# Diabetic Cardiomyopathy and Protection by Hypothalamic Parasympathetic Neuron Activation

> **NIH NIH P20** · UNIVERSITY OF HAWAII AT MANOA · 2024 · $273,875

## Abstract

PROJECT SUMMARY / ABSTRACT – Research Project Leader: Kathryn Schunke, PhD
Diabetic Cardiomyopathy and Protection by Hypothalamic Parasympathetic Neuron Activation
Cardiac autonomic neuropathy (CAN) is a serious complication of type 2 diabetes mellitus (T2DM) that is strongly
associated with approximately five-fold increased risk of cardiovascular mortality. CAN manifests as a decline in
parasympathetic tone and overactivation of sympathetic activity than contributes to resting tachycardia and fixed
heart rate, to development of myocardial infarction. Although it is a common complication, very little is known
regarding how CAN directly increases the risk for myocardial injury and disease, and thus there are no current
unified treatment algorithms other than life style changes, glycemic control and management of cardiovascular
risk factors. We have recently identified a novel mechanism for restoring cardio-protective parasympathetic tone
to the heart to reduce myocardial damage in diseases with similar autonomic dysfunction, such as heart failure,
myocardial infarct and sleep apnea. Brainstem parasympathetic cardiac vagal neurons (CVNs) receive powerful
excitation from a population of oxytocin (OXT) neurons that originate in the paraventricular nucleus of the
hypothalamus (PVN). These unique neurons co-release OXT and enhance excitatory glutamatergic
neurotransmission to CVNs. Based upon our novel results in diseases with similar autonomic imbalances, our
overall hypothesis is that PVN OXT neuron activation will restore diminished parasympathetic activity and
reverse the deleterious hypothalamic, brainstem and cardiac alterations that occur in an animal model of T2DM.
This overarching hypothesis will be tested in two Specific Aims. Aim 1 will determine how T2DM alters cardiac
function and autonomic tone, and determine if activation of PVN OXT neurons reverses these deleterious effects.
In-vivo studies using telemetry instrumented rats will test the hypothesis that T2DM reduces cardiac function
(quantified by echocardiography) and exercise tolerance, increases incidence of arrhythmia, and reduces heart
rate recovery, and that PVN OXT stimulation will reverse these deleterious effects. Additional assessments of
myocardial atherosclerosis, inflammation and fibrosis will probe potential mechanisms of loss-of-function and
arrhythmogenesis. Insulin resistance, glucose tolerance and food intake will be assessed in parallel and
correlated with disease progression and therapeutic regression. Aim 2 will characterize regulome underpinnings
of T2DM mediated CAN by identifying the molecular phenotype of autonomic imbalance. We will test the
hypothesis that T2DM alters gene expression of key pathways involved in maintaining mitochondrial metabolism,
antioxidant defense, nitric oxide signaling, and neurotrophic growth in both PVN OXT neurons and CVNs, which
can be reversed by PVN OXT activation. This will be accomplished using 10x Genomics Spatial Transcriptomic...

## Key facts

- **NIH application ID:** 10850472
- **Project number:** 2P20GM113134-06A1
- **Recipient organization:** UNIVERSITY OF HAWAII AT MANOA
- **Principal Investigator:** Kathryn Jaques Schunke
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $273,875
- **Award type:** 2
- **Project period:** 2017-08-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10850472

## Citation

> US National Institutes of Health, RePORTER application 10850472, Diabetic Cardiomyopathy and Protection by Hypothalamic Parasympathetic Neuron Activation (2P20GM113134-06A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10850472. Licensed CC0.

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