# Translational Programming of Beta-cells in Response to Glucose Toxicity

> **NIH NIH R01** · JOSLIN DIABETES CENTER · 2024 · $724,053

## Abstract

ABSTRACT
Control of insulin biosynthesis in beta-cells occurs primarily at the level of translation of the insulin mRNA. An 
acute rise in glucose levels stimulates insulin translation by a process that involves binding of proteins to the 5' 
untranslated region of the insulin mRNA. Simultaneous translational upregulation of other secretory granule 
proteins also contributes to glucose-stimulated insulin secretion and provides evidence that beta-cells 
coordinately regulate translation of functionally related mRNAs. By contrast, exposure of beta-cells to sustained 
high glucose suppresses glucose-stimulated insulin translation and secretion. The mechanisms responsible for
dysregulation of insulin translation and whether the deleterious effect of chronic high glucose impacts translation 
of other proteins are not known. This project will test the hypothesis that glucose toxicity leads to early alterations 
in mRNA-specific beta-cell translation that are mediated by intrinsic properties of mRNAs and by dynamic 
remodeling of the ribosome itself. Furthermore, we propose this programmatic translational dysregulation 
contributes to impaired glucose-stimulated insulin secretion. Knowledge gained from this study has the potential 
to identify novel therapeutic targets for prevention of progressive beta-cell failure in diabetes and for optimizing 
functionality of ex vivo generated beta-cells for cell replacement therapy.

## Key facts

- **NIH application ID:** 10904499
- **Project number:** 1R01DK138605-01A1
- **Recipient organization:** JOSLIN DIABETES CENTER
- **Principal Investigator:** JEAN E. SCHAFFER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $724,053
- **Award type:** 1
- **Project period:** 2024-08-02 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904499

## Citation

> US National Institutes of Health, RePORTER application 10904499, Translational Programming of Beta-cells in Response to Glucose Toxicity (1R01DK138605-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10904499. Licensed CC0.

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