# Administrative Supplement to Proinsulin ER Export and Beta Cell ER Homeostasis in Health and Diabetes (1R01DK110314)

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2021 · $65,142

## Abstract

PROJECT SUMMARY
Up to date, most of the diabetes-associated genes identified in genome-wide association studies are
enriched in the pancreatic beta cells. Beta cell failure plays a central role in the development and
progression of type 2 diabetes (T2D). The endoplasmic reticulum (ER) is a central organelle for the
massive production and processing of proinsulin. ER homeostasis is critical for normal beta cell
function and is maintained by the delicate balance between protein synthesis, folding, export and
degradation. In contrast, the disruption of ER homeostasis, by many genetic and environmental
diabetes-causing factors, induces ER stress and causes beta cell death in T2D. Compared to our
knowledge in protein synthesis, folding and degradation in beta cell ER, the role of ER export in
proinsulin biogenesis and ER homeostasis is much less understood. This proposal addresses this
knowledge gap. We have obtained strong preliminary results demonstrating that ER exit of proinsulin
requires COPII (coat protein complex II) coated vesicles and defective COPII dependent ER export
strongly induces ER stress. In addition to our results, evidence has recently begun to emerge that
reduced ER-Golgi transport is causative to lipotoxicity-induced ER stress in beta cells. On the basis of
these novel findings, we aim to determine how glucose- and lipid-toxicity affect the ER export of
protein cargo, particularly proinsulin, in beta cells and how defective ER export, in turn, contributes to
ER stress and beta cell dysfunction. Over a thousand proteins, referred to as the proteostasis
network, have been proposed to maintain ER homeostasis. However, to date, only a very small
number of ER proteins have been investigated for their involvement in ER stress or proinsulin
biogenesis in beta cells. A systematic proteomics analysis is needed to comprehensively understand
how different diabetes-causing conditions perturb beta cell ER homeostasis at the onset of T2D. In
this proposal, using systems biology approaches, we will test the central hypothesis that
diabetogenic factors such as glucolipotoxicity disrupt beta cell ER function through perturbing ER
protein homeostasis and COPII dependent ER export. There are two specific aims in this proposal: 1)
Determine how COPII dependent ER export is regulated in health and diabetes; 2) Determine how ER
chaperones and folding enzymes are altered in diabetes and how these changes affect beta cell ER
export. This study will use state-of-the-art quantitative proteomics and other systems biology
approaches to characterize the molecular mechanisms by which diabetes-causing conditions
differentially alter ER homeostasis. The emphasis will be on the ER export, an under-investigated
component of beta cell ER homeostasis.

## Key facts

- **NIH application ID:** 10318441
- **Project number:** 3R01DK110314-05S1
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Xuequn Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $65,142
- **Award type:** 3
- **Project period:** 2016-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318441

## Citation

> US National Institutes of Health, RePORTER application 10318441, Administrative Supplement to Proinsulin ER Export and Beta Cell ER Homeostasis in Health and Diabetes (1R01DK110314) (3R01DK110314-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10318441. Licensed CC0.

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