Comparison of Novel MicroRNA and Cell-Free DNA Biomarkers of Beta-Cell Death and Diabetes Progression

Abstract

Type 1 diabetes (T1D) is characterized by the loss of insulin-producing beta-cells. We currently lack diagnostic tools to measure T1D progression. Using systematic approaches involving unprejudiced discovery analyses in human tissues and clinical samples, we identify microRNAs that are: i) associated with insulin expression during embryonic development (N>60); ii) predictive of and necessary for insulin transcription (N=698); and iii) dysregulated in individuals with (vs. without) T1D (N=200). Insulin cfDNA (assessed by ddPCR) and microRNA (assessed by TaqMan qPCR) biomarkers were measured in around; i) N=400 Australian T1D individuals; ii) N=30 longitudinal samples from children at risk of T1D; iii) N=100 clinical trial samples from individuals receiving IFN-a or Exenatide vs. placebo; iv) N=400 Hong Kong Chinese individuals with T1D; v) N=700 Danish individuals at diagnosis of T1D and vi) N=400 Asian Indian T1D subjects. Among N=600 Australian samples, we identified miRNAs (N=5) that were significantly increased in the circulation of T1D individuals (vs. controls), decreased (at least 2 Fold Change/FC, P<0.05, N=7miRNAs) in T1DCx+ vs. T1DCx- (no T1D complications) or significantly increased (2 FC, P<0.05, N=5) in T1D individuals with detectable C-peptide vs. non-detectable C-peptide. Our studies highlight the potential of circulating microRNAs and cfDNA in quantifying beta cell death before clinical diagnosis of T1D. These data demonstrate that microRNA/cfDNA signatures not only facilitate the potential prediction of diabetes progression, but can also help in stratifying individuals at risk of T1D as well as assess treatment efficacies in trials aiming to retard beta-cell death. We also present our preliminary analysis of cross-ethnic variation in these cfDNA/miRNA biomarkers and present ongoing/future studies to develop a diagnostic test for T1D prediction. Disclosure M. Joglekar: None. R. Farr: None. W. Wong: None. K. Rother: None. A. Jenkins: Research Support; Self; Medtronic, Mylan, Sanofi-Aventis. C.S. Yajnik: None. R.C. Ma: Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp., Pfizer Inc.. Advisory Panel; Self; Boehringer Ingelheim GmbH, Nippon Boehringer Ingelheim Co. Ltd.. M.E. Craig: None. T. Jones: None. A. Hardikar: None.