# Circulating miRNA Signatures of Beta-Cell Response to Metformin or Insulin in Youth with Dysglycemia

> **NIH NIH R03** · UNIVERSITY OF WASHINGTON · 2020 · $77,750

## Abstract

ABSTRACT
Youth with prediabetes (impaired glucose tolerance) or type 2 diabetes (T2D) experience relatively rapid
beta-cell failure that is not prevented or delayed by metformin or insulin. Mechanisms underlying the
fulminant course of T2D and the lack of preventive benefit from metformin and insulin in youth are
unknown. Epigenetic biomarkers such as microRNAs (miRNAs) regulate genes important in glucose and
insulin metabolism and may play a role in mediating responsiveness to metformin or insulin. miRNAs are
short non-coding RNAs that regulate expression of genes important to glucose homeostasis, but their role in
systemic responses to metformin and insulin is poorly understood, especially in youth. Our objective is to
identify circulating miRNAs related to insulin resistance and beta-cell failure despite pharmacotherapy in
youth. To achieve this goal, we propose a secondary analysis of the Restoring Insulin Secretion (RISE)
Pediatric Mediation Study, a randomized controlled trial of glargine insulin followed by metformin or
metformin alone in youth ages 10–19 with dysglycemia. We will assay circulating miRNAs using RNA
sequencing (at baseline and at the end of the 12-month intervention) and fit regression (logistic and
generalized linear) models to identify miRNAs related to metformin and insulin response. The overarching
hypothesis of this application is that circulating miRNA profiles (reflecting tissue-specific miRNA changes)
contribute to progression of beta-cell failure and insulin resistance during treatment with metformin and/or
insulin in youth with dysglycemia. We will test the following aims: (1) To identify baseline circulating
miRNAs associated with improvement or worsening in beta-cell function (insulin sensitivity-
adjusted steady-state C-peptide and acute C-peptide response to arginine at maximal glycemic
potentiation [ACPRmax]) and insulin sensitivity (mean glucose infusion rate divided by mean
steady-state plasma insulin concentration [M/I]) at 12 months in youth with prediabetes or early T2D
after a 12-month intervention with glargine + metformin or metformin alone (n=32) and (2) to identify
changes in circulating miRNAs (between baseline and month 12) associated with improvement or
worsening in beta-cell function and insulin sensitivity at 12 months in youth with prediabetes or
early T2D after a 12-month intervention with glargine + metformin or metformin alone (n=32).
Successful completion of the proposed work will identify circulating miRNAs related to progression of beta-
cell failure and insulin resistance in youth. In addition, it will provide necessary pilot data that will inform
design of larger studies to determine the epigenetic mechanisms contributing to progression of beta-cell
failure and insulin resistance despite treatment with insulin and/or metformin in youth with prediabetes and
early T2D. Identifying epigenetic mechanisms of metformin and insulin failure is a critical next step in the
development of novel t...

## Key facts

- **NIH application ID:** 9975159
- **Project number:** 5R03DK122100-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Pandora Luke Januszewski
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $77,750
- **Award type:** 5
- **Project period:** 2019-07-10 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975159

## Citation

> US National Institutes of Health, RePORTER application 9975159, Circulating miRNA Signatures of Beta-Cell Response to Metformin or Insulin in Youth with Dysglycemia (5R03DK122100-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975159. Licensed CC0.

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