# Regulation of Autophagy-driven Pancreatic Beta Cell Function by Nutrient Sensor Proteins

> **NIH NIH F31** · UNIVERSITY OF MINNESOTA · 2022 · $32,763

## Abstract

PROJECT SUMMARY/ABSTRACT
O-GlcNAc transferase (OGT) is a nutrient sensor protein which is highly expressed in pancreatic β-cells. This
enzyme exclusively catalyzes the post-translational glycosylation of target cytosolic and nucleic proteins (O-
GlcNAcylation). β-cell OGT knockout mice develop severe diabetic phenotype, suggesting that OGT is crucial in
shaping glucose homeostasis. The long-term goal of this research is to understand the mechanisms of how
protein O-GlcNAcylation shape β-cell health and function. Our data suggest a strong relationship between OGT
and mechanistic target of Rapamycin complex 1, mTORC1, a key nutrient-sensor kinase in β-cells. While
aberrant autophagy and chronic mTORC1 activation is observed in islets from human diabetic patients, the
mechanisms of how these signaling pathways become dysregulated is unknown. We propose that in response
to nutrient stress, protein O-GlcNAcylation directly regulates mTORC1 activity and subsequent downstream
mitochondrial function through the process of autophagy. Our central hypothesis is that in nutrient stress
conditions, decreased O-GlcNAcylation leads to insulin secretion deficits through hypo-activation of mTORC1
and hyper-activation of autophagy. The main objective of this proposal is to delineate the signaling between OGT
and mTORC1-autophagy and their contribution to β-cell health and function. Specific Aim 1 will investigate how
O-GlcNAcylation regulates mTORC1 activity and β-cell mass and function. Specific Aim 2 will test whether O-
GlcNAcylation modulates autophagy in β-cells and to determine the consequences of dysregulated autophagy
in organelle homeostasis. This F31 proposal is innovative because there are currently no studies linking OGT
and mTORC1 crosstalk in pancreatic islets and their regulation of autophagy-dependent β-cell mass and insulin
secretion. Successful completion of the proposal will reveal the mechanisms linking nutrient stress conditions
such as hyper-glycemia and -lipidemia to aberrant changes in organelle dysfunction and identify specific β-cell
nodes of regulation between OGT and mTORC1 signaling that can be targeted for therapeutics to prevent the
development of type 2 diabetes. The proposal incorporates new and timely-needed training in conceptual
knowledge in islet biology, autophagy, and mitochondria, and technical skills including perifusion based insulin
secretion assay, specialize imaging techniques (TEM, confocal, live cell), and Seahorse XF mitochondrial
respiration assay. Scientific communication in oral and written presentation, as well as mentoring leadership will
be an integral part of training to become a successful academician. All the technical resources as well as
dedicated mentors at University of Minnesota and the department of Integrative Biology and Physiology are
available to assist the trainee to successfully complete his F31 proposal and to assist him achieved his career
and academic goals.

## Key facts

- **NIH application ID:** 10465614
- **Project number:** 1F31DK131860-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Seokwon Jo
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $32,763
- **Award type:** 1
- **Project period:** 2022-02-09 → 2025-02-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465614

## Citation

> US National Institutes of Health, RePORTER application 10465614, Regulation of Autophagy-driven Pancreatic Beta Cell Function by Nutrient Sensor Proteins (1F31DK131860-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10465614. Licensed CC0.

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