tRNA Biology in the Pathogenesis of Diabetes: Role of Genetic and Environmental Factors

Arroyo, María Nicol; Green, Jonathan Alex; Cnop, Miriam; Igoillo-Esteve, Mariana

doi:10.3390/ijms22020496

Cited by 18 publications

(16 citation statements)

References 216 publications

(388 reference statements)

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“…This tRNA is located within an intron of the ULK2 gene. No previous literature supports a role for this particular tRNA in diabetes; however, tRNAs are emerging as a novel group of molecules playing a role in diabetes-related processes such as glucose metabolism, pancreatic β-cell function, obesity and insulin resistance in type 2 diabetes ( 28 ). Dysregulation of amino acids in diabetes is a known phenomenon where for instance glycine has been shown to be reduced in patients with diabetic ketoacidosis ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Small RNAs are differentially expressed in autoimmune and non-autoimmune diabetes and controls

Sørgjerd

Mjelle

Beisvåg

et al. 2022

European Journal of Endocrinology

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Objective Diabetes is a heterogeneous disease and precise diagnosis of diabetes subgroups is necessary to initiate proper early treatment and clinical management of the disease. Circulating small RNAs (sRNAs) are potentially diagnostic biomarkers in diseases, including diabetes. Here we aimed to examine whether profiles of circulating sRNAs differed between patients with autoimmune and non-autoimmune diabetes and non-diabetic controls. Design This cross-sectional case-control study included participants from the third survey of the HUNT study. Methods We performed sRNA sequencing in serum from adult-onset type 1 diabetes (n=51), type 2 diabetes (n=50) and Latent Autoimmune Diabetes in Adult (LADA, n=51), as well as non-diabetic HUNT3 participants as control group (n=51). Differential expression analysis of the sRNAs were performed in R using limma-voom. Results We identified differences in sRNA expression between autoimmune (type 1 diabetes and LADA) and non-autoimmune diabetes (type 2 diabetes) and between patients with diabetes and non-diabetic controls. Focusing on microRNAs (miRNAs), we identified 10 differentially expressed mature miRNAs and 30 differentially expressed miRNA variants (isomiRs). We also identified significant changes within other sRNA classes, including a pronounced up-regulation of a transfer RNA-fragment in patients with diabetes compared to non-diabetic controls. We created cross-validated sRNA signatures based on the significant sRNAs that distinguished patients with diabetes from non-diabetic controls, and autoimmune from non-autoimmune diabetes, with high specificity and sensitivity. sRNA profiles did not distinguish between type 1 diabetes and LADA. Conclusions Circulating sRNAs are differentially expressed between patients with diabetes and non-diabetic controls and between autoimmune and non-autoimmune diabetes.

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Section: Discussionmentioning

confidence: 99%

Small RNAs are differentially expressed in autoimmune and non-autoimmune diabetes and controls

Sørgjerd

Mjelle

Beisvåg

et al. 2022

European Journal of Endocrinology

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show abstract

“…(3) Model fitting was performed using 'lmFit' function of 'limma' [38] to enumerate expression levels of T2D and control groups. (4) Contrasts were defined as 'T2D -control' and 'empirical Bayes' step was run to derive differential expression results (5) The DEG, defined as those with log 2 FC > 1 & Benjamini-Hochberg (BH)-adjusted p < 0.05 for up-regulated genes and log 2 FC < -0.5 & BH-adjusted p < 0.05 for down-regulated genes, were identified for each microarray.…”

Section: Identification Of Degmentioning

confidence: 99%

“…Type 2 diabetes (T2D) is by far the most common, accounting for over 90% of all diabetes cases [2], a condition found to have affected 6.3% (462 million) of the world population as in year 2017 [3]. Current evidence suggests a complex and multifactorial etiology of T2D characterized by genetic and environmental interactions [4], although T2D pathogenesis is not yet fully elucidated. Moreover, there is evidence of varying degrees of shared genetic origins in the pathogenesis of T2D and other diabetes phenotypes such as type 1 diabetes (T1D) [5], latent autoimmune diabetes in adults (LADA) [6], and maturity-onset diabetes of the young (MODY) [7].…”

Section: Introductionmentioning

confidence: 99%

Highly perturbed genes and hub genes associated with type 2 diabetes in different tissues of adult humans: A bioinformatics analytic workflow

Silva

Demmer

Jönsson

et al. 2022

Preprint

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Introduction: Type 2 diabetes (T2D) has a complex etiology which is not fully elucidated. Identification of gene perturbations and hub genes of T2D may assist in personalizing care. Objectives: We aimed to identify highly perturbed genes and hub genes associated with T2D in different tissues of adult humans via an extensive workflow. Methods: Workflow comprised five sequential steps: systematic review of NCBI GEO database; identification and classification of differentially expressed genes (DEG); identification of highly perturbed genes via meta-analysis; identification of hub genes via network analysis; downstream analyses. Three meta-analytic strategies: random effects model (REM); vote counting approach (VC); p-value combining approach (CA), were applied. Nodes having above average betweenness, closeness, and degree in the network were defined as hub genes. Downstream analyses included gene ontologies, Kyoto Encyclopedia of Genes and Genomes pathways, metabolomics, COVID-19 related genes, and Genotype-Tissue Expression profiles. Results: Analysis of 27 eligible microarrays identified 6284 DEG (4592 down-regulated and 1692 up-regulated) within four tissue types. Tissue-specific gene expression was significantly greater than tissue non-specific (shared) gene expression. Meta-analysis of DEG identified 49, 27, and 8 highly perturbed genes via REM, VC, and CA, respectively, producing a compiled set of 79 highly perturbed (41 down-regulated and 38 up-regulated) genes. The 28 hub genes comprised 13 up-regulated, 9 down-regulated, and 6 predicted genes. Downstream analyses identified enrichments of: shared genes with other diabetes phenotypes; insulin synthesis and action related pathways and metabolomics; mechanistic associations with apoptosis and immunity-related pathways, COVID-19 related gene sets; and cell types demonstrating over- and under-expression of marker genes of T2D. Conclusions: We identified highly perturbed genes and hub genes of T2D and revealed their associations with other diabetes phenotypes and COVID-19 as well as pathophysiological manifestations such as those related to insulin, immunity, and apoptosis. Broader utility of the proposed pipeline is envisaged.

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“…We propose a posttranscriptional gene silencing (RNAi) regulation of TCR genes in COVID-19 pathology, which may intersect with tRNA biology pathway enzymes such as tRNA aminoacyl synthetases that are emerging as important players of immuno-metabolic dysregulation and linked to the intergenerational inheritance of metabolic traits in diabetes mellitus [226][227][228].…”

Section: Pro-ferroptotic Labile Iron Pool (Lip) and Rna-binding Prote...mentioning

confidence: 99%

Diabetology: Feature Papers 2021

2022

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tRNA Biology in the Pathogenesis of Diabetes: Role of Genetic and Environmental Factors

Cited by 18 publications

References 216 publications

Small RNAs are differentially expressed in autoimmune and non-autoimmune diabetes and controls

Small RNAs are differentially expressed in autoimmune and non-autoimmune diabetes and controls

Highly perturbed genes and hub genes associated with type 2 diabetes in different tissues of adult humans: A bioinformatics analytic workflow

Diabetology: Feature Papers 2021

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