# Investigating Branched Chain Amino Acid Oxidation in Skeletal Muscle and its Contribution to Insulin Resistance

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2022 · $46,752

## Abstract

Project Summary
Branched chain amino acids (BCAAs) are essential amino acids, and their catabolism is controlled by the rate-
limiting BCAA dehydrogenase complex (BCKDH) and its inhibitory kinase BCKDK. Elevated plasma levels of
BCAAs have been associated with type 2 diabetes since the 1960s. Recent studies have suggested that
elevated BCAAs contribute to insulin resistance and the development of type 2 diabetes. However, the
mechanisms through which BCAAs drive insulin resistance remain unknown. We have previously shown
through steady-state in vivo heavy isotopic tracing that the db/db mouse model of insulin resistance and type 2
diabetes has increased BCAA oxidation in skeletal muscle and decreased oxidation in liver and adipose tissue.
High BCAA oxidation in skeletal muscle may lead to insulin resistance by a few potential mechanisms including
the promotion of fat uptake into muscle cells, as well as the inhibition of fat catabolism. Both of these
mechanisms would be predicted to cause an accumulation of lipids in skeletal muscle, leading to insulin
resistance. Based on these observations, I hypothesize that elevated BCAA oxidation in skeletal muscle
promotes the development of insulin resistance. To test this hypothesis, we have developed skeletal muscle-
specific BCKDH gain-of-function and loss-of-function mouse models. I will use a variety of techniques including
steady-state in vivo infusions of 13C-labeled nutrients and hyperinsulinemic-euglycemic clamps to determine if
increased BCAA oxidation in muscle suppresses fat oxidation and promotes systemic insulin resistance. With
these techniques and mouse models at my disposal, I will delineate specific mechanisms by which BCAAs
contribute to the development of insulin resistance and type 2 diabetes, which could lead to better, more
targeted treatment of patients with this disease.

## Key facts

- **NIH application ID:** 10462999
- **Project number:** 1F31DK132839-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Megan Chandler Blair
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10462999

## Citation

> US National Institutes of Health, RePORTER application 10462999, Investigating Branched Chain Amino Acid Oxidation in Skeletal Muscle and its Contribution to Insulin Resistance (1F31DK132839-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10462999. Licensed CC0.

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