Academic literature on the topic 'MicroRNAs - biomarkers - type 1 diabetes'
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Journal articles on the topic "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, and 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, no. 4 (January 23, 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.
Dissertations / Theses on the topic "MicroRNAs - biomarkers - type 1 diabetes"
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Ventriglia, Giuliana. "Circulating microRNA as biomarkers of autoimmune type 1 diabetes – Assessing the relevance of a target organ specific microRNA signature in type 1 diabetes." Doctoral thesis, Università di Siena, 2018. http://hdl.handle.net/11365/1050776.
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Type 1 diabetes (T1D) results from a T cell mediated destruction due to a breach in immune tolerance towards insulin producing β-cells, leading to an absolute insulin deficiency. To date, the pathogenesis of the disease is not fully understood and exogenous insulin still represents the gold standard as therapy. It is believed that in some genetically predisposed individuals environmental factors can lead to a breakdown in immunological tolerance. T regulatory cells (Tregs), a specialized subpopulation of T cell, are the major components of peripheral tolerance mechanisms due to their ability to restrain autoreactive effector T cells. Interestingly, microRNAs, small non-coding RNAs that negatively regulate gene expression, are emerging as crucial modulators of immune cell functions and their deregulation has been associated with autoimmune disease like T1D, thus representing major players in the regulation of immune homeostasis. Against this background, characterizing microRNA expression in Tregs deriving from tissues close to target organ in T1D patients will be crucial to gain a deeper insight into immune
deregulation. Interestingly, microRNAs have also been detected extracellularly in biological fluids, thus representing new potential disease biomarkers. The need of new biomarkers in the field is underlined by the complexity and heterogeneity of T1D with the clinical presentation being
preceded by a long asymptomatic phase in which most β-cells are destroyed. Moreover, immunomodulatory trials in T1D, although having failed their primary endpoints, have identified through post-hoc analysis subgroups of patients for whom interventions were beneficial. Therefore,
the identification of new biomarkers would help to specifically select patients that would benefit from specific immunotherapies. Thus, the main purpose of this work was to gain insight into the microRNA regulation occurring in Tregs residing in the pancreatic draining lymph nodes (PLN) of T1D patients and to establish circulating microRNAs as new biomarkers in diabetes autoimmune prone mice in order to monitor the lymphocyte mediated inflammatory state in the pancreas and to predict therapeutic responses in an Ag-specific combination therapy. Tregs circulating in the peripheral blood are likely to differ from those residing in the LN draining the organ targeted by an autoimmune response, indeed a previous finding showed that only Tregs deriving from PLN of T1D patients have an impaired regulatory activity in vitro. Therefore, in the first project (Chapter 4) we investigated the microRNA expression profile in Tregs isolated from blood and PLN of patients with T1D and non-diabetic subjects. Among the 72 microRNAs detected in purified cells, miR-125a was highly expressed only in Treg cells purified from PLN of patients with T1D. Bioinformatic analysis of the target genes revealed CCR2 as a possible gene modulated by miR-125a. Accordingly, elevated miR-125a levels were detected in Tregs isolated from the PLN but not from the peripheral blood of donors with T1D and it was associated with a reduced CCR2 expression. A specific β-cell expression of the CCR2 ligand CCL2 (MCP1) was also observed in the pancreata of multi-organ donors, suggesting that β-cells are prone to attract CCR2+ Tregs. These data showed a reduced expression of CCR2 on Tregs deriving from PLN of T1D patients; this Treg status may limit their migration and eventual function in the pancreas. In the second project (Chapter 5) we aimed to investigate whether circulating microRNA alterations could reflect the pathologic process within the specific diseased tissue. Indeed, we identified miR-409-3p, a miRNA that negatively regulates the expression of IFNγ, as downregulated in both plasma and pancreatic lymphocytic infiltrates of recent-onset diabetic vs. normoglycemic NOD mice. Furthermore, we showed that circulating miR-409-3p plasma levels
negatively correlated with in situ IFNγ expression in islet-infiltrating cells both in basal condition and following a therapeutic intervention with anti-CD3 treatment, thus highlighting the potential role of miR-409-3p as a biomarker of islet inflammation. Finally, we confirmed miR-409-3p downregulation in plasma samples derived from newly-diagnosed T1D patients vs. age-matched controls, indicating a possible application of circulating miR-409-3p as biomarker in order to monitor IFNγ mediated islet inflammation. The host lab previously showed that a combination therapy consisting of a 5 day course of anti-CD3 antibodies at disease onset along with a 6 weeks oral administration of live genetically modified
Lactococcus lactis (L. lactis) producing human proinsulin and IL-10, restored durable normoglycemia in approximately 60% of NOD mice. Even though L. lactis therapy was successful in the reversal of autoimmune diabetes in around 60% of NOD mice, 40% of them were nonresponsive
to therapy. The route to bring this successful antigen-based therapy from preclinical models to clinic will depend on implementation of biomarkers and profound understanding of diverse mechanisms underlining therapeutic success. Therefore, the aim of the third project (Chapter 6) was to establish whether circulating microRNAs could be used as predictor biomarkers for therapeutic response. Indeed, we found a circulating microRNA signature consisting of 6 microRNAs that were specifically upregulated at disease onset in non-responders mice. Moreover,
the combination of 2 microRNAs were able to distinguish with good specificity and sensitivity. responder and non-responders at diabetes onset, thus emerging as a valuable tool to tailor this intervention therapy towards a more effective clinical study. Moreover, bioinformatics target
analysis of the circulating microRNAs differentially expressed between responders and nonresponders in the plasma after treatment course, highlighted pathways related to the metabolic status of T cells, suggesting the induction of a T cell exhausted phenotype in responder mice.
To conclude, this PhD project demonstrated the importance of assessing microRNA regulation in Tregs deriving from tissue sites close to the organ targeted by the autoimmune attack, as it differs from circulating Tregs. Moreover, plasma circulating microRNAs appear to be promising novel biomarkers in order to: i) monitor IFNγ mediated islet inflammation ii) predict therapeutic response and understand the tolerance induction mechanisms induced by L. lactis-combined therapy. Molecular understanding of Tregs function in the site of the autoimmune attack together with the discovery of new circulating biomarkers will surely help to monitor T1D progression and enhance the effective translation of this Ag-specific L.lactis intervention therapy in future clinical trials.
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Santos, Aritania Sousa. "Expressão de microRNAs circulantes relacionados ao diabetes tipo 1 autoimune." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-14082018-124100/.
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INTRODUÇÃO: O diabetes tipo 1 autoimune (DM1A) está associado a alterações na imunidade inata e adaptativa. A agressão autoimune, órgão específica, determina a destruição das células beta do pâncreas e a deficiência da produção de insulina. O infiltrado inflamatório do tipo linfomononuclear, configurando a insulite, e a escassez ou a ausência das células ?, definem o quadro histológico do DM1A. Os autoanticorpos contra antígenos das células beta, que geralmente se desenvolvem na fase pré-clínica, conferem predisposição para DM1A. No entanto, é difícil definir quando e quais indivíduos progredirão para o diabetes manifesto, justificando a busca de outros biomarcadores que auxiliem nas indicações de tratamentos preventivos. Nesse contexto, sabe-se que os microRNAs (miRNAs), pequenos RNAs que atuam pós transcrição, desempenham papel crucial na regulação de genes, integrando fatores genéticos e ambientais e influenciando o funcionamento de órgãos e tecidos de maneira pontual ou sistêmica. OBJETIVOS: avaliar o envolvimento biológico e a relevância da expressão de miRNAs na resposta imunológica e na função das células ? na patogênese do DM1A. MÉTODOS: analisamos o perfil dos miRNAs séricos em 4 grupos, a saber: pacientes portadores de DM1A, até 6 meses do diagnóstico (DM1A recente), (n=30); pacientes portadores de DM1A com duração de 2-5 anos (DM1A 2-5)(n=26) e indivíduos com autoanticorpos pancreáticos positivos sem diabetes (AcP) (n=25), os quais foram comparados aos indivíduos controles saudáveis(n= 29). A expressão dos microRNAs foi obtida com ensaios individuais TaqMan® MicroRNA Assays 5x primers e TaqMan MicroRNA Human Array Card A, (Applied Biosystems- Forster City CA, USA) constituído por 377 alvos e 4 endógenos. Os dados de expressão foram analisados no Software Cloud, (Thermo Fisher Scientific) e no programa Limma (Linear Models for Microarray and RNA-Seq Data). RESULTADOS: Não houve diferença nas características demográficas, como idade, cor auto referida e sexo entre os grupos (p > 0,05). Pacientes portadores de DM1A (recente e com duração de 2-5 anos), diferiram do grupo controle pelos valores elevados de glicose, hemoglobina glicada, títulos de autoanticorpos pancreáticos, e menores de peptídeo C (p < 0,05) e foram semelhantes entre si. Os portadores de autoanticorpos (AcP) tinham características intermediárias entre os grupos: menores valores de HbA1c e de anticorpo anti-tirosina-fosfatase (anti-IA2) e maiores de peptídeo C em relação aos dois grupos com diabetes. Diferiram dos controles apenas pelos maiores títulos de anticorpo anti-insulina (IAA) e anti-descarboxilase do ácido glutâmico 65 (anti-GAD65). A frequência dos alelos HLA de risco para diabetes (-DR3 ou -DR4 e -DQ2 ou DQ-8) decresceu dos grupos DM1A recente e DM 2-5 para AcP e controles. Foram avaliados 135 miRNAs que estavam expressos em 20% ou mais das amostras dos quatro grupos analisados. Maior expressão foi observada em 13, 4 e 33 miRNAs dos grupos AcP, DM1A recente e DM1A 2-5 respectivamente e menor em 11, 7 e 31 miRNAs destes grupos. Destes, 4 miRNAs foram diferencialmente expressos nos grupos AcP, DM1A recente e DM1A 2-5 em relação ao grupo controle. Os miRNAs: miR -16, miR-195 e miR-454, relacionados com regeneração endócrina do pâncreas, efeito anti-inflamatório e resposta à injúria da célula ? estavam diminuídos nestes 3 grupos. O miR-200a, implicado em apoptose das células beta, estava aumentado nos grupos AcP e DM1A recente e diminuído nos pacientes com maior duração do diabetes (DM1A 2-5), possivelmente devido à escassez destas células. Outros 8 miRNAs apresentaram expressão diferente da do grupo controle em dois dos grupos avaliados, e tendência semelhante no terceiro grupo, sendo 4 deles elevados (miR-193a-5p, miR- 323-3p, miR-423-5p, e miR-92a) e 4, diminuídos (miR-191, miR-19a, miR- 376a, miR-590-5p) ou neutralidade no 3º grupo (miR-15b, miR-100, miR-181a e miR-483-5p) Resposta antagônica foi observada para o miR-25 e miR-485- 3p, diminuídos no grupo AcP e aumentados no DM1A 2- 5. Tais miRNAs estão relacionados com resposta imunológica, secreção de insulina, lesão de células ? e glicotoxicidade, à semelhança do observado para o miR-101-3p, validado por ensaios individuais numa casuística maior. CONCLUSÃO: nossos dados sugerem que miRNAs circulantes podem estar envolvidos na patogênese do DM1AINTRODUCTION: Autoimmune type 1 diabetes (T1D) is associated with changes in innate and adaptive immunity. The organ-specific autoimmune aggression determines the destruction of beta-cells in the pancreas and the deficient insulin production. The inflammatory infiltration of the lymphomononuclear type, configuring the insulite, and the scarcity or the absence of the beta cells, define the histological picture of T1D. Autoantibodies against beta-cell antigens, which usually develop in the preclinical phase, confer predisposition to T1D. However, it is difficult to define when and which individuals will progress to overt diabetes, justifying the search for other biomarkers that could be indicative of preventive treatments. In this context, it is known that the microRNAs (miRNAs) - small RNAs that act post transcription - play a crucial role in regulating genes and in integrating genetic and environmental factors, influencing the function of organs and tissues in a punctual or systemic way. OBJECTIVES: to evaluate the biological involvement and relevance of miRNA expression in the immune response and ?-cell function in the pathogenesis of T1D. METHODS: we analyzed the profile of serum miRNAs of 4 groups, namely: patients with T1D up to 6 months after diagnosis (recent T1D), (n = 30); patients with T1D lasting 2-5 years (T1D 2- 5) (n = 26) and individuals expressing pancreatic autoantibodies without diabetes (AbP) (n = 25), which were compared to healthy controls (n = 29). Expression of the microRNAs was obtained with individual assays TaqMan® MicroRNA Assays 5x primers and TaqMan MicroRNA Human Array Card A (Applied Biosystems-Forster City CA, USA), consisting of 377 targets and 4 endogenous. The expression data was analyzed in the Cloud Software (Thermo Fisher Scientific) and Limma (Linear Models for Microarray and RNASeq Data) program. RESULTS: There was no difference in demographic characteristics, such as age, self-reported color, and sex among groups (p > 0.05). Patients with T1D (both recent and 2-5 years), similar to each other, differed from the control group by high glucose, glycated hemoglobin levels, pancreatic autoantibody titers, and lower C peptide values (p < 0.05) . Pancreatic autoantibodies (AbP) carriers had intermediate characteristics among the groups: lower HbA1c and anti-tyrosine phosphatase antibody (anti- IA2) values and higher C-peptide levels than the two groups with diabetes. They differed from controls only by the higher titers of anti-insulin (IAA) and anti-decarboxylase of glutamic acid 65 (anti-GAD65) autoantibodies. The frequency of high risk HLA alleles for diabetes (-DR3 or -DR4 and -DQ2 or DQ- 8) decreased from the recent T1D and T1D 2-5 groups to the AbP and controls. We evaluated 135 miRNAs that were expressed in 20% or more of the samples from the four groups analyzed. Higher expression was observed in 13, 4 and 33 miRNAs of the Abp, recent T1D and T1D 2-5 groups respectively and lower in 11, 7 and 31 miRNAs of these groups. Of these, 4 miRNAs were differentially expressed in the AbP, recent T1D and T1D 2-5 groups in relation to the control group.The miRNAs: miR -16, miR-195 and miR-454, related to endocrine regeneration of the pancreas, anti-inflammatory effect and response to beta-cell injury were decreased in these 3 groups. miR-200a, implicated in beta-cell apoptosis, was increased in the recent and decreased AbP and T1D groups in patients with longer duration of diabetes (T1D 2-5y), possibly due to the shortage of these cells. Another eight miRNAs showed different expression of the control group in two of the evaluated groups, and a similar trend in the third group, four of them high (miR-193a-5p, miR-323-3p, miR-423-5p, and miR- 92a ) and four, decreased (miR-191, miR-19a, miR-376a, miR-590-5p) or neutrality in the 3rd group (miR-15b, miR-100, miR-181a and miR-483-5p) was observed for miR-25 and miR-485-3p, decreased in the AbP group and increased in T1D 2-5y. Such miRNAs are related to immune response, insulin secretion, ?-cell damage and glycotoxicity, similar to that observed for the miR- 101-3p, validated by individual trials in a larger cohort. CONCLUSION Our data suggests that circulating miRNAs may be involved in the pathogenesis of T1D
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Farr, Ryan. "Molecular Markers of Pancreatic β-cell Death." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17308.
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Abstract Loss of insulin-producing β-cells is central to the development of Type 1 diabetes (T1D). Currently, we lack diagnostic tools to quantitate this β-cell loss. Non-protein coding RNAs called microRNAs (miRNAs/miRs) play an important role in islet development and function. Recent detection of miRNAs in peripheral circulation, has renewed interest in microRNA biomarkers of diabetes. Comparably, circulating insulin cell-free (cf)DNA has been proposed as a direct biomarker of β-cell death. DNA methylation studies have identified specific sites within DNA that are unmethylated in β-cells but methylated in other cell types, thus providing a handle to discriminate between cfDNA from β-/non-β-cells. Previous research carried out in the Hardikar lab identified a signature of 20 miRNAs (the ‘RAPID’ signature) with potential as a biomarker of β-cell death. The RAPID signature was revised to accommodate other microRNAs finally constituting a panel of 50 microRNAs (PREDICT T1D panel). An analysis of these 50 miRNAs, as well as insulin cfDNA in serum/plasma from individuals before, during and after clinical diagnosis of T1D is presented. Human islet cell death assays using sodium nitroprusside exposure identified a subset of 27 miRNAs and insulin cfDNA associated with islet cell stress/death. Non-obese diabetic mice (N=32) were found to have elevated candidate miRNAs prior to immune infiltration and glycaemic dysfunction. This trend was also noted in the human progression to T1D; 26 miRNAs were elevated in (N=19) high-risk individuals and those at diagnosis (N=199) but decreased within 6-weeks after diagnosis. Furthermore, candidate miRNAs exhibited differential abundance with disease duration, residual C-peptide, and microvascular complications in 180 subjects with prolonged T1D. At diagnosis, miRNAs and cfDNA associated with GAD III autoantibody titres (N=167 P-values range from 0.044 to <0.0001) and HbA1c levels (N=187, P-values range from 0.047 to 0.00095). Such biomarkers may inform medical researchers as to how to predict the development of T1D, monitor response to interventions such as islet transplantation, vaccines & drugs aiming to retard β-cell loss. In basic research, such an assay may help to select treatments to block β-cell death and guide the development of new treatments to lessen the burden of diabetes.
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Anthony, Yancke. "Identification and validation of micrornas for diagnosing type 2 diabetes : an in silico and molecular approach." University of the Western Cape, 2015. http://hdl.handle.net/11394/4713.
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>Magister Scientiae - MScType 2 diabetes mellitus (T2DM), a metabolic disease characterized by chronic hyperglycemia, is the most prevalent form of diabetes globally, affecting approximately 95 % of the total number of people with diabetes i.e. approximately 366 million. Furthermore, it is also the most prevalent form in South Africa (SA), affecting approximately 3.5 million individuals. This disease and its adverse complications can be delayed or prevented if detected early. Standardized diagnostic tests for T2DM have a few limitations which include the inability to predict the future risk of normal glucose tolerance individuals developing T2DM, they are dependent on blood glucose concentration, its invasiveness, and they cannot specify between T1DM and T2DM. Therefore, there is a need for biomarkers which could be used as a tool for the early and specific detection of T2DM. MicroRNAs are small non-coding RNA molecules which play a key role in controlling gene expression and certain biological processes. Studies show that dysregulation of microRNAs may lead to various diseases including T2DM, and thus, may be useful biomarkers for disease detection. Therefore, identifying biomarkers like microRNAs as a tool for the early and specific detection of T2DM, have great potential for diagnostic purposes. The main focus of this investigation, therefore, is the early detection of T2DM by the identification and validation of novel biomarkers. Furthermore, based on previous studies, the aim of the investigation was to identify differentially expressed miRNAs as well as identify their potential target genes associated with the onset and progression of T2DM. An in silico approach was used to identify miRNAs found to be differentially expressed in the serum/plasma of T2DM individuals. Three publically available target prediction software were used for target gene prediction of the identified miRNA. The target genes were subjected to functional analysis using a web-based software, namely DAVID. Functions which were clustered with an enrichment score > 1.3 were considered significant. The ranked target genes mostly had gene ontologies linked with “transcription regulation”, “neuron signalling, and “metal ion binding”. The ranked target genes were then split into two lists – an up-regulated (ur) miRNA targeted gene list and a down-regulated (dr) miRNA targeted gene list. The in silico method used in this investigation produced a final total of 4 miRNAs: miR-dr-1, miR-ur-1, miR-ur-2, and miR-ur-3. Based on the bioinformatics results, miR-dr-1 and its target genes LDLR, PPARA and CAMTA1, seemed the most promising miRNA for biomarker validation, due to the function of the target genes being associated with T2DM onset and progression. The expression levels of the miRNAs were then profiled in kidney tissue of male Wistar rats that were on a high fat diet (HFD), streptozotocin (STZ)-induced T1DM, and non-diabetic control rats via qRT-PCR analysis. The hypothesis was that similar miRNA expression would be found in the HFD kidney samples compared to serum expression levels of the miRNA obtained from the two databases, since kidneys are involved in cleansing the blood from impurities. This hypothesis proved to be true for all miRNAs except for miR-ur-2. Additionally, miR-ur-1 seemed the most significant miRNA due to it having different expression ratios for T1DM and T2DM (i.e. -7.65 and 4.2 fold, respectively). Future work, therefore, include validation of the predicted target genes to the miRNAs of interest i.e. miR-dr-1: PPARA and LDLR and miR-ur-1: CACNB2, using molecular approaches such as the luciferase assays and western blots.
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F, Mancarella. "MicroRNAs role in type 1 diabetes pathogenesis: a dialogue between pancreatic islets and immune system." Doctoral thesis, Università di Siena, 2019. http://hdl.handle.net/11365/1069077.
Full textAbstract:
Type 1 diabetes (T1D) is a chronic multifactorial autoimmune disease that includes 5-10% of diabetes cases and is characterized by the immune-mediated insulin secreting β cell destruction with consequent loss of β cell mass and hyperglycemia. In autoimmune diabetes, the selective β cell destruction is the result of a series of mechanisms including, but not limiting to autoreactive T cells direct β cell destruction and inflammatory stress, resulting in a dramatic loss of functional β cell mass.
MicroRNAs are small non coding 19-24 nucleotides RNAs that negatively regulate gene expression, binding selectively their mRNAs target and leading to their translational repression and/or degradation. It was also remarked that miRNAs are involved in T1D pathogenesis, by regulating a series of processes both in β cells and lymphocytes that ranged from cell metabolic dysfunction and apoptosis to dedifferentiation and immune molecule secretion. Additionally, it has been suggested that secreted microRNAs can take part in the communication between immune system and pancreatic endocrine cells; therefore, studying such dialogue could help to better understand T1D pathogenesis and to the identification of biomarkers that reflect the diseased status of the target organ.
In order to investigate the role of miRNAs as biomarkers of T1D pathogenesis both at endocrine and immune interface, the study can be subdivided into the following sections:
1) MiRNAs as circulating biomarkers of diseased-target tissue- In this section, miR-409-3p was found downregulated in murine and human plasma of T1D subjects, highlight the importance to find a lymphocyte deriving circulating biomarker that reflect the target organ pathological status.
2) MiRNAs as modulators of β cell function- miR-183-5p was downregulated in pancreatic endocrine tissue of mouse and human diabetic patients, contributing to β cell protection from apoptosis through the modulation of anti-apoptotic factor Bach2 and through the potential induction of a dedifferentiation phenomenon. This study demonstrated that β cells are able to react to stress and to cell damage through a miRNA-mediated protective phenomenon.
3) Secreted/Immune-derived miRNAs as mediators of β cell apoptosis- Exosomes enriched in miR-142-3p/5p and miR-155 and secreted by T autoreactive lymphocytes, induced selective β cell apoptosis, through the modulation of proinflammatory chemokine expression. The selective AAV “Sponge” inactivation of miR-142-3p/5p, miR-150 and miR-155 induced β cell protection of prediabetic NOD mice from the autoimmune attack that occurs in T1D, inducing the reduction of the proinflammatory chemokine CXCL10 specifically in β cells than in α cells. Such study remarked the exosome-mediated communication dynamics between immune system components and endocrine cells in the center of this dialogue, miRNAs give their fundamental contribution and more importantly, as it has already been reported, it’s possible to actively and therapeutically interfere in this dialogue in order to positively change the β cell fate.
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Sharma, G. "Methods for the measurement of urinary biomarkers of oxidative stress application to type 1 diabetes mellitus." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1344091/.
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The principal aim of the study was to develop methods for the measurement of potential urinary biomarkers of oxidative stress using liquid chromatography/tandem mass spectrometry with minimum sample preparation to avoid artefact formation. Initially the development of an assay to measure the urinary concentrations of isoprostanes (8- isoPGF2α) was attempted but this did not prove to be sufficiently sensitive and gave nonreproducible results. An assay to measure the intact sulphate and glucuronide conjugates of urinary metabolites of vitamin E [α-tocopheronolactone (α-TLHQ) and α-carboxy-ethylhydroxychroman (α-CEHC)] was then developed, as it has been suggested that α-TLHQ with an oxidised chroman ring might be an indicator of oxidative stress. A novel method was also developed to quantitate urinary amino acids associated with NO• metabolism (Larginine - precursor, L-citrulline - product, L-ADMA –inhibitor of nitric oxide synthase and L-homocysteine – reduces bioavailability of nitric oxide). This method was extended to quantitate seven additional amino acids. The latter two methods were applied to 32 children with type 1 diabetes and compared with age and sex matched controls. The mean concentrations of all the α-THLQ conjugates were highly significantly increased in the diabetic subjects (p<0.002). The concentrations of the α-CEHC conjugates were also increased but not to the same degree of significance (p<0.05). When the diabetic children were divided into those who were poorly (n=24) and adequately (n=8) controlled, the α- THLQ conjugates remained highly significantly increased (p<0.002) in the poorly controlled group compared to controls. However, the concentrations of the α-CEHC conjugates were not significantly different. The diabetic subjects had a highly significantly increased concentration (p<0.0001) of all the urinary amino acids studied compared to controls. These results suggest that the measurement of urinary α-TLHQ conjugates may provide a useful biomarker of oxidative stress. The clinical relevance of the increased concentrations of urinary amino acids in children with type 1 diabetes requires further investigation.
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Schamarek, Imke [Verfasser]. "Association between biomarkers of subclinical inflammation and nerve conduction in individuals with recently diagnosed type 1 and type 2 diabetes / Imke Schamarek." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2018. http://d-nb.info/117038899X/34.
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Jagannathan, Ram. "Identification of biomarkers for type 2 diabetes : analysis of a primary prevention study among Asian Indians with impaired glucose tolerance." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/32118.
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Primary prevention of type 2 diabetes (T2DM) is an important strategy for curbing its rising global burden. Though lifestyle modification has provided an effective method of preventing/delaying incidence of diabetes in high-risk individuals, it has not been widely implemented even in developed countries due to its high-cost, need for expertise and difficulties in translating the benefits of lifestyle intervention to the community at large. Hence, there is an urgent need to identify an alternate mode of delivery to transmit healthy lifestyle information to high-risk individuals. In this trial, we sought to determine whether lifestyle advice through mobile phone text messaging could reduce incident diabetes compared to standard lifestyle advice in Asian Indian men with prediabetes. The study showed for the first time that mobile phone messaging is an effective and acceptable method to deliver advice and support towards lifestyle modification to prevent T2DM in men at high risk. The identification of novel predictors for T2DM is an arduous task. The glycaemic markers of diabetes (fasting plasma glucose, 2hr post glucose load and HbA1c) are, in fact, risk factors for microvascular complications of diabetes and it was on this basis that diagnostic cut-offs for diabetes were arrived at. Nevertheless, elevated levels of glycaemic markers in the sub-clinical, or pre-diabetic, range are associated with increased risk of progression to diabetes. However, there is already considerable deterioration of beta cell function by the time diabetic dysglycaemia occurs. The way forward is clearly to identify biomarkers that serve as reliable predictors of progression to diabetes rather than simply reflecting accompanying levels of glycaemia. In this thesis using the database of the above mentioned trial it was aimed to identify the predictors of T2DM in Asian Indian cohort with prediabetes at baseline. The classical risk factors studied here are: 1) increased prevalence of the hypertriglyceridemic waist phenotype, 2) a combination of HbA1c and gamma glutamyl transferase and 3) a measure of beta cell compensation (disposition index) predicted incident diabetes. Among these, the disposition index was the most powerful predictor in the cohort. In addition to these classical risk factors mentioned above, in a small nested-case control, cross sectional study, the association of adipokines (adiponectin, leptin, interleukin-6 (IL-6), retinol-binding protein4 (RBP4)) and vitamin D3 were assessed to study the mechanistic link of novel biomarkers with diabetes. In this cohort, lower levels of baseline adiponectin, and higher IL-6 and RBP4 were associated with diabetes. Though, many of these provided a novel mechanistic pathogenic link with diabetes they did not improve prediction over and above that of glycaemic measures in identifying individuals with diabetes. However, the non-glycaemic biomarkers appear to have a role in the underlying pathogenesis of diabetes.
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Oliveira, Ernna Hérida Domingues de. "Vias de regulação da expressão gênica promíscua no timo envolve Aire e microRNAs." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/17/17135/tde-15052014-100817/.
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O timo é um orgão linfóide primário, no qual ocorre a indução da tolerância imunológica central aos antígenos do próprio que são expressos pelos tecidos periféricos (PTAs). A medula tímica é formada por células tímicas medulares epiteliais (mTECs) que expressam centenas desses PTAs que representam virtualmente todos os órgãos e tecidos do corpo. Esse fenômeno foi denominado de expressão gênica promíscua (PGE) a qual é parcialmente regulada pelo modulador da transcrição Autoimmune regulator (Aire). Os precursores de células T oriundos da medula óssea migram para o timo (agora são denominados de timócitos) e na medula desse órgão, passam pela seleção negativa mediada pelas mTECs. As células sobreviventes evoluem para células T maduras e funcionais que migram para a periferia com capacidade de reconhecimento das moléculas de MHC e tolerantes aos PTAs. Além de controlar a transcrição de genes PTAs, Aire também controla a expressão de microRNAs (miRNAs), relacionados com a integridade e funcionalidade do microambiente tímico. A seleção negativa no timo é um processo essencial para a manutenção da autotolerância imunológica e o desbalanço desse processo está associado com o desenvolvimento de doenças autoimunes como, por exemplo, o diabetes mellitus do tipo 1 (DM1).Tendo em vista essas premissas, nosso trabalho se fundamentou em duas hipóteses: 1) Variações na expressão do gene Aire podem perturbar a expressão de genes PTAs e miRNAs no timo, causando alterações na PGE, 2) A expressão balanceada de genes como Aire e/ou PTAs nas mTECs, é fundamental para a integridade da tolerância central. O desbalanço na expressão desses genes, está associado com a emergência do diabetes mellitus tipo 1 no camundongo. Para testar nossa primeira hipótese efetuamos o silenciamento de Aire (Aire knockdown) por meio de eletrotransfeção de RNA interferente (siRNA) anti-Aire in vivo no timo de camundongos BALB/c. Análises do transcriptoma (mRNAs) e miRNoma (miRNAs) das mTECs, revelaram que silenciamento parcial e transitório de Aire foi suficiente para afetar a expressão de PTAs Aire dependentes bem como a de miRNAs. Redes de interação miRNA-mRNA, revelaram que o controle pós-transcricional da PGE também é afetado pelo silenciamento de Aire. Os resultados encontrados revelam que Aire e miRNAs podem formar uma via essencial durante a indução da tolerância central. Para testar nossa segunda hipótese comparamos o transcriptoma de mTECs de camundongos BALB/c (linhagem não-autoimune) com mTECs de camundongos non-obese diabetic NOD (modelo animal utilizado nos estudos de DM1 autoimune). Nossos resultados revelaram que a expressão transcricional de autoantígenos relacionados ao DM1 está desbalanceada em camundongos NOD já numa fase precoce, quando esses animais ainda não apresentavam a doença clínica (fase pré-diabética). Inesperadamente, os níveis transcrionais de Aire apresentaram-se equivalentes no timo dessas duas linhagens, porém os níveis da proteína AIRE estavam reduzidos no timo da linhagem NOD. Esses resultados sugerem a participação de algum mecanismo de atenuação póstrascricional de Aire nessa linhagem provavelmente envolvendo atuação de miRNAs. Isso poderia explicar o desbalanço de PTAs Aire-dependentes e a repressão autoantígenos relacionados ao DM1. Concluímos que nossos resultados, além de abrir novas perspectivas para pesquisas nesta área, contribuem com melhor compreensão dos mecanismos moleculares desencadeados por Aire e por miRNAs no controle da expressão de autoantígenos no timo o que é importante para a tolerância imunológica central.The thymus is a primary lymphoid organ, in which occurs in the induction of central immune tolerance to self peripheral tissue antigens (PTAs). The thymic medulla is formed by medullary thymic epithelial cells (mTECs) expressing hundreds of such PTAs representing virtually all organs and tissues of the body. This phenomenon has been termed promiscuous gene expression (PGE), which is partially regulated by the Autoimmune regulator (Aire) gene. The T cell precursors derived from the bone marrow migrate to the thymus (now termed thymocytes). A part of these thymocytes are eliminated by negative selection mediated mTEC cells. The surviving cells to evolve and functional mature T cells that migrate to the periphery and are capable of recognizing MHC molecules and are tolerant to PTAs. In addition to controlling the transcription of PTA genes, Aire also controls the expression of microRNAs (miRNAs). The negative selection in the thymus is a process essential to the maintenance of immunologic self-tolerance and imbalance of this process is associated with the development of autoimmune diseases such as type 1 diabetes mellitus (DM1) . Given these assumptions, our work was based on two hypothesis: 1) Changes in the expression of the Aire gene can disrupt the expression of PTA genes and miRNAs in the thymus, causing changes in PGE, 2) The balanced expression of Aire / or PTA genes in mTECs is fundamental for central tolerance. The imbalance in the expression of these genes is associated with the emergence of type 1 diabetes in mice. To test our first hypothesis we made Aire silencing (Aire knockdown) through electrotransfection of anti - Aire interfering RNA (siRNA) in vivo in the thymus of BALB/c mice. Analysis of the transcriptome (mRNAs) and miRNome (miRNAs) of mTECs revealed that partial and transient silencing of Aire was enough to affect the expression of Aire - dependent PTAs as well as miRNAs. miRNA -mRNA interaction networks revealed that the posttranscriptional control of PGE is also affected by the silencing of Aire. The results show that Aire and can form an miRNA pathway essential for the induction of central tolerance. To test our second hypothesis we compared the transcriptome of mTECs of BALB/c mice (non-autoimmune strain) with mTECs from non - obese diabetic NOD (animal model used in studies of autoimmune DM1) . Our results indicate that the transcriptional expression of DM1-related autoantigens are unbalanced in NOD mice in an very early stage, when these animals have not had clinical disease (pre-diabetic period). Unexpectedly, the transcriptional levels of Aire in the thymus was equivalent in these two strains, but the AIRE protein levels were reduced in thymus of NOD strain. These results suggest that some mechanism of post-transcriptional attenuation of Aire is acting in this lineage probably involving action of miRNAs . This could explain the imbalance of Aire - dependent PTAs and repression autoantigens related to DM1. Our results open perspectives for research in this area, contributing to better understanding the molecular mechanisms triggered by Aire and miRNAs in control of the expression of autoantigens in the thymus, which is important for the central immune tolerance.
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Walter, Debra L. "Renal Consequences of Coxsackievirus Infection and Type 1 Diabetes in Non-obese Diabetic Mice." Ohio University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1526020616767063.
Full textBook chapters on the topic "MicroRNAs - biomarkers - type 1 diabetes"
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Greco, Marta, Eusebio Chiefari, Maria Mirabelli, Alessandro Salatino, Salvatore Andrea Pullano, Antonio Aversa, Daniela Patrizia Foti, and Antonio Brunetti. "Insights into the World of MicroRNAs." In Biomarkers in Diabetes, 1–20. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-81303-1_34-1.
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Meheissen, Marwa Ahmed. "Markers of Bacterial Translocation in Type 2 Diabetes Mellitus." In Biomarkers in Diabetes, 1–23. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-81303-1_49-1.
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Zeng, Chang, and Wei Zhang. "Epigenetics and 5-Hydroxymethylcytosines as a Biomarker in Type 2 Diabetes." In Biomarkers in Diabetes, 1–18. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-81303-1_26-1.
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Hoong, Caroline Wei Shan. "Measures of Endothelial Function in Type 2 Diabetes: A Focus on Circulatory Biomarkers." In Biomarkers in Diabetes, 1–22. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-81303-1_68-1.
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Januszewski, Andrzej S., and Alicia J. Jenkins. "Assessing Insulin Sensitivity in People with Type 1 Diabetes Without Euglycemic-Hyperinsulinemic Clamps." In Biomarkers in Diabetes, 1–25. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-81303-1_18-1.
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Elfiani, Elfiani, Anggelia Puspasari, and Zulkhair Ali. "Engulfment and Cell Motility Protein (ELMO)-1 as a Biomarker in Type II Diabetes." In Biomarkers in Diabetes, 1–16. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-81303-1_59-1.
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Öztaş, Berrin, Fatma Ceyla Eraldemir, and Hale Maral Kır. "Serum Paraoxonase 1 as a Biomarker: Features and Applications in Type 2 Diabetes Mellitus." In Biomarkers in Diabetes, 1–13. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-81303-1_22-1.
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Januszewski, Andrzej S., and Alicia J. Jenkins. "Assessing Insulin Sensitivity in People with Type 1 Diabetes Without Euglycemic-Hyperinsulinemic Clamps." In Biomarkers in Diabetes, 349–73. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-031-08014-2_18.
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Januszewski, Andrzej S., and Alicia J. Jenkins. "Assessing Insulin Sensitivity in People with Type 1 Diabetes Without Euglycemic-Hyperinsulinemic Clamps." In Biomarkers in Diabetes, 1–25. Cham: Springer International Publishing, 2023. http://dx.doi.org/10.1007/978-3-030-81303-1_18-2.
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Öztaş, Berrin, Fatma Ceyla Eraldemir, and Hale Maral Kır. "Serum Paraoxonase 1 as a Biomarker: Features and Applications in Type 2 Diabetes Mellitus." In Biomarkers in Diabetes, 435–47. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-031-08014-2_22.
Full textConference papers on the topic "MicroRNAs - biomarkers - type 1 diabetes"
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Sarah Akil, Ammira, William Siero, Chi Pang, Fergus Cameron, Justine Ellis, Christine Rodda Rodda, Anne-louise Ponsonby, and Maria Craig. "Children With Type 1 Diabetes, Role Of Pro-inflammatory Cytokines As Disease Biomarkers." In Qatar Foundation Annual Research Conference Proceedings. Hamad bin Khalifa University Press (HBKU Press), 2014. http://dx.doi.org/10.5339/qfarc.2014.hbpp0488.
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Figueroa-crisostomo, Carah A., Ammira Sarah Akil, Andy Ho, Anand Hardikar, Ryan Farr, William Rawlinson, and Maria Craig. "Differentially Expressed Circulating And Cell Associated MicroRNAs In The Investigation Of The Role Of Viral Infection In Type 1 Diabetes." In Qatar Foundation Annual Research Conference Proceedings. Hamad bin Khalifa University Press (HBKU Press), 2014. http://dx.doi.org/10.5339/qfarc.2014.hbpp0482.
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Teixeira, Lívia, Izabela Conceição, Paulo Caramelli, Marcelo Luizon, and Karina Gomes. "ALZHEIMER’S DISEASE AND TYPE 2 DIABETES MELLITUS: COMMON MIRNAS, GENES AND REGULATORY BIOLOGICAL PATHWAYS." In XIII Meeting of Researchers on Alzheimer's Disease and Related Disorders. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1980-5764.rpda066.
Full textAbstract:
Background: The increased incidence of Type 2 Diabetes Mellitus (T2DM) in the 21st century, along with the higher risk of developing Alzheimer’s disease (AD) in diabetic patients have stimulated the search for pathways that link glycemic disorders to neurodegeneration. MicroRNAs (miRNAs) are non-coding RNAs that play key roles in regulating gene expression. Objective: To identify miRNAs, genes and their regulatory pathways in common in AD and T2DM. Methods: Literature search was carried out to find miRNAs commonly expressed in AD and T2DM. MiRTarBase database was used to provide experimentally validated information on the interactions between miRNAs and their target genes. The functional enrichment of molecular pathways differentially regulated by these miRNAs was performed using EnrichR with Reactome gene set annotation. Results: We found six circulating miRNAs commonly expressed in both diseases (hsa-mir-21; hsamir-103a-1; hsa-mir-103a-2; hsa-mir-107; hsa-mir-146a and hsa-mir-144), which regulate 129 target genes. The common pathways between AD and T2DM were related to inflammatory mediators, cell death and axon formation signalling with p-adjust <10-5. Conclusion: Our study provides evidence that AD and T2DM share common pathophysiological mechanisms and regulators miRNAs, and suggests miRNAs as potential markers related to both diseases.