# Defining the Generation and Cargo of Extracellular Vesicles During the Evolution of Type 1 Diabetes

> **NIH NIH R03** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $204,816

## Abstract

PROJECT SUMMARY/ABSTRACT
Type 1 Diabetes Mellitus (T1D) affects millions of individuals world-wide. Disappointing results of clinical trials
using immunomodulatory drug treatments have identified a critical need for alternative treatment approaches
and earlier identification of T1D, at a time prior to irremediable dysfunction or destruction of pancreatic β cells.
Recent data indicate that intrinsic β cell responses to inflammatory and metabolic stress ultimately impact β
survival, and emerging work suggests that β cell extracellular vesicles (EVs), membrane bound nanoparticles
including exosomes, microvesicles, and apoptotic bodies, play an important role in T1D pathogenesis.
Preliminary data generated as part of the applicant's K08 award demonstrate that β cell and circulating EV
cargo are altered in T1D. Based on this, our central hypothesis is that β cell EVs play a pathophysiologic
role in the development of T1D, with altered EV cargo before and after T1D development. The long-term
goals of this applicant are to define the role of β cell EVs in diabetes pathophysiology and to use changes in
circulating β cell EV cargo as the basis for biomarkers that successfully identify the onset of T1D in prediabetic
individuals. In Specific Aim 1, we will address the underlying mechanism of alterations in EV microRNA cargo
during T1D development by testing the working hypothesis that cytokine-induced increases in β cell
exosome miRNAs are influenced by the ceramide generating enzyme, neutral sphingomyelinase 2. This
hypothesis will be tested using chemical and genetic inhibition and overexpression of this enzyme in clonal
human β cells and islets. In Specific Aim 2, we propose experiments to develop and test β cell-specific EV
targets using both directed and unbiased approaches based on the working hypothesis that proteins specific
to β cells will also be present in β cell EVs, and could therefore allow for selective isolation of β cell EVs. In
addition to careful ex-vivo study of candidate reagents, we will test feasibility of this approach using an in-vivo
xenotransplant model. Completion of these experiments will address an important mechanistic question
regarding β cell EV biology and identify tools that may be harnessed to isolate circulating β cell or islet-derived
EVs. The molecular biology expertise accumulated through experiments and training in the applicant's K08
award and the research environment of the Indiana University Center for Diabetes and Metabolic Diseases
make the applicant uniquely suited to execute the Aims of this proposal. Importantly, this proposal has also
been designed to generate data and resources that the applicant will utilize in an R01 application defining the
physiologic significance and clinical biomarker potential of β cell EV miRNAs during T1D development.

## Key facts

- **NIH application ID:** 9832198
- **Project number:** 5R03DK117253-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Emily K Sims
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $204,816
- **Award type:** 5
- **Project period:** 2018-12-05 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9832198

## Citation

> US National Institutes of Health, RePORTER application 9832198, Defining the Generation and Cargo of Extracellular Vesicles During the Evolution of Type 1 Diabetes (5R03DK117253-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9832198. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*