# Harnessing Innervation to Promote Pancreatic Islet Function

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $383,750

## Abstract

The three components of the peripheral autonomic nervous system, the parasympathetic, sympathetic and
sensory nerves, work together to prevent life-threatening fluctuations in glucose homeostasis. They do so in
part by regulating insulin secretion from the pancreatic islet. Stimulating autonomic nerves with electrodes has
recently been recognized as a potential way to treat diseases (neuromodulation). Given its central role in
glucose metabolism and diabetes, the pancreatic beta cell is considered a primary target for neuromodulation.
To propose electrical stimulation of nerves to treat diabetes, however, it is essential to understand how islet
nerves impact insulin secretion from the beta cell. The objective of this application is to determine the
mechanisms nerves use to control insulin secretion. Recent anatomical studies show that sympathetic and
sensory nerves innervate the human islet, but parasympathetic innervation is sparse. Importantly, these nerves
do not contact beta cells directly but densely innervate the islet vasculature. We therefore hypothesize that
autonomic nerves control blood flow and vascular permeability to adjust insulin release into the bloodstream.
The rationale for the proposed research is that these mechanisms of nerve action could be intervention targets
for neuromodulation in human beings, which is relevant to the mission of the NIH. Guided by preliminary data,
our hypothesis will be tested by pursuing two specific aims: (1) determine the functional role of sympathetic
innervation for insulin secretion, and (2) determine the functional role of sensory nerves for insulin secretion.
Under the first aim, we will test that sympathetic nerves target vascular pericytes to change blood flow. We will
transplant human and mouse islets into the eye of diabetic mice. In the eye, islet grafts restore normoglycemia
and can be monitored non-invasively. Importantly, islet grafts are revascularized and reinnervated in patterns
that resemble those of islets in the pancreas. We will stimulate, inhibit, and ablate sympathetic input to islet
grafts and determine the effects on islet blood flow and simultaneously measure the effects on insulin plasma
levels and glycemia. We will also test whether chronic activation of sympathetic nerves prevents the
derangement of islet vasculature in mouse models of type 2 diabetes. Under the second aim, we will test that
sensory nerves respond to local perturbations in the islet microenvironment to change the vascular
permeability. To determine what activates sensory nerves in the islet, we will use mice that express functional
indicators in sensory neurons and measure activity in nerve terminals in the islet in living pancreas slices and
in vivo in neuronal cell bodies of the nodose ganglion after stimulating or injuring the islet. We will also activate
sensory nerve chronically to test the impact on islet health in mouse models of type 2 diabetes. The proposed
research is significant because the res...

## Key facts

- **NIH application ID:** 9903290
- **Project number:** 5R01DK113093-04
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Alejandro Caicedo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,750
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903290

## Citation

> US National Institutes of Health, RePORTER application 9903290, Harnessing Innervation to Promote Pancreatic Islet Function (5R01DK113093-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9903290. Licensed CC0.

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