Circulating microRNAs -192 and -194 are associated with the presence and incidence of diabetes mellitus

Andrea Jaeger,Arnold Von Eckardstein,Handrean Soran,Dimitris Nasias,Nikoleta Charizopoulou,Dimitris Kardassis,Alaa Othman,Heinz Drexel,Christoph H Saely,Lukas Zollinger,Axel Muendlein,Jonathan D Schofield,Ioannis Evangelakos

doi:10.1038/s41598-018-32274-9

Abstract

We sought to identify circulating microRNAs as biomarkers of prevalent or incident diabetes. In a pilot study of 18 sex- and age-matched patients with metabolic syndrome, nine of whom developed diabetes during 6 years of follow-up, an array of 372 microRNAs discovered significantly elevated serum levels of microRNAs -122, -192, -194, and -215 in patients who developed diabetes mellitus type 2 (T2DM). In two cross-sectional validation studies, one encompassing sex- and age-matched groups of patients with T2DM, impaired fasting glucose (IFG) and euglycemic controls (n = 43 each) and the other 53 patients with type 1 diabetes and 54 age- and BMI-matched euglycemic controls, serum levels of miR-192, miR-194, and mi215 were significantly higher in diabetic subjects than in probands with euglycemia or IFG. In a longitudinal study of 213 initially diabetes-free patients of whom 35 developed diabetes during 6 years of follow-up, elevated serum levels of microRNAs 192 and 194 were associated with incident T2DM, independently of fasting glucose, HbA1c and other risk factors. Serum levels of miR-192 and miR-194 were also elevated in diabetic Akt2 knockout mice compared to wild type mice. In conclusion, circulating microRNAs -192 and -194 are potential biomarkers for risk of diabetes.

Highlights

Diabetes is characterized by a relative or absolute lack of insulin that results in hyperglycaemia
By combining a biomarker discovery study with three targeted validation studies, we found elevated serum levels of miR-192, miR-194 and miR-215 associated with the presence of both T1DM and T2DM, and miR-192 and miR-194 associated with the incidence of T2DM
Serum levels of miR-192 and miR-194 were elevated in Akt2−/− mice[28] which have a diabetes-like syndrome due to blocked insulin signaling but not in E3L*CETP mice which develop a diabetes-like syndrome upon fat-overload[27]

Summary

Introduction

Diabetes is characterized by a relative or absolute lack of insulin that results in hyperglycaemia. Previous miRNA expression profiling studies aiming at the identification of novel biomarkers for T2DM, were performed in whole blood[14,15], plasma[16,17,18], serum[19,20], or exosomes[21] Zhu et al.[13] and Villard et al.[22] performed meta-analyses to identify consistently dysregulated miRNAs. Among 18 miRNA profiling studies Zhu et al.[13] identified seven circulating miRNAs (miR-29a, miR-34a, miR-375, miR-103, miR-107, miR-132, miR-142-3p and miR-144) as potential biomarkers of T2DM. Among 18 miRNA profiling studies Zhu et al.[13] identified seven circulating miRNAs (miR-29a, miR-34a, miR-375, miR-103, miR-107, miR-132, miR-142-3p and miR-144) as potential biomarkers of T2DM In their meta-analysis, Villard et al.[22] included eight studies that compared pre-diabetic patients vs control subjects and 14 studies that compared diabetic vs BMI-matched non-diabetic subjects. The current study addresses this gap and aims at identifying circulating miRNAs that are associated with present or incident diabetes

Methods

Results

Conclusion