# Dynamic RNA modifications that control gene expression in diabetes

> **NIH NIH K99** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $88,176

## Abstract

Project Summary
Genetic and environmental factors play important roles in the etiology of diabetes. How these factors interact to
promote disease remains unclear. N6-methyladenosine (m6A) is a dynamic mRNA modification that can direct
splicing fate and stabilization, promote translation of mRNAs, and integrate nutritional information. Drosophila
melanogaster, flies, with lowered levels of m6A in insulin-producing cells (IPCs) are diabetic; this phenotype is
exacerbated by exposure to a nutrient-rich diet. mRNAs that encode proteins in the insulin system are
methylated in the brain of flies. These results suggest that m6A plays a critical role in the insulin system. Yet,
the mechanisms through which m6A contributes to the development of diabetes are unknown. The power of
Drosophila genetics, the anatomy of the IPCs, the relative simplicity of the system, and the recent development
of direct RNA-sequencing will be leveraged to uncover mechanisms through which m6A controls gene
expression in IPCs. The central hypothesis is that reduced m6A in IPCs impairs necessary dynamic
translational control over the insulin system. Aims 1 and 2 (K99) will focus on cell-intrinsic mechanisms that are
sensitive to the loss of m6A regulation. These will uncover cell biological properties that depend on m6A for
proper insulin output. Aims 2 and 4 (R00) will probe cell-extrinsic factors, which require m6A, that integrate
external inputs. These will elucidate how m6A impacts insulin receptor translation and how the levels of m6A
respond to nutritional state. Together, this proposed work will define a role for m6A methylation of mRNA in the
function of IPCs and reveal how metabolic inputs modulate m6A control over mRNAs. This will advance our
understanding of RNA control and may facilitate the discovery of therapeutic targets for diabetes prevention
and therapy.

## Key facts

- **NIH application ID:** 10370792
- **Project number:** 1K99DK128539-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Daniel James Wilinski
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $88,176
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370792

## Citation

> US National Institutes of Health, RePORTER application 10370792, Dynamic RNA modifications that control gene expression in diabetes (1K99DK128539-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10370792. Licensed CC0.

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