# Diabetes, glucose metabolism, and neuroplasticity in the vagal complex

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $482,993

## Abstract

Project Summary
Diabetes mellitus is a major health concern, affecting over 30 million people in the United States. Serious
complications resulting from diabetes including include heart disease, stroke, hypertension, blindness, nervous
system damage, and autonomic dysfunction. A major impediment to developing successful diabetes
treatments (versus treating symptoms) is the relative knowledge gap regarding the multifaceted and redundant
systems that are affected by and contribute to control of metabolic homeostasis. This proposal investigates
disease-related plasticity of central neural circuitry controlling autonomic function. Experiments utilize murine
models of type 1 and type 2 diabetes. Second-order viscerosensory neurons in the nucleus tractus solitarius
(NTS) are glucosensors and contribute significantly to autonomic regulation of glucose homeostasis by
signaling integrated visceral and humoral signals to brain areas that directly regulate systemic glucose levels,
including the dorsal motor nucleus of the vagus nerve (DMV), which contains vagal motor neurons. Vagal
motor function is altered in diabetes, leading to autonomic dysregulation, including excess hepatic glucose
production and gastric motility dysfunction. We have found that changes in activity of GABA neurons or altering
glucose pathways in the NTS affect systemic [glucose]. Glutamate and GABA receptors are reorganized, and
synaptic excitation of NTS GABA neurons is persistently increased in the vagal complex after a few days of
hyperglycemia in a model of type 1 diabetes. The majority of GABA neurons in the NTS is responsive to
elevated [glucose], being either excited or inhibited, but glucose-excitatory responses are blunted in diabetic
mice. Vertical sleeve gastrectomy rapidly improves glycemic index in patients and animal models of diabetes,
independent of weight loss; convergent data suggest the brainstem dorsal vagal complex (DVC) is integral to
this response. Electrophysiological recordings from NTS neurons in slices, chemogenetic and pharmacological
manipulation of NTS neuron activity, and direct glutamate and glucose measurements from the NTS of control
and diabetic mice will be used to obtain functional cellular and molecular data relevant to the contribution of the
NTS to glucose metabolism in the streptozotocin-treated mouse and the BKS-db mouse, models of type 1 and
type 2 diabetes, respectively. The broad hypothesis of this proposal is that altered neural function in the vagal
complex reflects a neurogenic component of diabetic pathology. The experiments in this proposal aim to: 1)
Identify cellular outcomes of glucose responsiveness in the caudal DVC associated with diabetes; 2);
Determine effects of DVC manipulation on systemic glucose metabolism; and 3) Determine effects of bariatric
surgery on diabetes-related neuroplasticity in the vagal complex. Results will guide future development of
novel disease-modifying therapies, based on modulating specific neural funct...

## Key facts

- **NIH application ID:** 9917092
- **Project number:** 1R01DK122811-01A1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Bret N Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $482,993
- **Award type:** 1
- **Project period:** 2020-04-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917092

## Citation

> US National Institutes of Health, RePORTER application 9917092, Diabetes, glucose metabolism, and neuroplasticity in the vagal complex (1R01DK122811-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9917092. Licensed CC0.

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