# Alleviation of Glucotoxicity in Pancreatic Beta Cells

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $502,878

## Abstract

Summary
 Type 2 Diabetes (T2D) results from a combination of insulin resistance, most often brought about by
obesity, and a gradual and unrelenting erosion of the ability of pancreatic beta cells to secrete sufficient insulin
to meet the increased metabolic demand for insulin. A major mediator of beta cell dysfunction is glucose
toxicity, mediated by sustained hyperglycemia. During the pathogenesis of T2D a vicious cycle ensues, where
insulin resistance increases the demand for more insulin, but beta cells become “exhausted” and unable to
secret enough insulin to maintain glucose homeostasis, leading to increased hyperglycemia, more beta cell
exhaustion and death, erosion of beta cell mass, and eventually the need for insulin therapy. Therefore, there
is an urgent need for new therapies that block the vicious cycle and preserve beta cell mass. We believe we
have uncovered a molecular mechanism that explains the vicious cycle that erodes beta cell function and beta
cell mass during T2D. This proposal will explore the molecular details of this mechanism and test the feasibility
of therapeutic interventions that preserve rodent and human beta cells in models of glucose toxicity and T2D.
The overarching hypothesis of this proposal is that the feed-forward mechanism of ChREBPβ expression
becomes dysregulated in T2D and drives glucose toxicity through expression of the pro-oxidative activity of
Txnip, the effects of which can be mitigated by the activation of Nrf2. Furthermore, maneuvers that break the
vicious cycle of ChREBPβ production, or mitigate its actions through Txnip inhibition, or Nrf2 activation,
protects beta cell mass and alleviates diabetic burden. This proposal will test this hypothesis by exploring the
molecular regulatory mechanisms between these 3 factors, and by depleting either ChREBPβ or Txnip, or
elevating NRF2, in mouse models of diabetes or glucotoxicity, or in glucotoxic or T2D human islets. Specific
Aim 1 will explore the regulatory relationships between ChREBPβ, Txnip, and NRF2 that determine beta cell
fate. Specific Aim 2 will examine how depletion of ChREBPβ, or Txnip, or activation of NRF2 affects beta cell
function and glucose homeostasis in diabetic and glucotoxic mouse models. Specific Aim 3 will test if depletion
of ChREBPβ, or TXNIP, or activation of NRF2 affects beta cell function and survival in glucotoxic or T2D
human islets. Our results will inform the design of therapies that will mitigate beta cell glucose toxicity and may
result in very specific drugs that target beta cells to preserve beta cell mass and function and alleviate diabetic
symptoms and complications.

## Key facts

- **NIH application ID:** 10316752
- **Project number:** 1R01DK130300-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** DONALD K. SCOTT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $502,878
- **Award type:** 1
- **Project period:** 2021-07-20 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10316752

## Citation

> US National Institutes of Health, RePORTER application 10316752, Alleviation of Glucotoxicity in Pancreatic Beta Cells (1R01DK130300-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10316752. Licensed CC0.

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