# Regulation of Skeletal Muscle Metabolism by Insulin Signaling

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $398,289

## Abstract

Project Summary
The number of individuals with type 2 diabetes mellitus (T2DM) remains at an all-time high and is predicted to
increase over the next decade. Therefore, it is of significant medical interest to define the underlying mechanisms
driving T2DM to improve therapeutic efficacy. Insulin resistance, a condition known as reduced effectiveness to
the hormone insulin, is associated with altered glucose homeostasis and muscle dysfunction. Despite decades
of investigation, critical knowledge gaps remain in the molecular mechanisms that are responsible for the
initiation and propagation of insulin resistance. The skeletal muscle plays a significant role in glucose
homeostasis and accounts for a majority of glucose disposal following a meal. Defects in the insulin signaling
pathway in the skeletal muscle have been hypothesized to be the primary cause of insulin resistance leading to
hyperglycemia, altered protein metabolism and cardiovascular disease. Accumulating evidence has implicated
the serine/threonine kinase Akt (protein kinase B) as a critical regulator of insulin action. To directly test the
hypothesis that reduced insulin signaling via AKT causes insulin resistance and alters muscle function, we
generated mice that lack AKT signaling specifically in skeletal muscle and surprisingly found that insulin can
stimulate skeletal muscle glucose uptake and utilization in the absence of AKT. These data are inconsistent with
the canonical molecular model of insulin resistance and suggest AKT is not an obligate intermediate in the control
of skeletal muscle glucose metabolism by insulin in all conditions. The identification of this AKT-independent
pathway and its role carbohydrate homeostasis will be the focus of Aim 1 of this proposal. Although mice lacking
AKT in skeletal muscle have normal glucose uptake and insulin sensitivity, we found that they nevertheless
exhibit significant muscle atrophy and mitochondrial dysfunction with a corresponding defect in muscle
performance, confirming that AKT is required for muscle growth and function in vivo. The downstream
mechanisms responsible for AKT’s control of muscle growth and function will be defined in Aim 2. Collectively,
this proposal will build upon these important observations and elucidate the Akt-dependent and independent
pathways that control the metabolic actions of insulin in vivo. These experiments have the potential to profoundly
affect our mechanistic understanding of the pathways underlying insulin resistance and will lead to the
identification of new therapeutic targets for T2DM, cardiovascular and skeletomuscular diseases.

## Key facts

- **NIH application ID:** 9862942
- **Project number:** 1R01DK123252-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Paul Michael Titchenell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $398,289
- **Award type:** 1
- **Project period:** 2020-03-23 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9862942

## Citation

> US National Institutes of Health, RePORTER application 9862942, Regulation of Skeletal Muscle Metabolism by Insulin Signaling (1R01DK123252-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9862942. Licensed CC0.

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