# Proinsulin Trafficking for Insulin Biosynthesis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $508,561

## Abstract

Pancreatic ß-cells store insulin and release it in response to an elevation of blood glucose. Additionally, with
each meal, healthy ß-cells synthesize new insulin to replace what they have lost. The synthesis pathway begins
with introducing into the endoplasmic reticulum (ER) on average ~6,000 new proinsulin molecules every second
per ß-cell. Under normal conditions, these molecules must fold their insulin moiety to the native state, including
the formation of 3 evolutionarily conserved disulfide bonds. However, we have now definitively identified
proinsulin misfolded states that occur in the ER of human islets, rodent islets, or ß-cell lines, and get worse (more
abundant) with perturbations of the ER folding environment. We believe that this is an important contributor to
abnormally increased ß-cell ER stress – and it is even worse in the disease of Mutant INS-gene induced Diabetes
of Youth (MIDY) – caused by any one of >30 heterozygous (dominant-negative) INS gene coding sequence
mutations. A portion of the work in the current proposal will focus on MIDY models, but we also present important
new data highlighting the formation of misfolded protein complexes containing proinsulin that are especially
abundant in islet ß-cells without INS mutation, preceding the onset of type 2 diabetes (T2D). In our first
Aim, we will further analyze the ER environment and diabetogenic conditions promoting the formation of
misfolded complexes of proinsulin, using molecular, cellular, and physiological tools. In our second Aim, we
propose to understand more about the molecular mechanism of misfolding by using various MIDY models, and
particularly, we propose experiments that will allow us to determine how much misfolded proinsulin must
accumulate in order to trigger diabetes. Finally, in our third Aim, we propose a strategy to limit proinsulin
misfolding with the intent to ameliorate, delay, or prevent diabetes.

## Key facts

- **NIH application ID:** 9971230
- **Project number:** 2R01DK048280-26A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** PETER ARVAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $508,561
- **Award type:** 2
- **Project period:** 1994-09-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971230

## Citation

> US National Institutes of Health, RePORTER application 9971230, Proinsulin Trafficking for Insulin Biosynthesis (2R01DK048280-26A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971230. Licensed CC0.

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