Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity

Abstract

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.

miRNA-Mediated Immune Regulation in Islet Autoimmunity and Type 1 Diabetes

“…Another study analyzed plasma miRNAs, immune cell subsets, and specific features of T1D and revealed correlations between miRNAs and T1D onset (let7c-5p, let7d-5p, let7f-5p, let7i-5p, miR146a-5p, miR423-3p, miR423-5p), C-peptide levels in the serum (miR142-5p, miR29c-3p), glycated hemoglobin (miR26a-5p, miR223-3p), and ketoacidosis (miR29c-3p). Furthermore, the analysis pointed towards a link between plasma miRNAs and certain immune cell subsets, which was limited to T1D patients (87). In diabetic NOD mice, miR409-3p was reduced in the plasma as well as in islet infiltrates, and miR409-3p levels were associated with insulitis severity.…”

“…Based on the high numbers of miRNAs and their involvement in virtually all biological processes, including immune regulation, multiple studies investigated their biomarker potential in the context of islet autoimmunity and T1D (42,56,66,(85)(86)(87)(88)(89)(90)(91). In contrast to the majority of disease symptoms, biomarkers enable the objectively quantifiable characterization of a disease and its progression.…”

Does microRNA Perturbation Control the Mechanisms Linking Obesity and Diabetes? Implications for Cardiovascular Risk

“…miRNAs are also present in body fluids, such as blood, urine and cerebrospinal fluid [ 29 ], showing stability dictated possibly by their association with either vesicular structures as the extracellular vesicles (EVs) or associated with RNA-binding proteins (Argonaute2 [Ago2]) or lipoprotein complexes (high-density lipoprotein [HDL]) [ 30 ].…”

Diabetes Mellitus and Cardiovascular Risk Assessment in Mothers with a History of Gestational Diabetes Mellitus Based on Postpartal Expression Profile of MicroRNAs Associated with Diabetes Mellitus and Cardiovascular and Cerebrovascular Diseases

“…Asymptomatic carotid stenosis [63], familial hypercholesterolemia and coronary artery disease [64], angina pectoris [65], ischemic dilated cardiomyopathy [66], small and large abdominal aortic aneurysm [61], myocardial ischemia/reperfusion [67,68], diabetes mellitus [14,24,52,54] hsa-miR-26a-5p 3p22.2 12q14.1 [69] Heart failure, cardiac hypertrophy [70], myocardial infarction [51,71,72], ischemia/reperfusion injury [73], pulmonary arterial hypertension [74], T1DM [75], diabetic nephropathy [57] hsa-miR-29a-3p 7q32.3…”

“…Intracranial aneurysms [111], coronary heart disease [112], myocardial infarction [113], myocardial hypertrophy [114], dilated cardiomyopathy [115], pulmonary arterial hypertension [116], acute ischemic stroke [89], ascending aortic aneurysm [49] hsa-miR-145-5p 5q33 Hypertension [117,118], dilated cardiomyopathy [119], myocardial infarction [120,121], stroke [121], acute cerebral ischemic/reperfusion [122], T2DM [24,123], T1DM [52], diabetic retinopathy [124], gestational diabetes mellitus [125] hsa-miR-146a-5p 5q33.3 [126,127] Angiogenesis [128], hypoxia, ischemia/reperfusion-induced cardiac injury [129], myocardial infarction [17], coronary atherosclerosis, coronary heart disease in patients with subclinical hypothyroidism [130], acute ischemic stroke, acute cerebral ischemia [131], T2DM [24,52], T1DM [75], diabetic nephropathy [57] hsa-miR-181a-5p 1q32.1 9q33.3 [132] Regulation of hypertension-related genes [50], atherosclerosis [132], metabolic syndrome, coronary artery disease [133], non-alcoholic fatty liver disease [134], ischaemic stroke, transient ischaemic attack, acute myocardial infarction [135,136], obesity and insulin resistance [62,…”