez-Muñoz, Laia, David Perna-Barrull, Marta Murillo, Maria Pilar Armengol, Marta Alcalde, Marti Catala, Silvia Rodriguez-Fernandez, et al. "Immunoregulatory Biomarkers of the Remission Phase in Type 1 Diabetes: miR-30d-5p Modulates PD-1 Expression and Regulatory T Cell Expansion." Non-Coding RNA 9, no. 2 (February 28, 2023): 17. http://dx.doi.org/10.3390/ncrna9020017.

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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 higher expression of CD200. In the spleen, a decrease in PD-1+ T lymphocytes and reduced PDCD1 expression were observed. Moreover, miR-30d-5p inhibition led to an increased islet leukocytic infiltrate and changes in both effector and memory T lymphocytes. In conclusion, the miRNA signature found during PR shows new putative biomarkers and highlights the immunomodulatory role of miR-30d-5p, elucidating the processes driving this phase.

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Vasu, Srividya, Kenjiro Kumano, Carly M. Darden, Irum Rahman, Michael C. Lawrence, and Bashoo Naziruddin. "MicroRNA Signatures as Future Biomarkers for Diagnosis of Diabetes States." Cells 8, no. 12 (November 28, 2019): 1533. http://dx.doi.org/10.3390/cells8121533.

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Diabetes results from the inability of pancreatic islets to maintain blood glucose concentrations within a normal physiological range. Clinical features are usually not observed until islets begin to fail and irreversible damage has occurred. Diabetes is generally diagnosed based on elevated glucose, which does not distinguish between type 1 and 2 diabetes. Thus, new diagnostic approaches are needed to detect different modes of diabetes before manifestation of disease. During prediabetes (pre-DM), islets undergo stress and release micro (mi) RNAs. Here, we review studies that have measured and tracked miRNAs in the blood for those with recent-onset or longstanding type 1 diabetes, obesity, pre-diabetes, type 2 diabetes, and gestational diabetes. We summarize the findings on miRNA signatures with the potential to stage progression of different modes of diabetes. Advances in identifying selective biomarker signatures may aid in early detection and classification of diabetic conditions and treatments to prevent and reverse diabetes.

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Liu, Yiwen, Minglei Ma, Jie Yu, Fan Ping, Huabing Zhang, Wei Li, Lingling Xu, and Yuxiu Li. "Decreased Serum microRNA-21, microRNA-25, microRNA-146a, and microRNA-181a in Autoimmune Diabetes: Potential Biomarkers for Diagnosis and Possible Involvement in Pathogenesis." International Journal of Endocrinology 2019 (September 9, 2019): 1–9. http://dx.doi.org/10.1155/2019/8406438.

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Objective. Previous studies have revealed dysregulated circulating microRNAs (miRNAs) in patients with type 1 diabetes (T1D). Here, we explored the serum levels of miR-21, miR-25, miR-146a, and miR-181a in patients with autoimmune diabetes (T1D and latent autoimmune diabetes of adults (LADA)) compared with type 2 diabetes (T2D) and nondiabetic individuals. Design, patients, and measurements. The serum levels of miR-21, miR-25, miR-146a, and miR-181a in patients with T1D (n = 29), LADA (n = 16), and T2D (n = 31) and in nondiabetic individuals (n = 19) were determined by quantitative real-time polymerase chain reaction, and receiver-operating characteristic (ROC) curves were evaluated to determine the discriminatory performances of these four miRNAs. Furthermore, target genes and pathways potentially modulated by these four miRNAs were predicted by bioinformatics analysis to investigate the possible functions of these miRNAs in autoimmune diabetes. Subsequently, multiple logistic regression analysis was performed to identify independent predictors for autoimmune diabetes, and a nomogram was established. Results. miR-21, miR-25, miR-146a, and miR-181a were significantly downregulated in the serum of patients with autoimmune diabetes compared with those in T2D patients and nondiabetic individuals (p<0.001). The areas under the ROC curves of these four miRNAs were greater than 0.80 (p<0.001). Bioinformatics analysis suggested that miR-21, miR-25, miR-146a, and miR-181a regulated multiple genes in pathways associated with immunity, inflammatory responses, hyperglycemia, and metabolism, which are involved in the pathogenesis of autoimmune diabetes. Multiple logistic regression analysis identified miR-25 (odds ratio (OR): 0.001, p<0.05), miR-146a (OR: 0.136, p<0.05), and fasting C-peptide levels (OR: 0.064, p<0.05) as independent predictors of autoimmune diabetes. Conclusions. miR-25 and miR-146a may serve as potential circulating biomarkers and provide insights into the pathogenesis of autoimmune diabetes.

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Liu, Li, Jinhua Yan, Haixia Xu, Yunxia Zhu, Hua Liang, Wen Pan, Bin Yao, Xiao Han, Jianping Ye та Jianping Weng. "Two Novel MicroRNA Biomarkers Related to β-Cell Damage and Their Potential Values for Early Diagnosis of Type 1 Diabetes". Journal of Clinical Endocrinology & Metabolism 103, № 4 (23 січня 2018): 1320–29. http://dx.doi.org/10.1210/jc.2017-01417.

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Abstract Context New strategies and biomarkers are needed in the early detection of β-cell damage in the progress of type 1 diabetes mellitus (T1DM). Objective To explore whether serum microRNAs (miRNA) should be served as biomarkers for T1DM. Design, Settings, and Patients The miRNA profile was established with miRNA microarray in discovery phase (six T1DM, six controls). A miRNA-based model for T1DM diagnosis was developed using logistic regression analysis in the training dataset (40 T1DM, 56 controls) and then validated with leave-one-out cross validation and another independent validation dataset (33 T1DM, 29 controls). Main Outcome Measures Quantitative reverse transcription polymerase chain reaction was applied to confirm the differences of candidate miRNAs between T1DM and controls. Area under the receiver-operating characteristic (ROC) curve (AUC) was used to evaluate diagnostic accuracy. INS-1 cells, streptozotocin-treated mice (n = 4), and nonobese diabetic (NOD) mice (n = 12) were used to evaluate the association of miRNAs with β-cell damage. Results A miRNA -based model was established in the training dataset with high diagnostic accuracy for T1DM (AUC = 0.817) based on six candidate differential expressed miRNAs identified in discovery phase. The validation dataset showed the model’s satisfactory diagnostic performance (AUC = 0.804). Secretions of miR-1225-5p and miR-320c were significantly increased in streptozotocin-treated mice and INS-1 cells. Noteworthy, the elevation of these two miRNAs was observed before glucose elevation in the progress of diabetes in NOD mice. Conclusions Two miRNA biomarkers (miR-1225-5p and miR-320c) related to β-cell damage were identified in patients with recent-onset T1DM. The miRNA-based model established in this study exhibited a good performance in diagnosis of T1DM.

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Assmann, Taís S., Mariana Recamonde-Mendoza, Bianca M. De Souza, and Daisy Crispim. "MicroRNA expression profiles and type 1 diabetes mellitus: systematic review and bioinformatic analysis." Endocrine Connections 6, no. 8 (November 2017): 773–90. http://dx.doi.org/10.1530/ec-17-0248.

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Growing evidence indicates that microRNAs (miRNAs) have a key role in processes involved in type 1 diabetes mellitus (T1DM) pathogenesis, including immune system functions and beta-cell metabolism and death. Although dysregulated miRNA profiles have been identified in T1DM patients, results are inconclusive; with only few miRNAs being consistently dysregulated among studies. Thus, we performed a systematic review of the literature on the subject, followed by bioinformatic analysis, to point out which miRNAs are dysregulated in T1DM-related tissues and in which pathways they act. PubMed and EMBASE were searched to identify all studies that compared miRNA expressions between T1DM patients and non-diabetic controls. Search was completed in August, 2017. Those miRNAs consistently dysregulated in T1DM-related tissues were submitted to bioinformatic analysis, using six databases of miRNA–target gene interactions to retrieve their putative targets and identify potentially affected pathways under their regulation. Thirty-three studies were included in the systematic review: 19 of them reported miRNA expressions in human samples, 13 in murine models and one in both human and murine samples. Among 278 dysregulated miRNAs reported in these studies, 25.9% were reported in at least 2 studies; however, only 48 of them were analyzed in tissues directly related to T1DM pathogenesis (serum/plasma, pancreas and peripheral blood mononuclear cells (PBMCs)). Regarding circulating miRNAs, 11 were consistently dysregulated in T1DM patients compared to controls: miR-21-5p, miR-24-3p, miR-100-5p, miR-146a-5p, miR-148a-3p, miR-150-5p, miR-181a-5p, miR-210-5p, miR-342-3p, miR-375 and miR-1275. The bioinformatic analysis retrieved a total of 5867 validated and 2979 predicted miRNA–target interactions for human miRNAs. In functional enrichment analysis of miRNA target genes, 77 KEGG terms were enriched for more than one miRNA. These miRNAs are involved in pathways related to immune system function, cell survival, cell proliferation and insulin biosynthesis and secretion. In conclusion, eleven circulating miRNAs seem to be dysregulated in T1DM patients in different studies, being potential circulating biomarkers of this disease.

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Xu, Guanlan, Lance A. Thielen, Junqin Chen, Truman B. Grayson, Tiffany Grimes, S. Louis Bridges, Hubert M. Tse, et al. "Serum miR-204 is an early biomarker of type 1 diabetes-associated pancreatic beta-cell loss." American Journal of Physiology-Endocrinology and Metabolism 317, no. 4 (October 1, 2019): E723—E730. http://dx.doi.org/10.1152/ajpendo.00122.2019.

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Pancreatic beta-cell death is a major factor in the pathogenesis of type 1 diabetes (T1D), but straightforward methods to measure beta-cell loss in humans are lacking, underlining the need for novel biomarkers. Using studies in INS-1 cells, human islets, diabetic mice, and serum samples of subjects with T1D at different stages, we have identified serum miR-204 as an early biomarker of T1D-associated beta-cell loss in humans. MiR-204 is a highly enriched microRNA in human beta-cells, and we found that it is released from dying beta-cells and detectable in human serum. We further discovered that serum miR-204 was elevated in children and adults with T1D and in autoantibody-positive at-risk subjects but not in type 2 diabetes or other autoimmune diseases and was inversely correlated with remaining beta-cell function in recent-onset T1D. Thus, serum miR-204 may provide a much needed novel approach to assess early T1D-associated human beta-cell loss even before onset of overt disease.

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Santos, Aritania Sousa, Ludmila Rodrigues Pinto Ferreira, Amanda Cabral da Silva, Laís Isidoro Alves, Jullian Gabriel Damasceno, Leslie Kulikowski, Edecio Cunha-Neto, and Maria Elizabeth Rossi da Silva. "Progression of Type 1 Diabetes: Circulating MicroRNA Expression Profiles Changes from Preclinical to Overt Disease." Journal of Immunology Research 2022 (July 19, 2022): 1–15. http://dx.doi.org/10.1155/2022/2734490.

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Aims/Hypothesis. The role of microRNAs (miRNAs) in type 1 diabetes (T1D) pathogenesis and progression has been described but remains elusive. Objectives. To evaluate the potential biological involvement of miRNA expression in the immune response and beta cell function in T1D. Methods.We screened 377 serum miRNAs of 110 subjects divided into four groups: healthy individuals (control group) and patients at different stages of T1D progression, from the initial immunological manifestation presenting islet autoantibodies (AbP group) until partial and strong beta cell damage in the recent (recent T1D group) and long-term T1D, with 2 to 5 years of disease (T1D 2-5y group).Results. The results revealed 69 differentially expressed miRNAs (DEMs) in relation to controls. Several miRNAs were correlated with islet autoantibodies (IA2A, GADA, and Znt8A), age, and C-peptide levels, mainly from AbP, and recent T1D groups pointing these miRNAs as relevant to T1D pathogenesis and progression. Several miRNAs were related to metabolic derangements, inflammatory pathways, and several other autoimmune diseases. Pathway analysis of putative DEM targets revealed an enrichment in pathways related to metabolic syndrome, inflammatory response, apoptosis and insulin signaling pathways, metabolic derangements, and decreased immunomodulation. One of the miRNAs’ gene targets was DYRK2 (dual-specificity tyrosine-phosphorylation-regulated kinase 2), which is an autoantigen targeted by an antibody in T1D. ROC curve analysis showed hsa-miR-16 and hsa-miR-200a-3p with AUCs greater than for glucose levels, with discriminating power for T1D prediction greater than glucose levels. Conclusions/Interpretation. Our data suggests a potential influence of DEMs on disease progression from the initial autoimmune lesion up to severe beta cell dysfunction and the role of miRNAs hsa-miR-16 and hsa-miR-200a-3p as biomarkers of T1D progression.

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Malczewska, Anna, Mark Kidd, Somer Matar, Beata Kos-Kudla, and Irvin M. Modlin. "A Comprehensive Assessment of the Role of miRNAs as Biomarkers in Gastroenteropancreatic Neuroendocrine Tumors." Neuroendocrinology 107, no. 1 (2018): 73–90. http://dx.doi.org/10.1159/000487326.

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Background/Aims: A key issue in neuroendocrine neoplasia management is the identification of blood signatures that specifically define the activity of a cancer or local tumor microenvironment. MicroRNAs (miRNAs) may represent such a candidate. To evaluate their clinical utility as biomarkers in gastroenteropancreatic neuroendocrine tumors (GEP-NETs), we assessed their expression in tissue and blood. Methods: A systematic review of PubMed was undertaken to identify studies investigating miRNAs in GEP-NETs and their utility as blood or tissue biomarkers. Results: Twenty-two studies using a range of methodologies with different normalization protocols were identified: tumor – gastric NET type 1 (n = 1 study: MiR-222, regulates p27KIP1), pancreatic (n = 6: MiR-21 [inflammatory marker, oncogene] and MiR-144 [PI3K/AKT signaling], both up- and downregulated depending on the method), small intestinal (n = 7: no consistent signature), and colorectal (n = 3: no consistent signature); blood – gastric NET type 1 (n = 1: MiR-222), pancreatic (n = 3: MiR-21), and small intestinal (n = 3: no consistent signature). The studies all included heterogeneous cohorts, were insufficiently powered, and utilized different methodologies, and age- and gender-matched controls were not used. Different miRNA isolation methods and detection protocols resulted in inconsistent expression comparing tumor and blood. A scientific discrepancy was the downregulated expression of some circulating candidates compared to tissue levels, suggesting methodological issues or physiological responses to the tumor. Both are of concern in defining the biometrics of a marker. Conclusions: A potential biomarker for GEP-NETs included MiR-21 (small bowel and pancreas), but this epithelial tumor marker requires prospective validation. Overall, significant scientific investigation remains to identify and demonstrate neuroendocrine specificity and to validate candidate miRNA biomarkers.

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Khokhar, Manoj, Dipayan Roy, Sojit Tomo, Ashita Gadwal, Praveen Sharma, and Purvi Purohit. "Novel Molecular Networks and Regulatory MicroRNAs in Type 2 Diabetes Mellitus: Multiomics Integration and Interactomics Study." JMIR Bioinformatics and Biotechnology 3, no. 1 (February 23, 2022): e32437. http://dx.doi.org/10.2196/32437.

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Background Type 2 diabetes mellitus (T2DM) is a metabolic disorder with severe comorbidities. A multiomics approach can facilitate the identification of novel therapeutic targets and biomarkers with proper validation of potential microRNA (miRNA) interactions. Objective The aim of this study was to identify significant differentially expressed common target genes in various tissues and their regulating miRNAs from publicly available Gene Expression Omnibus (GEO) data sets of patients with T2DM using in silico analysis. Methods Using differentially expressed genes (DEGs) identified from 5 publicly available T2DM data sets, we performed functional enrichment, coexpression, and network analyses to identify pathways, protein-protein interactions, and miRNA-mRNA interactions involved in T2DM. Results We extracted 2852, 8631, 5501, 3662, and 3753 DEGs from the expression profiles of GEO data sets GSE38642, GSE25724, GSE20966, GSE26887, and GSE23343, respectively. DEG analysis showed that 16 common genes were enriched in insulin secretion, endocrine resistance, and other T2DM-related pathways. Four DEGs, MAML3, EEF1D, NRG1, and CDK5RAP2, were important in the cluster network regulated by commonly targeted miRNAs (hsa-let-7b-5p, hsa-mir-155-5p, hsa-mir-124-3p, hsa-mir-1-3p), which are involved in the advanced glycation end products (AGE)-receptor for advanced glycation end products (RAGE) signaling pathway, culminating in diabetic complications and endocrine resistance. Conclusions This study identified tissue-specific DEGs in T2DM, especially pertaining to the heart, liver, and pancreas. We identified a total of 16 common DEGs and the top four common targeting miRNAs (hsa-let-7b-5p, hsa-miR-124-3p, hsa-miR-1-3p, and has-miR-155-5p). The miRNAs identified are involved in regulating various pathways, including the phosphatidylinositol-3-kinase-protein kinase B, endocrine resistance, and AGE-RAGE signaling pathways.

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Hackl, Matthias, Elisabeth Semmelrock, and Johannes Grillari. "The Role of microRNAs in Osteoporosis Diagnostics." Osteologie 30, no. 03 (September 2021): 222–29. http://dx.doi.org/10.1055/a-1514-1800.

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AbstractMicroRNAs (miRNAs) are short (18–24 nucleotides) non-coding RNA sequences that regulate gene expression via binding of messenger RNA. It is estimated that miRNAs co-regulate the expression of more than 70% of all human genes, many of which fulfil important roles in bone metabolism and muscle function. In-vitro and in-vivo experiments have shown that the targeted loss of miRNAs in distinct bone cell types (osteoblasts and osteoclasts) results in altered bone mass and bone architecture. These results emphasize the biological relevance of miRNAs for bone health.MiRNAs are not only considered as novel bone biomarkers because of their biological importance to bone metabolism, but also on the basis of other favorable properties: 1) Secretion of miRNAs from cells enables “minimally invasive” detection in biological fluids such as serum. 2) High stability of miRNAs in serum enables the retrospective analysis of frozen blood specimens. 3) Quantification of miRNAs in the serum is based on the RT-PCR - a robust method that is considered as the gold standard for the analysis of nucleic acids in clinical diagnostics.With regard to osteoporosis, it has been shown that many of the known risk factors are characterized by distinct miRNA profiles in the affected tissues: i) age-related loss of bone mass, ii) sarcopenia, iii) changes in estrogen metabolism and related changes Loss of bone mass, and iv) diabetes. Therefore, numerous studies in recent years have dealt with the characterization of miRNAs in the serum of osteoporosis patients and healthy controls, and were able to identify recurring miRNA patterns that are characteristic of osteoporosis. These novel biomarkers have great potential for the diagnosis and prognosis of osteoporosis and its clinical outcomes.The aim of this article is to give a summary of the current state of knowledge on the research and application of miRNA biomarkers in osteoporosis.

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Masi, Laureane Nunes, Tamires Duarte Afonso Serdan, Adriana Cristina Levada-Pires, Elaine Hatanaka, Leonardo dos Reis Silveira, Maria Fernanda Cury-Boaventura, Tania Cristina Pithon-Curi, Rui Curi, Renata Gorjão, and Sandro Massao Hirabara. "Regulation of Gene Expression by Exercise-Related Micrornas." Cellular Physiology and Biochemistry 39, no. 6 (2016): 2381–97. http://dx.doi.org/10.1159/000452507.

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Gene expression control by microRNAs (miRs) is an important mechanism for maintenance of cellular homeostasis in physiological and pathological conditions as well as in response to different stimuli including nutritional factors and exercise. MiRs are involved in regulation of several processes such as growth and development, fuel metabolism, insulin secretion, immune function, miocardium remodeling, cell proliferation, differenciation, survival, and death. These molecules have also been proposed to be potential biomarkers and/or therapeutical targets in obesity, type 2 diabetes mellitus, cardiovascular diseases, metabolic syndrome, and cancer. MiRs are released by most cells and potentially act on intercellular communication to borderer or distant cells. Various studies have been performed to elucidate the involvement of miRs in exercise-induced effects. The aims of this review are: 1) to bring up the main advances for the comprehension of the mechanisms of action of miRs; 2) to present the main results on miR involvement in physical exercise; 3) to discuss the physiological effects of miRs modified by exercise. The state of the art and the perspectives on miRs associated with physical exercise will be presented. Thus, this review is important for updating recent advances and driving further strategies and studies on the exercise-related miR research.

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Grieco, Giuseppina E., Dorica Cataldo, Elena Ceccarelli, Laura Nigi, Giovanna Catalano, Noemi Brusco, Francesca Mancarella, et al. "Serum Levels of miR-148a and miR-21-5p Are Increased in Type 1 Diabetic Patients and Correlated with Markers of Bone Strength and Metabolism." Non-Coding RNA 4, no. 4 (November 27, 2018): 37. http://dx.doi.org/10.3390/ncrna4040037.

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Type 1 diabetes (T1D) is characterized by bone loss and altered bone remodeling, resulting into reduction of bone mineral density (BMD) and increased risk of fractures. Identification of specific biomarkers and/or causative factors of diabetic bone fragility is of fundamental importance for an early detection of such alterations and to envisage appropriate therapeutic interventions. MicroRNAs (miRNAs) are small non-coding RNAs which negatively regulate genes expression. Of note, miRNAs can be secreted in biological fluids through their association with different cellular components and, in such context, they may represent both candidate biomarkers and/or mediators of bone metabolism alterations. Here, we aimed at identifying miRNAs differentially expressed in serum of T1D patients and potentially involved in bone loss in type 1 diabetes. We selected six miRNAs previously associated with T1D and bone metabolism: miR-21; miR-24; miR-27a; miR-148a; miR-214; and miR-375. Selected miRNAs were analyzed in sera of 15 T1D patients (age: 33.57 ± 8.17; BMI: 21.4 ± 1.65) and 14 non-diabetic subjects (age: 31.7 ± 8.2; BMI: 24.6 ± 4.34). Calcium, osteocalcin, parathormone (PTH), bone ALkaline Phoshatase (bALP), and Vitamin D (VitD) as well as main parameters of bone health were measured in each patient. We observed an increased expression of miR-148a (p = 0.012) and miR-21-5p (p = 0.034) in sera of T1D patients vs non-diabetic subjects. The correlation analysis between miRNAs expression and the main parameters of bone metabolism, showed a correlation between miR-148a and Bone Mineral Density (BMD) total body (TB) values (p = 0.042) and PTH circulating levels (p = 0.033) and the association of miR-21-5p to Bone Mineral Content-Femur (BMC-FEM). Finally, miR-148a and miR-21-5p target genes prediction analysis revealed several factors involved in bone development and remodeling, such as MAFB, WNT1, TGFB2, STAT3, or PDCD4, and the co-modulation of common pathways involved in bone homeostasis thus potentially assigning a role to both miR-148a and miR-21-5p in bone metabolism alterations. In conclusion, these results lead us to hypothesize a potential role for miR-148a and miR-21-5p in bone remodeling, thus representing potential biomarkers of bone fragility in T1D.

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Chang, Wenguang, and Jianxun Wang. "Exosomes and Their Noncoding RNA Cargo Are Emerging as New Modulators for Diabetes Mellitus." Cells 8, no. 8 (August 8, 2019): 853. http://dx.doi.org/10.3390/cells8080853.

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Diabetes belongs to a group of metabolic disorders characterized by long term high blood glucose levels due to either inadequate production of insulin (Type 1 diabetes, T1DM) or poor response of the recipient cell to insulin (Type 2 diabetes, T2DM). Organ dysfunctions are the main causes of morbidity and mortality due to high glucose levels. Understanding the mechanisms of organ crosstalk may help us improve our basic knowledge and find novel strategies to better treat the disease. Exosomes are part of a newly emerged research area and have attracted a great deal of attention for their capacity to regulate communications between cells. In conditions of diabetes, exosomes play important roles in the pathological processes in both T1DM and T2DM, such as connecting the immune cell response to pancreatic tissue injury, as well as adipocyte stimulation to insulin resistance of skeletal muscle or liver. Furthermore, in recent years, nucleic acids containing exosomes—especially microRNAs (miRNAs) and long noncoding RNAs (lncRNAs)—have been shown to mainly regulate communications between organs in pathological processes of diabetes, including influencing metabolic signals and insulin signals in target tissues, affecting cell viability, and modulating inflammatory pancreatic cells. Moreover, exosome miRNAs show promise in their use as biomarkers or in treatments for diabetes and diabetic complications. Thus, this paper summarizes the recent work on exosomes related to diabetes as well as the roles of exosomal miRNAs and lncRNAs in diabetic pathology and diagnosis in order to help us better understand the exact roles of exosomes in diabetes development.

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Abaci, Neslihan, Ozlem Gok, Zeynep Karaali, Arzu Ergen, and SemaSirma Ekmekci. "Serum sirtuin 1 protein as a potential biomarker for type 2 diabetes: Increased expression of sirtuin 1 and the correlation with microRNAs." Journal of Research in Medical Sciences 24, no. 1 (2019): 56. http://dx.doi.org/10.4103/jrms.jrms_921_18.

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Milas, Oana, Florica Gadalean, Adrian Vlad, Victor Dumitrascu, Cristina Gluhovschi, Gheorghe Gluhovschi, Silvia Velciov, et al. "Deregulated profiles of urinary microRNAs may explain podocyte injury and proximal tubule dysfunction in normoalbuminuric patients with type 2 diabetes mellitus." Journal of Investigative Medicine 66, no. 4 (December 25, 2017): 747–54. http://dx.doi.org/10.1136/jim-2017-000556.

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MicroRNAs (miRNAs) are short non-coding RNA species that are important post-transcriptional regulators of gene expression. The aim of the study was to establish a potential explanation of podocyte damage and proximal tubule (PT) dysfunction induced by deregulated miRNAs expression in the course of type 2 diabetes mellitus (DM). A total of 68 patients with type 2 DM and 11 healthy subjects were enrolled in a cross-sectional study and assessed concerning urinary albumin:creatinine ratio (UACR), urinary N-acetyl-β-D-glucosamininidase (NAG), urinary kidney injury molecule-1, urinary nephrin, podocalyxin, synaptopodin, estimated glomerular filtration rate (eGFR), urinary miRNA21, miRNA124, and miRNA192. In univariable regression analysis, miRNA21, miRNA124, and miRNA192 correlated with urinary nephrin, synaptopodin, podocalyxin, NAG, KIM-1, UACR, and eGFR. Multivariable regression analysis yielded models in which miRNA192 correlated with synaptopodin, uNAG, and eGFR (R2=0.902; P<0.0001), miRNA124 correlated with synaptopodin, uNAG, UACR, and eGFR (R2=0.881; P<0.0001), whereas miRNA21 correlated with podocalyxin, uNAG, UACR, and eGFR (R2=0.882; P<0.0001). Urinary miRNA192 expression was downregulated, while urinary miRNA21 and miRNA124 expressions were upregulated. In patients with type 2 DM, there is an association between podocyte injury and PT dysfunction, and miRNA excretion, even in the normoalbuminuria stage. This observation documents a potential role of the urinary profiles of miRNA21, miRNA124, and miRNA192 in early DN. Despite their variability across the segments of the nephron, urinary miRNAs may be considered as a reliable tool for the identification of novel biomarkers in order to characterize the genetic pattern of podocyte damage and PT dysfunction in early DN of type 2 DM.

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Formichi, Caterina, Daniela Fignani, Laura Nigi, Giuseppina Emanuela Grieco, Noemi Brusco, Giada Licata, Claudia Sabato, Elisabetta Ferretti, Guido Sebastiani, and Francesco Dotta. "Circulating microRNAs Signature for Predicting Response to GLP1-RA Therapy in Type 2 Diabetic Patients: A Pilot Study." International Journal of Molecular Sciences 22, no. 17 (August 31, 2021): 9454. http://dx.doi.org/10.3390/ijms22179454.

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Type 2 diabetes (T2D) represents one of the major health issues of this century. Despite the availability of an increasing number of anti-hyperglycemic drugs, a significant proportion of patients are inadequately controlled, thus highlighting the need for novel biomarkers to guide treatment selection. MicroRNAs (miRNAs) are small non-coding RNAs, proposed as useful diagnostic/prognostic markers. The aim of our study was to identify a miRNA signature occurring in responders to glucagon-like peptide 1 receptor agonists (GLP1-RA) therapy. We investigated the expression profile of eight T2D-associated circulating miRNAs in 26 prospectively evaluated diabetic patients in whom GLP1-RA was added to metformin. As expected, GLP1-RA treatment induced significant reductions of HbA1c and body weight, both after 6 and 12 months of therapy. Of note, baseline expression levels of the selected miRNAs revealed two distinct patient clusters: “high expressing” and “low expressing”. Interestingly, a significantly higher percentage of patients in the high expression group reached the glycemic target after 12 months of treatment. Our findings suggest that the evaluation of miRNA expression could be used to predict the likelihood of an early treatment response to GLP1-RA and to select patients in whom to start such treatment, paving the way to a personalized medicine approach.

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Lu, Ya-Ke, Xi Chu, Shuo Wang, Yue Sun, Jie Zhang, Jing Dong, and Yu-Xiang Yan. "Identification of Circulating hsa_circ_0063425 and hsa_circ_0056891 as Novel Biomarkers for Detection of Type 2 Diabetes." Journal of Clinical Endocrinology & Metabolism 106, no. 7 (February 20, 2021): e2688-e2699. http://dx.doi.org/10.1210/clinem/dgab101.

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Abstract Context Circular RNAs (circRNAs), which are involved in the development of diseases by regulating gene expression, have become promising novel biomarkers for diseases. Objective The aim of the present study was to identify the circulating circRNA biomarkers for early detection of type 2 diabetes (T2D). Methods The circRNA expression profiles were screened by microarray and compared between 5 new T2D cases and 5 healthy controls. The expression of candidate circRNAs that may be involved in the insulin phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway were validated by RT-qPCR in a second sample with 30 T2D cases and 30 controls. The association between circRNAs and T2D and their clinical significances were further assessed by logistic regression model, correlation analysis, and ROC curve in a large cohort comprising 313 subjects. The microRNA (miRNA) targets of circRNAs were verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. Results Low expressed circ_0063425 and hsa_circ_0056891 were independent predictors of T2D, impaired fasting glucose (IFG), and insulin resistance. The 2-circRNA panel had a high diagnostic accuracy for discriminating T2D and IFG from healthy controls, especially when body mass index was integrated. miR-19a-3p and miR-1-3p were identified as the miRNA targets of hsa_circ_0063425 and hsa_circ_0056891, respectively. Significant positive correlations were found between the expression levels of AKT and hsa_circ_0063425, PI3K and hsa_circ_0056891, in the total sample and subgroups stratified by glucose levels. Conclusion Downregulated hsa_circ_0063425 and hsa_circ_0056891 might contribute to the pathogenesis of T2D. They are valuable circulating biomarkers for early detection of T2D, which may be involved in regulation of PI3K/AKT signaling.

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Huang, Jiung-Pang, Chih-Chun Chang, Chao-Yu Kuo, Kuang-Jing Huang, Etienne M. Sokal, Kuan-Hsing Chen, and Li-Man Hung. "Exosomal microRNAs miR-30d-5p and miR-126a-5p Are Associated with Heart Failure with Preserved Ejection Fraction in STZ-Induced Type 1 Diabetic Rats." International Journal of Molecular Sciences 23, no. 14 (July 6, 2022): 7514. http://dx.doi.org/10.3390/ijms23147514.

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Exosomal microRNAs (EXO-miRNAs) are promising non-invasive diagnostic biomarkers for cardiovascular disease. Heart failure with preserved ejection fraction (HFpEF) is a poorly understood cardiovascular complication of diabetes mellitus (DM). Little is known about whether EXO-miRNAs can be used as biomarkers for HFpEF in DM. We aimed to investigate the relationship between EXO-miRNAs and HFpEF in STZ-induced diabetic rats. We prepared STZ-induced diabetic rats exhibiting a type 1 DM phenotype with low body weight, hyperglycemia, hyperlipidemia and hypoinsulinemia. Histological sections confirmed atrophy and fibrosis of the heart, with collagen accumulation representing diabetic cardiomyopathy. Significant decreases in end-diastolic volume, stroke volume, stroke work, end-systolic elastance and cardiac output indicated impaired cardiac contractility, as well as mRNA conversion of two isoforms of myosin heavy chain (α-MHC and β-MHC) and increased atrial natriuretic factor (ANF) mRNA indicating heart failure, were consistent with the features of HFpEF. In diabetic HFpEF rats, we examined a selected panel of 12 circulating miRNAs associated with HF (miR-1-3p, miR-21-5p, miR-29a-5p, miR-30d-5p, miR-34a-5p, miR-126a-5p, miR-143-3p, miR-145-5p, miR-195-5p, miR-206-3p, miR-320-3p and miR-378-3p). Although they were all expressed at significantly lower levels in the heart compared to non-diabetic controls, only six miRNAs (miR-21-5p, miR-30d-5p, miR-126a-5p, miR-206-3p, miR-320-3p and miR-378-3p) were also reduced in exosomal content, while one miRNA (miR-34a-5p) was upregulated. Similarly, although all miRNAs were correlated with reduced cardiac output as a measure of cardiovascular performance, only three miRNAs (miR-30d-5p, miR-126a-5p and miR-378-3p) were correlated in exosomal content. We found that miR-30d-5p and miR-126a-5p remained consistently correlated with significant reductions in exosomal expression, cardiac expression and cardiac output. Our findings support their release from the heart and association with diabetic HFpEF. We propose that these two EXO-miRNAs may be important for the development of diagnostic tools for diabetic HFpEF.

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Yang, Ze-Min, Long-Hui Chen, Min Hong, Ying-Yu Chen, Xiao-Rong Yang, Si-Meng Tang, Qian-Fa Yuan, Zhen-Yu He, and Wei-Wen Chen. "Serum MicroRNA Profiling and Bioinformatics of Patients with Spleen-Deficiency Syndrome." Evidence-Based Complementary and Alternative Medicine 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/8726720.

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To investigate serum microRNA (miRNA) profile and bioinformatics of patients with spleen-deficiency syndrome (SDS) and explore pathogenesis of SDS patients from miRNA levels, 10 patients with type 2 diabetes mellitus (T2DM), within which 5 patients were with SDS and the remaining were with blood stasis syndrome (BSS), and 5 healthy volunteers were recruited. Serum miRNA profiles of SDS patients were identified by quantitative PCR array. Target prediction and functional annotation for miRNAs were performed by miRSystem database. The present study identified 11 candidate serum miRNAs for SDS patients, and their targets were significantly enriched in 18 KEGG pathways and 7 GO molecular functions. Those enriched KEGG pathways included (1) metabolisms of carbohydrate, protein, amino acid, and fatty acid, (2) signaling pathways of insulin, ErbB, chemokine, calcium, and type II diabetes mellitus, (3) invasions of bacterium,Escherichia coli, andShigella(Shigellosis), and (4) endocytosis and phagocytosis. Those enriched GO molecular functions were mainly involved in transcription regulation and regulation of metabolism. Our findings might elucidate the pathogenesis of SDS patients with disorders of substance metabolism and hypoimmunity from miRNA levels, as well as providing some miRNA biomarkers for clinical syndrome differentiation of SDS.

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Malygina, A. A., Z. E. Belaya, A. G. Nikitin, P. A. Koshkin, I. I. Sitkin, A. M. Lapshina, P. M. Khandaeva, A. S. Lutsenko, D. A. Trukhina, and G. A. Melnichenko. "Differences in plasma miRNA levels in inferior petrosal sinus samples of patients with ACTH-dependent Cushing’s syndrome." Problems of Endocrinology 67, no. 6 (November 12, 2021): 18–30. http://dx.doi.org/10.14341/probl12817.

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BACKGROUND: For the last decades microRNAs (miR) have proven themselves as novel biomarkers for various types of diseases. Identification of specific circulating microRNA panel that differ patient with Cushing’s disease (CD) and ectopic ACTH syndrome (EAS) could improve the diagnostic procedure.AIM: to evaluate the differences in miR levels in plasma samples drained from inferior petrosal sinuses in patients with CD and EAS.MATERIALS AND METHODS: single-center, case-control study: we enrolled 24 patients with ACTH-dependent Cushing’s syndrome (CS) requiring bilateral inferior petrosal sinus sampling (BIPSS). Among them 12 subjects were confirmed as CD (males=2, females=10; median age 46,5 [IR 33,8;53,5]) and 12 as EAS (males=4, females=8, median age 54 [IR 38,75;60,75]). BIPSS was performed through a percutaneous bilateral approach. Once catheters were properly placed, blood samples were withdrawn simultaneously from each petrosal sinus and a peripheral vein. Plasma samples from both sinuses were centrifuged and then stored at -80 C. MiRNA isolation from plasma was carried out by an miRneasy Plasma/Serum Kit (Qiagen, Germany) on the automatic QIAcube station according to the manufacturer protocol. To prevent degradation, we added 1 unit of RiboLock Rnase Inhibitor (Thermo Fisher Scientific, USA) per 1 μL of RNA solution. The concentration of total RNA in the aqueous solution was evaluated on a NanoVue Plus spectrophotometer (GE Healthcare, USA). The libraries were prepared by the QIAseq miRNA Library Kit following the manufacturer standard protocols. MiR expression was then analyzed by sequencing on Illumina NextSeq 500 (Illumina, USA).RESULTS: 108 miRNAs were differently expressed (p <0,05) in inferior petrosal sinus samples of patients with CD vs EAS. We divided these miRNAs into 3 groups based on the significance of the results. The first group consisted of samples with the highest levels of detected miR in both groups. Four miRNAs were included: miR-1203 was downregulated in CD vs EAS — 36.74 (p=0,013), and three other were upregulated in CD vs EAS: miR-383-3p 46.36 (p=0,01), miR-4290 6.84 (p=0,036), miR-6717-5p 4.49 (p=0,031). This miRs will be validated in larger cohorts using RT-qPCR.CONCLUSION: Plasma miR levels differ in inferior petrosal samples taken from patients with CD vs EAS. These miRs need to be validated by different methods and in peripheral plasma samples in order to be used as potentially non-invasive biomarkers to differentiate ACTH-dependent CS.

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Lodde, Valeria, Giampaolo Murgia, Elena Rita Simula, Maristella Steri, Matteo Floris, and Maria Laura Idda. "Long Noncoding RNAs and Circular RNAs in Autoimmune Diseases." Biomolecules 10, no. 7 (July 14, 2020): 1044. http://dx.doi.org/10.3390/biom10071044.

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Immune responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled, autoimmune diseases can occur. Autoimmune diseases (ADs) are a family of disorders characterized by the body’s immune response being directed against its own tissues, with consequent chronic inflammation and tissue damage. Despite enormous efforts to identify new drug targets and develop new therapies to prevent and ameliorate AD symptoms, no definitive solutions are available today. Additionally, while substantial progress has been made in drug development for some ADs, most treatments only ameliorate symptoms and, in general, ADs are still incurable. Hundreds of genetic loci have been identified and associated with ADs by genome-wide association studies. However, the whole list of molecular factors that contribute to AD pathogenesis is still unknown. Noncoding (nc)RNAs, such as microRNAs, circular (circ)RNAs, and long noncoding (lnc)RNAs, regulate gene expression at different levels in various diseases, including ADs, and serve as potential drug targets as well as biomarkers for disease progression and response to therapy. In this review, we will focus on the potential roles and genetic regulation of ncRNA in four autoimmune diseases—systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes mellitus.

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López-Armas, Gabriela C., Arailym Yessenbekova, Rocío E. González-Castañeda, Kevin J. Arellano-Arteaga, Ana Guerra-Librero, Nurzhanyat Ablaikhanova, Javier Florido, Germaine Escames, Darío Acuña-Castroviejo, and Iryna Rusanova. "Role of c-miR-21, c-miR-126, Redox Status, and Inflammatory Conditions as Potential Predictors of Vascular Damage in T2DM Patients." Antioxidants 11, no. 9 (August 27, 2022): 1675. http://dx.doi.org/10.3390/antiox11091675.

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The development of type 2 diabetes mellitus (T2DM) vascular complications (VCs) is associated with oxidative stress and chronic inflammation and can result in endothelial dysfunctions. Circulating microRNAs play an important role in epigenetic regulation of the etiology of T2DM. We studied 30 healthy volunteers, 26 T2DM patients with no complications, and 26 T2DM patients with VCs, to look for new biomarkers indicating a risk of developing VCs in T2DM patients. Peripheral blood samples were used to determine redox state, by measuring the endogenous antioxidant defense system (superoxide dismutase, SOD; catalase, CAT; glutathione reductase, GRd; glutathione peroxidase, GPx; and glucose-6-phosphate dehydrogenase, G6DP) and markers of oxidative damage (advanced oxidation protein products, AOPP; lipid peroxidation, LPO). Additionally, inflammatory marker levels (IL-1, IL-6, IL-18, and TNF-α), c-miR-21, and c-miR-126 expression were analyzed. T2DM patients showed the highest oxidative damage with increased GSSG/GSH ratios, LPO, and AOPP levels. In both diabetic groups, we found that diminished SOD activity was accompanied by increased CAT and decreased GRd and G6PD activities. Diabetic patients presented with increased relative expression of c-miR-21 and decreased relative expression of c-miR-126. Overall, c-miR-21, SOD, CAT, and IL-6 had high predictive values for diabetes diagnoses. Finally, our data demonstrated that IL-6 exhibited predictive value for VC development in the studied population. Moreover, c-miR-21 and c-miR-126, along with GPx and AOPP levels, should be considered possible markers for VC development in future studies.

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Dogan, Soner, Munevver B. Cicekdal, Umit Ozorhan, Goktug Karabiyik, Busra T. Kazan, Isin D. Ekici, Bayram Yilmaz, et al. "Roles of adiponectin and leptin signaling-related microRNAs in the preventive effects of calorie restriction in mammary tumor development." Applied Physiology, Nutrition, and Metabolism 46, no. 8 (August 2021): 866–76. http://dx.doi.org/10.1139/apnm-2020-1000.

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Calorie restriction (CR) is suggested to prevent the development of mammary tumors (MTs); however, the mechanism remains to be clarified. We aimed to determine the microRNA (miRNA) profile in mice applied to 2 different CR protocols; chronic (CCR) and intermittent (ICR) and follow the MT development. In addition, the roles of miRNAs involved in adiponectin and/or leptin signaling pathways were investigated. Mice were divided into 3 groups: ad-libitum (AL), CCR, or ICR, which comprised 3 weeks of AL feeding followed by 1 week of 60% CR in a cyclic manner. Blood and tissue collection were performed at weeks 10, 17/18, 49/50 and 81/82. Long-term CCR provided better protection compared with ICR for MT development with a delay in the MT occurrence. Adiponectin expression in mammary fat pad were significantly higher in CCR group compared with AL. Using GeneChip Array, 250 of 3195 miRNAs were differentially expressed among the dietary groups. Thirteen of 250 miRNAs were related to adiponectin and/or leptin signaling genes. Results were verified by reverse transcription polymerase chain reaction. Specifically, miR-326-3p, miR-500-3p and miR-129-5p, which are related to adiponectin and/or leptin signaling, may play important roles in the preventive effects of CR in MT development and in ageing. Thus, these miRNAs might be putative biomarkers to target for diagnostic and treatment purposes. Novelty: Type of CR and micro RNA interaction is related to ageing. miR-326-3p, miR-500-3p and miR-129-5p expression levels were differentially expressed in MT development and in ageing. The genes associated with adiponectin and/or leptin signaling pathways are regulated by certain miRNAs in the protective effects of CR.

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Nielsen, Lotte B., Cheng Wang, Kaspar Sørensen, Claus H. Bang-Berthelsen, Lars Hansen, Marie-Louise M. Andersen, Philip Hougaard, et al. "Circulating Levels of MicroRNA from Children with Newly Diagnosed Type 1 Diabetes and Healthy Controls: Evidence That miR-25 Associates to Residual Beta-Cell Function and Glycaemic Control during Disease Progression." Experimental Diabetes Research 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/896362.

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This study aims to identify key miRNAs in circulation, which predict ongoing beta-cell destruction and regeneration in children with newly diagnosed Type 1 Diabetes (T1D). We compared expression level of sera miRNAs from new onset T1D children and age-matched healthy controls and related the miRNAs expression levels to beta-cell function and glycaemic control. Global miRNA sequencing analyses were performed on sera pools from two T1D cohorts (n= 275 and 129, resp.) and one control group (n= 151). We identified twelve upregulated human miRNAs in T1D patients (miR-152, miR-30a-5p, miR-181a, miR-24, miR-148a, miR-210, miR-27a, miR-29a, miR-26a, miR-27b, miR-25, miR-200a); several of these miRNAs were linked to apoptosis and beta-cell networks. Furthermore, we identified miR-25 as negatively associated with residual beta-cell function (est.: −0.12,P= 0.0037), and positively associated with glycaemic control (HbA1c) (est.: 0.11,P= 0.0035) 3 months after onset. In conclusion this study demonstrates that miR-25 might be a “tissue-specific” miRNA for glycaemic control 3 months after diagnosis in new onset T1D children and therefore supports the role of circulating miRNAs as predictive biomarkers for tissue physiopathology and potential intervention targets.

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Levstek, Tina, Teo Mlinšek, Marija Holcar, Katja Goričar, Metka Lenassi, Vita Dolžan, Bojan Vujkovac, and Katarina Trebušak Podkrajšek. "Urinary Extracellular Vesicles and Their miRNA Cargo in Patients with Fabry Nephropathy." Genes 12, no. 7 (July 9, 2021): 1057. http://dx.doi.org/10.3390/genes12071057.

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Current biomarkers of Fabry nephropathy lack sensitivity in detecting early kidney damage and do not predict progression of nephropathy. Urinary extracellular vesicles (uEVs) and their molecular cargo could reflect early changes in renal impairment as they are secreted by the cells lining the urinary tract. We aimed to conduct a proof-of-concept study to investigate whether analysis of uEV characteristics and expression of uEV-derived microRNAs (miRNAs) could be applicable in studies to predict the development and progression of nephropathy in Fabry disease. A total of 20 Fabry patients were divided into two groups, depending on the presence of nephropathy. Chronological urine samples collected during 10-year follow-up were used for uEVs isolation with size exclusion chromatography. Nanoparticle tracking analysis was used to determine concentration and size of uEVs. We evaluated the expression of five uEV-derived miRNAs by qPCR (miR-23a-3p, miR-29a-3p, miR-30b-5p, miR-34a-5p, miR-200a-3p). There was no difference in the concentration and size of uEVs between patients with and without nephropathy at last follow-up or longitudinally. However, we found increased expression of miR-29a-3p and miR-200a-3p in uEVs isolated from chronological samples of patients with Fabry nephropathy. This may indicate an attempt by the organism to prevent the progression of renal damage leading to end-stage renal disease as previously reported in type 1 diabetes. In addition, we found an increased expression of miR-30b-5p in the 10-year period in uEVs of patients without renal dysfunction. miR-30b-5 was reported to have a protective role in podocyte injury and may possibly be important in Fabry nephropathy. These findings indicate that uEVs and their molecular cargo could be a promising target of studies focusing on elucidation of Fabry nephropathy. Nevertheless, total concentration and size of uEVs were neither indicative of the presence nor progression of Fabry nephropathy, while the role of the analyzed miRNAs in Fabry nephropathy progression was merely indicated and needs further in-depth studies.

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32

Banerjee, Joyita, Swagata Roy, Neetu Mishra, and Yogita Dhas. "Circulating MicroRNAs as Novel Biomarkers for Type 2 Diabetes." Indian Journal of Public Health Research & Development 8, no. 4 (2017): 714. http://dx.doi.org/10.5958/0976-5506.2017.00420.x.

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33

Tonyan, Z. N., Y. A. Nasykhova, A. A. Mikhailova, and A. S. Glotov. "MicroRNAs as Potential Biomarkers of Type 2 Diabetes Mellitus." Russian Journal of Genetics 57, no. 7 (July 2021): 764–77. http://dx.doi.org/10.1134/s1022795421060107.

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34

Tooley, James E., and Kevan C. Herold. "Biomarkers in type 1 diabetes." Current Opinion in Endocrinology & Diabetes and Obesity 21, no. 4 (August 2014): 287–92. http://dx.doi.org/10.1097/med.0000000000000076.

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35

Perfetti, Alessandra, Simona Greco, Enrico Bugiardini, Rosanna Cardani, Paola Gaia, Carlo Gaetano, Giovanni Meola, and Fabio Martelli. "Plasma microRNAs as biomarkers for myotonic dystrophy type 1." Neuromuscular Disorders 24, no. 6 (June 2014): 509–15. http://dx.doi.org/10.1016/j.nmd.2014.02.005.

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36

Jin, Yulan, and Jin-Xiong She. "Novel Biomarkers in Type 1 Diabetes." Review of Diabetic Studies 9, no. 4 (2012): 224–35. http://dx.doi.org/10.1900/rds.2012.9.224.

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37

Bonifacio, Ezio. "Predicting Type 1 Diabetes Using Biomarkers." Diabetes Care 38, no. 6 (May 21, 2015): 989–96. http://dx.doi.org/10.2337/dc15-0101.

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38

Cassiday, Laura. "Candidate biomarkers for type 1 diabetes." Journal of Proteome Research 7, no. 2 (February 2008): 482. http://dx.doi.org/10.1021/pr083717a.

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39

Wang, Hsiuying. "MicroRNAs, Parkinson’s Disease, and Diabetes Mellitus." International Journal of Molecular Sciences 22, no. 6 (March 14, 2021): 2953. http://dx.doi.org/10.3390/ijms22062953.

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Parkinson’s disease (PD) is a neurodegenerative disorder that affects 1% of the population over the age of 60. Diabetes Mellitus (DM) is a metabolic disorder that affects approximately 25% of adults over the age of 60. Recent studies showed that DM increases the risk of developing PD. The link between DM and PD has been discussed in the literature in relation to different mechanisms including mitochondrial dysfunction, oxidative stress, and protein aggregation. In this paper, we review the common microRNA (miRNA) biomarkers of both diseases. miRNAs play an important role in cell differentiation, development, the regulation of the cell cycle, and apoptosis. They are also involved in the pathology of many diseases. miRNAs can mediate the insulin pathway and glucose absorption. miRNAs can also regulate PD-related genes. Therefore, exploring the common miRNA biomarkers of both PD and DM can shed a light on how these two diseases are correlated, and targeting miRNAs is a potential therapeutic opportunity for both diseases.

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40

Flowers, E., A. M. Kanaya, Y. Fukuoka, I. E. Allen, B. Cooper, and B. E. Aouizerat. "Preliminary evidence supports circulating microRNAs as prognostic biomarkers for type 2 diabetes." Obesity Science & Practice 3, no. 4 (October 27, 2017): 446–52. http://dx.doi.org/10.1002/osp4.134.

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41

Insel, Richard, Sanjoy Dutta, and Joseph Hedrick. "Type 1 Diabetes: Disease Stratification." Biomedicine Hub 2, Suppl. 1 (November 21, 2017): 1–16. http://dx.doi.org/10.1159/000481131.

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Type 1 diabetes, a disorder characterized by immune-mediated loss of functional pancreatic beta cells, is a disease continuum with specific presymptomatic stages with defined risk of progression to symptomatic disease. Prognostic biomarkers have been developed for disease staging and for stratification of subjects that address the heterogeneity in rate of disease progression. Using biomarkers for stratification of subjects at different stages of type 1 diabetes will enable smaller and shorter intervention clinical trials with greater effect size. Addressing the heterogeneity of the disease will allow precision medicine-based approaches to prevention and interception of presymptomatic stages of disease and treatment and cure of symptomatic disease.

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42

Zhu, Hongmei, and Siu-wai Leung. "MicroRNA biomarkers of type 2 diabetes: A protocol for corroborating evidence by computational genomics and meta-analyses." PLOS ONE 16, no. 4 (April 6, 2021): e0247556. http://dx.doi.org/10.1371/journal.pone.0247556.

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Background Few microRNAs were found consistently dysregulated in type 2 diabetes (T2D) that would gain confidence from Big Pharma to develop diagnostic or therapeutic biomarkers. This study aimed to corroborate evidence from eligible microRNAs-T2D association studies according to stringent quality criteria covering both biological and statistical significance in T2D for biomarker development. Methods and analyses Controlled microRNA expression profiling studies on human with T2D will be retrieved from PubMed, ScienceDirect, and Embase for selecting the statistically significant microRNAs according to pre-specified search strategies and inclusion criteria. Multiple meta-analyses with restricted maximum-likelihood estimation and empirical Bayes estimation under the random-effects model will be conducted by metafor package in R. Subgroup and sensitivity analyses further examine the microRNA candidates for their disease specificity, tissue specificity, blood fraction specificity, and statistical robustness of evidence. Biologically relevant microRNAs will then be selected through genomic database corroboration. Their association with T2D is further measured by area under the curve (AUC) of receive operating characteristic (ROC). Meta-analysis of AUC of potential biomarkers will also be conducted. Enrichment analysis on potential microRNA biomarkers and their target genes will be performed by iPathwayGuide and clusterProfiler, respectively. The corresponding reporting guidelines will be used to assess the quality of included studies according to their profiling methods (microarray, RT-PCR, and RNA-Seq). Ethics and dissemination No ethics approval is required since this study does not include identifiable personal patient data. Protocol registration number CRD42017081659.

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43

Paschou, Stavroula A., Gerasimos Siasos, Niki Katsiki, Nikolaos Tentolouris, and Dimitrios Tousoulis. "The Role of microRNAs in the Development of Type 2 Diabetes Complications." Current Pharmaceutical Design 26, no. 46 (December 30, 2020): 5969–79. http://dx.doi.org/10.2174/1381612826666201102102233.

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: MicroRNAs represent a class of small (19-25 nucleotides) single-strand pieces of RNA that are noncoding ones. They are synthesized by RNA polymerase II from transcripts that fold back on themselves. They mostly act as gene regulatory agents that pair with complementary sequences on mRNA and produce silencing complexes, which, in turn, suppress coding genes at a post-transcriptional level. There is now evidence that microRNAs may affect insulin secretion or insulin action, as they can alter pancreatic beta cells development, insulin production, as well as insulin signaling. Any molecular disorder that affects these pathways can deteriorate insulin resistance and lead to type 2 diabetes mellitus (T2DM) onset. Furthermore, the expression of several microRNAs is up- or down-regulated in the presence of diabetic microvascular complications (i.e., peripheral neuropathy, nephropathy, retinopathy, foot ulcers), as well as in patients with coronary heart disease, stroke, and peripheral artery disease. However, more evidence is needed, specifically regarding T2DM patients, to establish the use of such microRNAs as diagnostical biomarkers or therapeutic targets in daily practice.

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44

Kraczkowska, Weronika, Lucyna Stachowiak, Andrzej Pławski, and Paweł Piotr Jagodziński. "Circulating miRNA as potential biomarkers for diabetes mellitus type 2: should we focus on searching for sex differences?" Journal of Applied Genetics 63, no. 2 (January 5, 2022): 293–303. http://dx.doi.org/10.1007/s13353-021-00678-5.

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Abstract microRNAs are non-coding molecules, approximately 22 nucleotides in length, that regulate various cellular processes. A growing body of evidence has suggested that their dysregulated expression is involved in the pathogenesis of diverse diseases, including diabetes mellitus type 2 (DM2). Early onset of this chronic and complex metabolic disorder is frequently undiagnosed, leading to the development of severe diabetic complications. Notably, DM2 prevalence is rising globally and an increasing number of articles demonstrate that DM2 susceptibility, development, and progression differ between males and females. Therefore, this paper discusses the role of microRNAs as a source of novel diagnostic biomarkers for DM2 and aims to underline the importance of sex disparity in biomarkers research. Taking into account an urgent need for the development of sex-specific diagnostic strategies in DM2, recent results have shown that circulating miRNAs are promising candidates for sex-biased biomarkers.

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45

Tijsen, Anke J., Yigal M. Pinto, and Esther E. Creemers. "Circulating microRNAs as diagnostic biomarkers for cardiovascular diseases." American Journal of Physiology-Heart and Circulatory Physiology 303, no. 9 (November 1, 2012): H1085—H1095. http://dx.doi.org/10.1152/ajpheart.00191.2012.

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One of the major challenges in cardiovascular disease is the identification of reliable clinical biomarkers that can be routinely measured in plasma. MicroRNAs (miRNAs) were recently discovered to circulate in the bloodstream in a remarkably stable form. Because of their stability and often tissue- and disease-specific expression and the possibility to measure them with high sensitivity and specificity, miRNAs are emerging as new diagnostic biomarkers. In this review we will provide an overview of the potential of circulating miRNAs as biomarkers for a wide range of cardiovascular diseases such as coronary artery disease, myocardial infarction, hypertension, heart failure, viral myocarditis, and type-2 diabetes mellitus. Furthermore, we will discuss the challenges with regard to further validation in large patient cohorts, and we will discuss how the measurement of multiple miRNAs simultaneously might improve the accuracy of the diagnostic test.

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46

Pavlov, V. G., M. V. Budzinskaya, D. V. Petrachkov, A. E. Goldsmid, R. A. Karamullina, I. V. Poluboyarinova, and V. V. Fadeyev. "Structural biomarkers in patients with type 1 diabetes." Modern technologies in ophtalmology, no. 4 (December 7, 2020): 99–100. http://dx.doi.org/10.25276/2312-4911-2020-4-99-100.

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47

Greenhill, Claire. "IGFs potential biomarkers for type 1 diabetes mellitus." Nature Reviews Endocrinology 16, no. 3 (January 6, 2020): 130–31. http://dx.doi.org/10.1038/s41574-020-0317-0.

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48

Meerson, Ari, Azwar Najjar, Elias Saad, Wisam Sbeit, Masad Barhoum, and Nimer Assy. "Sex Differences in Plasma MicroRNA Biomarkers of Early and Complicated Diabetes Mellitus in Israeli Arab and Jewish Patients." Non-Coding RNA 5, no. 2 (April 5, 2019): 32. http://dx.doi.org/10.3390/ncrna5020032.

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MicroRNAs play functional roles in the etiology of type 2 diabetes mellitus (T2DM) and complications, and extracellular microRNAs have attracted interest as potential biomarkers of these conditions. We aimed to identify a set of plasma microRNAs, which could serve as biomarkers of T2DM and complications in a mixed Israeli Arab/Jewish patient sample. Subjects included 30 healthy volunteers, 29 early-stage T2DM patients, and 29 late-stage T2DM patients with renal and/or vascular complications. RNA was isolated from plasma, and the levels of 12 candidate microRNAs were measured by quantitative reverse transcription and polymerase chain reaction (qRT-PCR). MicroRNA levels were compared between the groups and correlated to clinical measurements, followed by stepwise regression analysis and discriminant analysis. Plasma miR-486-3p and miR-423 were respectively up- and down-regulated in T2DM patients compared to healthy controls. MiR-28-3p and miR-423 were up-regulated in patients with complicated T2DM compared to early T2DM, while miR-486-3p was down-regulated. Combined, four microRNAs (miR-146a-5p, miR-16-2-3p, miR-126-5p, and miR-30d) could distinguish early from complicated T2DM with 77% accuracy and 79% sensitivity. In male patients only, the same microRNAs, with the addition of miR-423, could distinguish early from complicated T2DM with 83.3% accuracy. Furthermore, plasma microRNA levels showed significant correlations with clinical measurements, and these differed between men and women. Additionally, miR-183-5p levels differed significantly between the ethnic groups. Our study identified a panel of specific plasma microRNAs which can serve as biomarkers of T2DM and its complications and emphasizes the importance of sex differences in their clinical application.

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Salama, Iman I., Samia M. Sami, Ghada A. Abdellatif, Amira Mohsen, Hanaa Rasmy, Solaf Ahmed Kamel, Mona Hamed Ibrahim, Mona Mostafa, Walaa A. Fouad, and Hala M. Raslan. "Plasma microRNAs biomarkers in mild cognitive impairment among patients with type 2 diabetes mellitus." PLOS ONE 15, no. 7 (July 29, 2020): e0236453. http://dx.doi.org/10.1371/journal.pone.0236453.

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50

Yu, Jingwei, Wen Su, Xiaoyan Zhang, Feng Zheng, and Youfei Guan. "MicroRNAs in type 2 diabetes mellitus: Important for the pathogenesis but uncertain as biomarkers." Journal of Diabetes 12, no. 9 (May 29, 2018): 697–700. http://dx.doi.org/10.1111/1753-0407.12772.

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