# NAD+ and SIRT1 Regulate Mitochondrial Function in Diabetic Neuropathy

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $115,875

## Abstract

PROJECT SUMMARY/ABSTRACT
The rationale for this proposal is that there is currently no specific medication that prevents or reverses
diabetic neuropathy in humans and this is a major gap in scientific knowledge. Oxidative stress and
mitochondrial (Mt) dysfunction are recognized as important causative factors in neurodegenerative disease
and in diabetic neuropathy. Our central hypothesis is that nicotinamide riboside (NR) and nicotinamide
mononucleotide (NMN) are precursors that in the presence of nicotinamide mononucleotide
adenylyltransferase 2 (Nmnat2) increase tissue NAD+ levels in the peripheral nervous system. This in turn
activates SIRT1, and in turn downstream transcription factors, which differentially regulate specific Mt
complexes to optimize Mt respiration and prevent Mt degeneration. Our objectives are to determine if NR or
NMN can be used as a therapy for experimental diabetic neuropathy, determine if the SIRT1- PGC-1α
signaling pathway provides molecular targets for treatment of neuropathy, identify potential Mt respiratory
chain targets that may respond to treatment, determine if the axonal enzyme that converts NMN to NAD,
Nmnat2, is present in regenerating axons in skin biopsies from diabetic animals and human subjects and if
measurement of Nmnat2 may be useful as a marker for response to NR. In the Methods, we will use a variety
of molecular, electrophysiology, and pathology tools to achieve the aims of the study. Animal models of type 1
and 2 diabetes will be used to determine the effect of NAD+ and SIRT1 overexpression on neuropathy. In
isolated Mt or whole DRG neurons we will manipulate NAD+ and SIRT1 to assess the effect on overall Mt
function and specific Mt respiratory complexes. Nmnat2 levels will be determined in control and age and
gender matched skin biopsies from subjects with different severity of diabetes and diabetic neuropathy. The
preliminary findings support the overall objectives of the proposal and provide promising evidence that NR
and NMN would provide a potential therapy for diabetic neuropathy and that NAD+ activation of the SIRT1-
PGC-1α signaling pathway is important in regulating Mt respiration. The status of the project based on our
recent manuscripts shows that PGC-1α has a key role in regulating Mt function in diabetic neuropathy and that
knockdown of PGC-1α intensifies the neuropathy. This novel research will examine the upstream activator of
PGC-1α, namely SIRT1 in diabetic neuropathy and help further explore a new potential therapy (NR) that can
be taken into clinical studies in a timely manner.

## Key facts

- **NIH application ID:** 10406480
- **Project number:** 3R01DK107007-05S1
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** JAMES W RUSSELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $115,875
- **Award type:** 3
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406480

## Citation

> US National Institutes of Health, RePORTER application 10406480, NAD+ and SIRT1 Regulate Mitochondrial Function in Diabetic Neuropathy (3R01DK107007-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10406480. Licensed CC0.

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