Post-transcriptional markers associated with clinical complications in Type 1 and Type 2 diabetes mellitus

Massaro, Juliana Doblas; Polli, Claudia; Silva, Matheus Costa e; Alves, Cléber R.; Passos, Geraldo A. S.; Sakamoto-Hojo, Elza T.; Miranda, Wallace Rodrigues de Holanda; Cézar, Nathalia Joanne Bispo; Rassi, Diane Meyre; Crispim, Felipe; Dib, Sérgio Atala; Foss‐Freitas, Maria Cristina; Pinheiro, Daniel Guariz; Donadi, Eduardo Antônio

doi:10.1016/j.mce.2019.03.008

Cited by 46 publications

(32 citation statements)

References 69 publications

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“…Liu et al measured miRNA profiles in the mononuclear cells collected from 63 diabetic patients with or without complications. The study confirmed that miR-125a-5p, miR-145-3p, miR-99b-5p, and miR-873-5p were enriched in peripheral blood mononuclear cells, and the targeted gene families of these miRs were associated with DN (22). A comprehensive study on the serum miRNA profile of type 1 diabetes patients with DN revealed that serum miR-518d-3p and miR-618 were upregulated compared to diabetic patients without DN (23).…”

Section: Mirnas and Microvascular Dysfunctionsupporting

confidence: 56%

“…In the context of diabetes, hyperglycemia, hypoxia, and inflammation affect miRNA biogenesis and release. Consequently, these alterations in the miRNA profile are associated with multiple microvascular complications (20)(21)(22)(23). Of note, a significant portion of miRNAs was found to be specifically packaged into extracellular vesicles that express cell-type-specific proteins to mediate their different functions (24).…”

Section: Function Of Micrornasmentioning

confidence: 99%

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Emerging Roles of microRNAs as Biomarkers and Therapeutic Targets for Diabetic Neuropathy

et al. 2020

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Diabetic neuropathy (DN) is the most prevalent chronic complication of diabetes mellitus. The exact pathophysiological mechanisms of DN are unclear; however, communication network dysfunction among axons, Schwann cells, and the microvascular endothelium likely play an important role in the development of DN. Mounting evidence suggests that microRNAs (miRNAs) act as messengers that facilitate intercellular communication and may contribute to the pathogenesis of DN. Deregulation of miRNAs is among the initial molecular alterations observed in diabetics. As such, miRNAs hold promise as biomarkers and therapeutic targets. In preclinical studies, miRNA-based treatment of DN has shown evidence of therapeutic potential. But this therapy has been hampered by miRNA instability, targeting specificity, and potential toxicities. Recent findings reveal that when packaged within extracellular vesicles, miRNAs are resistant to degradation, and their delivery efficiency and therapeutic potential is markedly enhanced. Here, we review the latest research progress on the roles of miRNAs as biomarkers and as potential clinical therapeutic targets in DN. We also discuss the promise of exosomal miRNAs as therapeutics and provide recommendations for future research on miRNA-based medicine.

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Section: Mirnas and Microvascular Dysfunctionsupporting

confidence: 56%

Section: Function Of Micrornasmentioning

confidence: 99%

Emerging Roles of microRNAs as Biomarkers and Therapeutic Targets for Diabetic Neuropathy

et al. 2020

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“…Technological advances in the past decade have made it possible to generate high-throughput omics data in a large number of human samples, which has led to reports describing signatures of insulin resistance and T2D in serum proteomic [8,9] and metabolomic [10][11][12][13][14] data that in some cases mirror insulin resistance-associated patterns in the gut microbiota [15]. By contrast, largescale transcriptomics studies in the context of prediabetes and T2D are lacking, as transcriptomic studies for T2D have mainly focused on key T2D tissues such as pancreatic islets [16][17][18][19], skeletal muscle [20] and adipose tissue [21] that are not easily accessible, and those focusing on blood have been limited to small cohorts (n < 100) [22][23][24][25][26][27][28]. A recent study described whole blood transcriptomics associations with HbA1c levels in T2D patients [29], but it is still unknown if similar associations exist in people at risk but yet free of diabetes.…”

Section: Introductionmentioning

confidence: 99%

Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study

et al. 2020

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Background The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D. Methods Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts. Results We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling. Conclusions Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.

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“…According to 2 independent studies carried out by Liu et al [ 15 ] and Wei et al [ 16 ], miR-181a-5p has the ability to reduce endoplasmic reticulum (ER) stress through glucose-regulated protein, 78 kDa (GRP78), which is a major ER chaperone and signaling regulator and has been identified as a target of miR-181a-5p. As to miR-143-3p, the correlations of its overexpression and diabetes have been proved by Massaro et al [ 17 ] and Dahlman et al [ 18 ]. In the light of previous studies, miR-143-3p can inhibit tumor cell proliferation, migration, and invasion in many different malignant tumors, such as melanoma [ 19 ], osteosarcoma [ 20 ], and lung cancer [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Differentially Expressed miRNAs and mRNAs Reveals That miR-181a-5p Plays a Key Role in Diabetic Dermal Fibroblasts

Liu

Zhu

et al. 2020

Journal of Diabetes Research

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A diabetic nonhealing wound causes heavy economic burden and compromised quality of life in patients. The human dermal fibroblast (HDF), which is an important kind of effector cell in the wound healing process, represents different biological behaviors in the normal and diabetic skins. Given this, we attempt to explore functional changes in diabetic skin-derived HDFs and try to find out the “hub” genes that modulate diabetic HDFs and may be the potential therapeutic targets of diabetic wound healing. We searched the GEO database for related miRNA (GSE68185, GSE84971) and mRNA (GSE49566, GSE78891) profiles. After eliminating batch effects and identifying differentially expressed genes (DEGs), we applied enrichment analyses and found that 3 miRNAs and 30 mRNAs were differentially expressed in diabetic HDFs. Enrichment analyses showed that these genes are closely related to wound healing, for example, extracellular matrix (ECM) organization, angiogenesis, cell proliferation, and migration. Subsequently, we constructed the gene correlation network of DEGs to identify hub genes by merging the protein-protein interaction network, weighted gene coexpression network, and predicted miRNA-mRNA regulatory network. Based on the gene correlation network, we identified the top 3 hub genes: miR-181a-5p, POSTN, and CDH11. Among these, POSTN is a predicted target of miR-181a-5p and is supposed to work together with CDH11 as a functional group. Finally, we verified the expression pattern of the hub genes by in vitro quantification experiments in glucose-cultured HDFs. Our study suggested that miR-181a-5p possibly plays a key role in modulation of HDF behaviors during the diabetic state. However, the effects and mechanisms of miR-181a-5p in high glucose-cultured HDFs remain to be explored in the future.

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Post-transcriptional markers associated with clinical complications in Type 1 and Type 2 diabetes mellitus

Cited by 46 publications

References 69 publications

Emerging Roles of microRNAs as Biomarkers and Therapeutic Targets for Diabetic Neuropathy

Emerging Roles of microRNAs as Biomarkers and Therapeutic Targets for Diabetic Neuropathy

Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study

Comprehensive Analysis of Differentially Expressed miRNAs and mRNAs Reveals That miR-181a-5p Plays a Key Role in Diabetic Dermal Fibroblasts

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