# Metabolic basis of beta cell stress adaptation

> **NIH NIH R56** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $194,219

## Abstract

PROJECT SUMMARY/ABSTRACT
Type 1 diabetes (T1D) results from an autoimmune-mediated destruction of pancreatic β-cells and affects
approximately 3 million people in the United States and 10–20 million worldwide. The rapidly increasing
incidence of T1D, as much as 3-5% per year, is of great concern. Although autoimmune-mediated β-cell
destruction is the major cause of T1D, emerging data suggest that intrinsic β-cell stress, defective adaptive stress
responses, and β-cell dedifferentiation can contribute to the loss of functional β-cell mass not only in T2D, but
also in T1D. Despite these intriguing findings, mechanisms by which β-cells recover from stress and restore their
function and identity remain largely unknown, and there is an urgent need to address this critical gap in
knowledge to improve the therapeutic options of patients with diabetes. We recently reported that deletion of
the key stress response sensor, IRE1α, in β-cells of non-obese diabetes (NOD) mice (IRE1αβ-/-), leads to
transient β-cell dedifferentiation. Interestingly, these mice recover from stress and are protected from T1D.
IRE1αβ-/- mice serve as an excellent model to study how β-cells adapt to stress and restore their identity and
function under stress conditions. Ample data show that cellular stress triggers numerous adaptive responses,
including metabolic rewiring. Consistent with this observation, our preliminary data obtained from this model
showed significant alterations in metabolism and mitochondrial morphology. Based on our preliminary data, we
hypothesize that stress adaptation in β-cells is governed by metabolic reprogramming and mitochondrial
remodeling. To test this hypothesis, we propose the following specific aims: Aim 1: Identify the temporal
dynamics and regulation of mitochondrial processes and bioenergetics in β-cells of IRE1αβ-/- mice: (1)
Through imaging, and metabolic flux analyses at different states of differentiation, we will examine
mitochondrial respiration and fusion, and (2) unravel the regulation of key fusion genes and the activity of the
master regulator of respiration in β-cells of IRE1αβ-/-. Aim 2: Determine the role of metabolic reprogramming
and mitochondrial remodeling in identity, function, and stress recovery of β-cells of IRE1αβ-/- mice. We
will genetically and pharmacologically (1) alter the metabolic state in stressed islets from T1D animal models,
(2) modulate the mitochondrial dynamics in stressed β-cells of IRE1αβ-/- mice ex vivo, and then examine β-cell
function, identity, and survival in these systems. Aim 3: Elucidate the effects of metabolic alterations on β-
cell redifferentiation and function in a mouse model of T2D and human islets. To complement our studies
with the NOD model, we will perform the experiments from Aim 2, in β-cells of leptin-deficient obese ob/ob mice
(a model of T2D), and in islets from T2D donors. This work will define the role of oxidative metabolism and
mitochondrial dynamics in stress adaptation, mainten...

## Key facts

- **NIH application ID:** 10339887
- **Project number:** 1R56DK128136-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Feyza Engin
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $194,219
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339887

## Citation

> US National Institutes of Health, RePORTER application 10339887, Metabolic basis of beta cell stress adaptation (1R56DK128136-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10339887. Licensed CC0.

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