# Painful Versus Insensate Diabetic Neuropathy

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2022 · $404,337

## Abstract

Project Summary
 Patients with prediabetes and diabetes are at an elevated risk for diabetic peripheral neuropathy (DPN).
DPN primarily affects the distal limbs and is associated with pain, loss of sensation, gait abnormalities and
reduced quality of life. This renewal will focus on a dietary intervention using a ketogenic diet (KD) to prevent
and reverse symptoms of DPN. Consumption of a KD results in elevated ketone bodies, with beta-
hydroxybutyrate (bOHB) and acetoacetate as key mediators. Generated by the liver, ketone bodies can be used
directly by non-hepatic cells, such as neurons, as an alternative fuel source to glucose or in a signaling capacity.
Axon degeneration in DPN, particularly small fibers, leads to reduced epidermal innervation for which there are
currently no clinical treatments. The metabolic and energetic status of sensory axons contributes to axon loss,
and the addition of ketone bodies as a fuel source could be an important modulator of cellular energy and
metabolic function. Pain is a major contributor to decreased quality of life in patients with DPN, which is
compromised by a lack of effective clinical treatments. Our overall hypothesis is that ketone bodies improve
features of DPN through actions directly on sensory neurons. We will test our hypothesis using dietary
interventions in mouse models of prediabetes and diabetes, as well as incorporate a Cre-lox mouse model
lacking the ability to utilize ketone bodies in sensory neurons (advCre-SCOT-/- mice) to determine whether direct
effects of ketones on peripheral sensory neurons drive these beneficial effects. Aim 1 will test whether ketone
bodies act directly on sensory neurons to stimulate axon growth in DPN. Experiments will include both in vitro
and in vivo assessment of axon growth as a result of a KD, and explore cellular signaling pathways involved in
axon guidance, energy signaling pathways, and mitochondrial function. Aim 2 will test whether ketone bodies
reduce pain (mechanical allodynia) in DPN by scavenging MGO. Experiments will incorporate ex vivo
electrophysiology to identify response and firing properties of identified sensory neurons in settings of MGO and
a KD. Additional experiments will test whether a KD has similar anti-nociceptive action in a chemotherapy-
induced neuropathy model where changes in metabolism do not play a role. Results from these studies will fill
an important gap in DPN research by providing new information about how a KD can improve neuronal
metabolism and stimulate axon growth. These results will identify interventions that could be developed for pain
control in DPN, including new mechanisms related to MGO toxicity.

## Key facts

- **NIH application ID:** 10367801
- **Project number:** 2R01NS043314-16
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Douglas E Wright
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $404,337
- **Award type:** 2
- **Project period:** 2003-01-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367801

## Citation

> US National Institutes of Health, RePORTER application 10367801, Painful Versus Insensate Diabetic Neuropathy (2R01NS043314-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10367801. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*