Molecular markers of beta-cell mortality — ASN Events
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  3. Molecular markers of beta-cell mortality

Molecular markers of beta-cell mortality (#204)

Ryan J Farr 1 , Mugdha V Joglekar 1 , Andrzej S Januszewski 1 , Ammira S Akil 2 , Caroline J Taylor 3 4 , Virginia Cotta 3 4 , Maria Craig 2 , Alicia Jenkins 1 , Anandwardhan A 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

The loss of insulin-producing (beta) cells is central to the development of Type 1 diabetes (T1D). Beta-cell death occurs months to years prior to clinical T1D. Currently, we lack tools to quantitate beta-cell loss prior to T1D onset.

Circulating microRNAs (miRs) and cell-free (cf)DNA are increasingly recognised as biomarkers of disease progression, including T1D. We have optimised protocols to quantitate circulating miRs (ultra-high throughput qPCR1) and cell-free insulin DNA using methylation-specific plasmids on digital droplet PCR (ddPCR). Our initial islet miR-profiling studies (NGS/qPCR validation) identified 50 miRs with potential to predict T1D progression. We hypothesise that these miRs and insulin cfDNA correlate with beta-cell death and diabetes progression.

This cross-sectional study used plasma from a cohort of 180 T1D individuals (average T1D duration of 20±13yrs), including 58 with microvascular diabetes complications (T1DCx+), and 138 age and gender‑matched controls. C-peptide was measured using ultra-sensitive ELISA. Data were analysed using t-test, ANOVA or Spearman correlation as appropriate.

Several (10-14%) miRs were dysregulated in circulation of T1D individuals versus controls (with or without Cx and/or detectable c-peptide). Eight (16%) miRs positively correlated (P<0.05) with C-peptide levels in T1D (no correlation in controls). Two (4%) miRs inversely correlated (P<0.05) with T1D onset. Nine (18%) miRs inversely correlated (P<0.05) with T1D duration. Nine (18%) miRs had significantly lower abundance in subjects with T1D duration >20yrs compared to ≤20yrs. Table 1 summarises the major miRNA findings. I will also present our current analyses on the potential application of insulin cfDNA in predicting diabetes progression.

Our studies highlight the potential of circulating miRs and cfDNA in quantifying beta-cell mortality.  We show that as beta-cells are lost in established diabetes (reduction in C-peptide) there is a reduction of released miRs.  These miRNAs and insulin cfDNA are robust molecular markers of beta-cell death in Type 1 diabetes.  

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  1. Farr RJ, Januszewski AS, Joglekar MV, Liang H, McAulley AK, Hewitt AW, et al. A comparative analysis of high-throughput platforms for validation of a circulating microRNA signature in diabetic retinopathy. Sci Rep. 2015;5:10375.
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