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Predicting islet cell death using miRNAs: small molecules giving big insights. (#157)

Ryan Farr 1 , Mugdha V Joglekar 1 , Ammira Akil 2 , Andrzej Januszewski 1 , Caroline Taylor 3 4 , Virginia Cotta 3 4 , Maria Craig 2 , Alicia Jenkins 1 , Anandwardhan Hardikar 1
  1. NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
  2. Virology Research Laboratory, POW and UNSW Research Laboratories, Randwick, NSW, Australia
  3. Australian Catholic University, Melbourne, VIC, Australia
  4. O'Brien Institute, Melbourne, VIC, Australia

Death of insulin-producing beta cells is a common feature of type 1 diabetes (T1D), as well as islet transplantation, Latent Autoimmune Diabetes of Adults (LADA) and type 2 diabetes (T2D). This cell death is a slow process that commences several months-years prior to clinical onset of T1D. We currently lack tools to quantitatively detect this cell loss, or to predict the progression of established T1D.

The contents of beta cells, including microRNAs (miRNAs), are released into the extracellular milieu upon their death. MicroRNAs, a class of small non-coding (nc)RNAs, are promising biomarkers as i) some of these are significantly altered in circulation between individuals with or without diabetes, ii) show high stability in blood, iii) offer ease of detection and iv) are resistant to freeze-thaw degradation.

We identified a set of ncRNAs that are either enriched in beta cells or differentially expressed in individuals with diabetes. This set of ncRNAs, which we call the RAPID signature (RNA-based Analysis for Predicting Islet Death) can potentially predict beta cell death during diabetes progression.

We performed a robust comparison of multiple micro- and nano-fluidics qPCR platforms to ascertain the preferred technology for miRNA profiling. The OpenArray™ (OA) system was the most reproducible of those tested (median assay CV 2.1%) and best correlated (R2=0.88) with the standard 96-well platform (ViiA7™). Next Generation Sequencing and qPCR studies on developing human pancreases and adult islets found 20 miRNAs that are enriched during pancreas development and remain highly expressed in adult islets. Twenty four other miRNAs were differentially expressed (fold change>2, P-value<0.05) in individuals with newly diagnosed or established T1D, compared to age and gender matched controls (Figure 1). Validation of these miRNAs in multiple T1D individuals (vs controls) will refine the RAPID signature into a minimal set of miRNAs that can reliably measure beta cell death and diabetes progression.

Our studies will aid medical researchers and clinicians in predicting the development of T1D, monitoring responses to interventions that aim to retard or reverse beta cell loss, and also guide the development of new treatments to lessen the burden of diabetes.

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