# Glycophagy in liver and skeletal muscle insulin sensitivity and energy metabolism

> **NIH NIH K01** · LSU PENNINGTON BIOMEDICAL RESEARCH CTR · 2022 · $139,363

## Abstract

Project Summary / Abstract
Liver and skeletal muscle insulin resistance represent two core defects in individuals with Type 2 Diabetes.
Although dysregulated glycogen metabolism is linked to insulin sensitivity, it is not entirely understood how
glycogen metabolism modifies insulin sensitivity. New preliminary data generated by the applicant suggests that
the autophagic degradation of glycogen (i.e. glycophagy) by the lysosomal enzyme alpha acid glucosidase
(GAA) plays a previously unrecognized role in modulating liver and skeletal insulin sensitivity and energy
metabolism. In mice, high-fat diet feeding reduced insulin sensitivity, an effect associated with an increase in
liver GAA levels, whereas exercise or muscle contraction increased insulin sensitivity, an effect associated with
reduced muscle GAA levels. Follow-up mechanistic studies in liver or skeletal muscle cells showed that acute
inhibition of glycophagy reduced glycolytic capacity while increasing insulin sensitivity, mitochondrial biogenesis,
and fatty acid oxidation, effects that were associated with an induction of SIRT1 signaling and reduced oxidative
stress. To better define the link between glycophagy, insulin sensitivity, and energy metabolism in mice, the
applicant used CRISPR/Cas 9 technology to generate a novel mouse model with inducible liver or skeletal
muscle specific knockout of GAA. The overarching objective of this K01 proposal is to define the role of
glycophagy in liver and skeletal muscle insulin sensitivity and energy metabolism in mice. Additionally, the
applicant has assembled an interdisciplinary grant advisory panel to provide mentorship and guidance for the
proposed research. The training plan was designed to build upon the applicant’s prior expertise in metabolism
by providing additional training in analytical techniques, research concepts, data analysis, grant and manuscript
writing, didactic training in tracer methodology, establishing productive collaborations, and leadership skills. This
proposal will help the applicant initiate his own investigative niche in the field of glycophagy and serve as a
springboard to his independent research career.

## Key facts

- **NIH application ID:** 10737834
- **Project number:** 7K01DK125258-04
- **Recipient organization:** LSU PENNINGTON BIOMEDICAL RESEARCH CTR
- **Principal Investigator:** Timothy D. Heden
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $139,363
- **Award type:** 7
- **Project period:** 2020-08-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10737834

## Citation

> US National Institutes of Health, RePORTER application 10737834, Glycophagy in liver and skeletal muscle insulin sensitivity and energy metabolism (7K01DK125258-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10737834. Licensed CC0.

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