# Potential mechanism underlying parasympathetic neuronal dysfunction in diabetes

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $603,326

## Abstract

Project Summary
Diabetes-induced imbalance of autonomic efferent neuronal tone (reduced parasympathetic activity and
increased sympathetic activity) is involved in sudden cardiac death and is responsible for high mortality in
diabetic patients. Increasing cardiovascular vagal tone significantly reduces the mortality. Although
cardiovascular vagal function is severely damaged in diabetic patients, the potential mechanisms concerning
reduced cardiovascular vagal function in diabetes are poorly understood. Cardiovascular postganglionic vagal
neurons in intracardiac ganglia modulate the acetylcholine release via producing cell excitation and finally
regulate cardiovascular function. Our previous studies have shown that nicotinic acetylcholine receptor (nAChR)
currents and cell excitability are reduced in vagal neurons, which contribute to cardiovascular vagal dysfunction
in type 2 diabetes mellitus (T2DM). Based on our previous studies and preliminary data, we hypothesize that
leptin resistance-uncoupling protein 2 (UCP2)-hydrogen peroxide (H2O2) signaling pathway and norepinephrine-
α1 adrenergic receptor-UCP2-H2O2 axis inactivate nAChR channels and further contribute to cardiovascular
vagal dysfunction in T2DM. Using multi-faceted technical approaches (from whole animals to cellular-molecular
levels) in sham and high-fat diet/low-dose streptozotocin-induced T2DM rats, we design in vivo and in vitro
studies to verify above hypotheses. In Specific Aim 1, we will measure if H2O2 overproduction in vagal
postganglionic neurons decreases nAChR currents and induces cardiovascular vagal dysfunction in T2DM. In
Specific Aim 2, we will test if leptin/leptin receptors influence nAChR currents and cardiovascular vagal function
in T2DM. In Specific Aim 3, we will determine if sympathetic neurotransmitter norepinephrine-α1 adrenergic
receptor axis reduces nAChR currents and cardiovascular vagal function in T2DM. These studies will further our
understanding of the cellular and molecular mechanisms underlying the impairment of vagal neuronal function
in T2DM and will discover potential therapeutic targets for improving cardiovascular vagal function and reducing
mortality in the T2DM state.

## Key facts

- **NIH application ID:** 10800306
- **Project number:** 1R01HL168500-01A1
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Yu-Long Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $603,326
- **Award type:** 1
- **Project period:** 2024-02-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800306

## Citation

> US National Institutes of Health, RePORTER application 10800306, Potential mechanism underlying parasympathetic neuronal dysfunction in diabetes (1R01HL168500-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10800306. Licensed CC0.

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