# Metabolic control of beta-cell secretory organelle function

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $449,864

## Abstract

Compelling evidence highlights the central role of islet β-cell failure in the transition from insulin resistance to
Type 2 diabetes (T2D). Defects in the β-cell's secretory pathway accompany T2D onset and include changes
to insulin trafficking, reduced insulin storage, and impaired proinsulin processing. The cellular mechanisms
underlying these defects are not completely understood, yet could have considerable therapeutic value if β-cell
function could be restored. Our data highlight altered ER redox homeostasis as a novel mechanism that
contributes to β-cell dysfunction in human and rodent diabetes models. Using novel proinsulin trafficking
reporters, we identified a delay in the ER export of proinsulin that leads to inadequate insulin granule
production. We linked delayed proinsulin export to hyperoxidation of the ER lumen and showed that restoration
of ER redox homeostasis rescued proinsulin export and insulin granule formation. The hyperoxidized ER
environment may interfere with proinsulin export by contributing to the formation of misfolded disulfide-linked
proinsulin oligomers previously reported in human T2D β-cells. Ultimately, this proinsulin trafficking delay limits
the production of insulin granules, which may explain the increase of proinsulin and loss of insulin granules
prominent in T2D. Our proposed studies are designed to define the molecular mediators of β-cell ER redox
control and address how ER hyperoxidation develops in T2D. Our preliminary data have identified a novel
mechanism linking defects in mitochondrial and redox metabolism with changes to ER function in the decline of
insulin production in T2D. Our central hypothesis is that metabolically supplied reductive redox donors are
necessary for the β-cell's ER redox buffering capacity to sustain efficient proinsulin folding for insulin
production. The goals of this proposal are to establish a critical link between glucose metabolism and ER redox
control (Aim 1), define key mediators that buffer ER redox capacity (Aim 2), and determine how proinsulin
folding impacts ER redox homeostasis (Aim 3).

## Key facts

- **NIH application ID:** 10937299
- **Project number:** 1R01DK140093-01
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Samuel Brandon Stephens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $449,864
- **Award type:** 1
- **Project period:** 2024-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10937299

## Citation

> US National Institutes of Health, RePORTER application 10937299, Metabolic control of beta-cell secretory organelle function (1R01DK140093-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10937299. Licensed CC0.

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