# Extracellular Vesicles, Insulin Action and Exercise on Vascular Function in Type 2 Diabetes

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $714,984

## Abstract

PROJECT ABSTRACT
Insulin resistance in the vasculature is often linked to obesity and type 2 diabetes (T2D). This occurs prior to
metabolic derangement as evidenced by endothelial dysfunction that, in turn, contributes to the rises in blood
pressure and glucose. However, the mechanism by which vascular dysfunction occurs throughout the
progression from obesity to T2D is unknown. A better understanding of the mechanisms responsible for
differences in vascular function between people with obesity and T2D compared to lean healthy controls can
provide critical mechanistic understandings into disease progression as well as potentially identify novel
therapeutic targets. Extracellular vesicles (EVs) are produced by cells in the body that carry bioactive substances
in the blood to modulate signaling is distant tissues. Based on our preliminary work, not only does insulin promote
greater clearance of EVs, but the reduction relates to metabolic insulin sensitivity, arterial compliance and fuel
utilization. Consistent with this, we have seen that EVs from healthy controls promote vasodilation under insulin
stimulation in contrast to people with obesity that blunt this action via potential miRNA differences. Herein, we
propose overall that insulin acts on extracellular vesicles (EVs) to influence vascular insulin sensitivity. We
hypothesize that insulin will 1) promote EV uptake; 2) activate EV cargo (e.g., insulin signaling/miRNA/eNOS) to
3) foster vasoreactivity of blood vessels in response to insulin. In this longitudinal prospective trial, 40-70y T2D
patients will be matched-paired to adults with lean to obese BMIs with normal glucose tolerance (NGT). Then
people with obesity and T2D will exercise for 16 weeks as a means of testing improved insulin sensitivity with
changes in plasma EVs physiology. First, we will examine how EVs mediate Insulin induced vascular effects
utilizing in-vitro and ex/in-vivo models (AIM 1). Then, we will identify EV cargo as effector of insulin mediated
signaling by performing highly sensitive targeted and unbiased EV RNA and protein cargo analysis (AIM 2).
Lastly, we will ascertain that exercise modulates EV mediated insulin sensitivity (AIM 3). These collective EV
measures will be related to insulin-stimulated arterial stiffness (pulse wave velocity and augmentation index),
and nitric oxide-mediated arterial function in conduit (flow mediated dilation), resistance (post-ischemic flow
velocity) and microvascular (contrast enhanced ultrasound) vessels to translate mechanism to function in
humans. If these hypotheses are correct, they will indicate 1) insulin acts on EVs as a novel mechanism of
vascular function, 2) provide the first indication of whether EVs release cargo to impact endothelial function and
3) showcase a novel mechanism by which exercise contributes to CVD risk reduction. Thus, identification of EV,
insulin action and exercise interactions will lay foundation for improving precision medicine that corrects vasc...

## Key facts

- **NIH application ID:** 10882893
- **Project number:** 1R01DK133598-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Uta Erdbruegger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $714,984
- **Award type:** 1
- **Project period:** 2024-04-25 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882893

## Citation

> US National Institutes of Health, RePORTER application 10882893, Extracellular Vesicles, Insulin Action and Exercise on Vascular Function in Type 2 Diabetes (1R01DK133598-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10882893. Licensed CC0.

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