# Targeting methylglyoxal-induced diabetic neuropathic pain through the integrated stress response

> **NIH NIH R01** · UNIVERSITY OF TEXAS DALLAS · 2024 · $608,698

## Abstract

Diabetes affects over 10% of the US population and another 35% are at imminent risk of developing diabetes.
As many as half of the diabetic population will develop chronic pain that is poorly treated with current
medications. Chronic pain is a major contributor to a poor quality of life in diabetic individuals. While we do not
know the exact cause of diabetic neuropathic pain, increases plasma levels of methylglyoxal (MGO), a
chemical by-product of energy production, have been correlated with pain in diabetes. We have recently shown
that MGO induces the integrated stress response (ISR) in nociceptors, causing them to become
hyperexcitable. The ISR controls protein synthesis by repressing eukaryotic initiation factor 2α (eIF2α) and
recruiting eIF2A to the mRNA translation machinery. This leads to a global suppression of translation while
promoting the translation of select mRNA transcripts, particularly those with an upstream open reading frame.
We predict that eIF2A-mediated translation following the induction of ISR regulates the excitability of these
cells. Our initial work shows that the ISR is engaged in mouse and rat models of diabetes as well as human
sensory neurons treated with MGO. Our overarching hypothesis is that the ISR causes pain in diabetes and
that the ISR pathway can be targeted for treating pain in diabetes. As such, initial experiments in mice lacking
eIF2A show that the loss of eIF2A protects these mice against evoked and spontaneous pain caused by a
single or repeated MGO injections. Aim 1 will harness the power of mouse genetics to generate Nav1.8+
nociceptor-specific knockout of eIF2A. We aim to show that the ISR in mouse nociceptors is required for MGO-
evoked and diabetic neuropathic pain. We will further use this model to examine the translatome and identify
which mRNAs are translated under the influence of eIF2A, especially after MGO treatment. For Aim 2, we will
use cultured neurons and nervous tissues from organ donors to find out how MGO changes gene expression
and excitability of human neurons and whether treatment with an ISR inhibitor (ISRIB) can reverse these
aberrant changes. Our access to donor tissue presents a unique opportunity to test these hypotheses in a
model system that is representative of the people that this research will benefit. Finally, Aim 3 will take
advantage of a rat model of type II diabetes, the Zucker Diabetic Fatty (ZDF) rats, to understand how targeting
the ISR can be used to treat diabetic pain. We plan to use non-opioid therapies that are currently in
development, such as ISRIB, in the ZDF rats. We aim to show that targeting the ISR is an effective strategy for
preventing and reversing diabetic neuropathic pain and its electrophysiology correlates. We will also perform
RNA sequencing on ZDF rats treated with ISRIB to examine pathways influenced by ISR in a whole animal
model of diabetes. By using rodent and human models we will create a unique opportunity to clinically model
therapies ...

## Key facts

- **NIH application ID:** 10923791
- **Project number:** 5R01DK134893-02
- **Recipient organization:** UNIVERSITY OF TEXAS DALLAS
- **Principal Investigator:** MUNMUN CHATTOPADHYAY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $608,698
- **Award type:** 5
- **Project period:** 2023-09-07 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923791

## Citation

> US National Institutes of Health, RePORTER application 10923791, Targeting methylglyoxal-induced diabetic neuropathic pain through the integrated stress response (5R01DK134893-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10923791. Licensed CC0.

---

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