# Sphingolipid and Fatty Acid Biology in Prediabetes and Neuropathy

> **NIH NIH R00** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $249,000

## Abstract

ABSTRACT
Prediabetes – a condition that precedes type 2 diabetes – affects more than 80 million Americans. Peripheral
neuropathy is a diabetic complication that results in a loss of sensation in the limbs due to peripheral nerve
damage, and it can develop in both type 2 diabetic as well as prediabetic patients. Despite the prevalence and
severity of peripheral neuropathy, there are currently no disease-modifying options. Novel therapeutic targets
are therefore of critical importance for future treatments. Dyslipidemia is characterized by increased levels of
saturated fatty acids in the plasma, resulting in altered levels of sphingolipids. Ceramides are one type of
sphingolipid that are lipotoxic to neurons. Accumulation of saturated fatty acids leads to mitochondrial
dysfunction, and cellular apoptosis and may play a central role in the development of peripheral neuropathy.
However, monounsaturated fatty acids protect neurons from ceramide-mediated toxicity in vitro, likely via the
formation of intracellular lipid droplets. Reversal of ceramide accumulation using monounsaturated fatty acid
supplementation may therefore be an effective strategy for normalizing ceramide profiles and preventing
peripheral neuropathy. We hypothesize that peripheral neuropathy in prediabetes is the result of toxic
ceramide accumulation in neurons in vivo. We further hypothesize that supplementing prediabetic mice with
monounsaturated fatty acids will enhance lipid droplet synthesis in neurons to prevent ceramide accumulation
and subsequent neurotoxicity. We will test these hypotheses by: 1) determining the ceramide profile of
prediabetic mice with neuropathy in both plasma and peripheral nerves, 2) evaluating the efficacy of
monounsaturated fatty acid supplementation on ceramide accumulation in prediabetic mice during neuropathy,
and 3) determining the mechanisms by which ceramides damage the peripheral nervous system as well as
determining the mechanisms by which monounsaturated fatty acid ameliorate this damage. Together, these
studies will demonstrate that dyslipidemia plays a central role in the development of peripheral neuropathy and
provide an immediate therapeutic target for future treatments.

## Key facts

- **NIH application ID:** 10476670
- **Project number:** 4R00DK119366-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Amy E. Rumora
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2021-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476670

## Citation

> US National Institutes of Health, RePORTER application 10476670, Sphingolipid and Fatty Acid Biology in Prediabetes and Neuropathy (4R00DK119366-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10476670. Licensed CC0.

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