# Lysine acetylation and skeletal muscle insulin action

> **NIH NIH R56** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $150,367

## Abstract

PROJECT SUMMARY
Impaired insulin-stimulated glucose uptake is a common metabolic complication in aged and obese skeletal
muscle. This insulin “resistance” increases morbidity risk and is a primary defect that underlies the etiology of
type 2 diabetes. Despite the fact that the trafficking of GLUT4 to the plasma membrane is fundamental to insulin-
stimulated glucose uptake, there is still much unknown about the signals that underlie GLUT4 translocation after
insulin stimulation in skeletal muscle. The long-term objective of this research is to define the molecular
regulation of insulin-stimulated glucose transport in skeletal muscle. Currently, phosphorylation-based signaling
from the insulin receptor through phosphoinositide 3-kinase to Akt2 and Akt substrate of 160kD is considered
the principal mechanism underlying insulin-stimulated GLUT4 translocation and glucose uptake. We believe,
however, that lysine acetylation of proteins key to GLUT4 trafficking is necessary for insulin-stimulated glucose
uptake. Accordingly, the primary objective of this application is to elucidate the importance of the
acetyltransferases, p300 (E1A binding protein p300) and CBP (cAMP response element-binding protein [CREB]
binding protein), to insulin-mediated GLUT4 mobilization to the plasma membrane and skeletal muscle glucose
uptake. Our central hypothesis is that lysine acetylation of specific residues on distinct GLUT4 trafficking-related
proteins by cytosolic p300/CBP is required for insulin-stimulated GLUT4 translocation to the plasma membrane
and a resultant increase in glucose uptake by skeletal muscle; as part of this, we hypothesize that p300/CBP
are regulated by Akt2. To address our hypothesis, we will measure skeletal muscle glucose uptake, cytosolic
lysine acetylation, canonical insulin signaling and GLUT4 translocation in response to insulin in adult mouse
skeletal muscle and muscle cells lines in which we modulate p300/CBP activity. Our model predicts that
concurrent inhibition of p300 and CBP acetyltransferase activity will abrogate insulin-stimulated glucose
transport, whilst p300/CBP activation will augment these measures. Specifically, Aim #1 will elucidate the
importance of cytosolic versus nuclear p300/CBP and gene transcription to our model, Aim #2 will determine
how p300/CBP are regulated in response to insulin stimulation and, Aim #3 will define the proteins that are
acetylated by p300/CBP in response to insulin and the functional importance of the acetylation sites on target
proteins to insulin-stimulated GLUT4 translocation and glucose uptake. Together, these studies will broaden our
understanding of the contribution of p300/CBP and lysine acetylation to skeletal muscle glucose metabolism in
response to insulin. Ultimately, we expect this knowledge to provide a new framework for developing novel
therapies to modulate insulin action in skeletal muscle. By extension, such work is anticipated to advance the
treatment of diseases and complication...

## Key facts

- **NIH application ID:** 10477154
- **Project number:** 1R56DK131121-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Carrie E McCurdy
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $150,367
- **Award type:** 1
- **Project period:** 2021-09-17 → 2023-09-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477154

## Citation

> US National Institutes of Health, RePORTER application 10477154, Lysine acetylation and skeletal muscle insulin action (1R56DK131121-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10477154. Licensed CC0.

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