Abstract
Despite treatment, a significant proportion of patients with type 2 diabetes (T2D) do not experience clinical
improvement (i.e., lack treatment response). In analyses of data from the Restoring Insulin Secretion (RISE)
Study, a randomized controlled trial testing the potential of medical and surgical therapies to improve and
maintain ß-cell function, members of our team have demonstrated substantial heterogeneity in treatment
response at the level of the ß cell using gold standard measures from hyperglycemic clamps. We know little,
however, about contributing factors to heterogeneity of T2D treatment response and lack tools to prospectively
identify treatment responders and non-responders. A major reason for this is lack of circulating biomarkers that
predict or reflect treatment response at the level of the ß cell. Epigenetic regulation of genes important in glucose
and insulin metabolism by short non-coding RNAs such as microRNAs (miRNAs) may mediate improvement or
preservation of ß-cell function with treatment, and circulating miRNAs may be predictive biomarkers of treatment
response. In the ß cell, regulation of gene expression by miRNAs is crucial to both insulin secretion and cell
turnover. In addition, miRNAs secreted into the circulation may reflect tissue-level differences in expression
and/or participate actively in inter-organ crosstalk. While miRNAs in a variety of tissues and in the circulation
have been shown to be altered by exposure to the RISE interventions in humans or in vitro models, effects of
most of these miRNAs in the ß cell are not yet described. Using data and samples from the RISE Pediatric
Medication Study (n=49; R03DK122100; PI Wander), we identified 9 plasma miRNAs that are prospectively
related to treatment response in youth aged 10–19 years including two novel miRNAs, miR-4468 and miR-6727,
which are predicted to regulate islet apoptosis via Bcl-2 like 1 and islet amyloid polypeptide. Our objective is to
characterize miRNAs that are related to preservation or improvement in ß-cell function among adult RISE
participants, defined by clamp-derived measures of ß-cell response paired with insulin sensitivity, after treatment
with medications or gastric banding. To achieve this goal, we propose a two-part study. In Aim 1, we will assay
circulating miRNAs using next-generation sequencing at baseline and after treatment in a nested case-control
sample of treatment responders vs. non-responders in RISE. In Aim 2, we will examine effects of miR-4468, miR-
6727, and miRNAs identified in Aim 1 on ß-cell function, survival, and de-differentiation in gain-of-function in
vitro experiments using locked nucleic acid-based miRNA mimics in human islets. Our overarching hypothesis is
that circulating miRNAs contribute to treatment heterogeneity via effects on insulin secretion and ß-cell survival.
To our knowledge, this project will be the first to directly test the role of treatment-related miRNAs in mediating or
reflecting treatment response. Better understanding of miRNAs as biomarkers of treatment heterogeneity will
facilitate T2D precision medicine by prospectively identifying subgroups likely to benefit from specific treatments
and promote development of targeted interventions to prevent or delay the progression of T2D.
