Alterations in skeletal muscle fatty acid handling predisposes middle-aged mice to diet-induced insulin resistance.

Journal Article (Journal Article)


Although advanced age is a risk factor for type 2 diabetes, a clear understanding of the changes that occur during middle age that contribute to the development of skeletal muscle insulin resistance is currently lacking. Therefore, we sought to investigate how middle age impacts skeletal muscle fatty acid handling and to determine how this contributes to the development of diet-induced insulin resistance.

Research design and methods

Whole-body and skeletal muscle insulin resistance were studied in young and middle-aged wild-type and CD36 knockout (KO) mice fed either a standard or a high-fat diet for 12 weeks. Molecular signaling pathways, intramuscular triglycerides accumulation, and targeted metabolomics of in vivo mitochondrial substrate flux were also analyzed in the skeletal muscle of mice of all ages.


Middle-aged mice fed a standard diet demonstrated an increase in intramuscular triglycerides without a concomitant increase in insulin resistance. However, middle-aged mice fed a high-fat diet were more susceptible to the development of insulin resistance-a condition that could be prevented by limiting skeletal muscle fatty acid transport and excessive lipid accumulation in middle-aged CD36 KO mice.


Our data provide insight into the mechanisms by which aging becomes a risk factor for the development of insulin resistance. Our data also demonstrate that limiting skeletal muscle fatty acid transport is an effective approach for delaying the development of age-associated insulin resistance and metabolic disease during exposure to a high-fat diet.

Full Text

Duke Authors

Cited Authors

  • Koonen, DPY; Sung, MMY; Kao, CKC; Dolinsky, VW; Koves, TR; Ilkayeva, O; Jacobs, RL; Vance, DE; Light, PE; Muoio, DM; Febbraio, M; Dyck, JRB

Published Date

  • June 2010

Published In

Volume / Issue

  • 59 / 6

Start / End Page

  • 1366 - 1375

PubMed ID

  • 20299464

Pubmed Central ID

  • PMC2874697

Electronic International Standard Serial Number (EISSN)

  • 1939-327X

International Standard Serial Number (ISSN)

  • 0012-1797

Digital Object Identifier (DOI)

  • 10.2337/db09-1142


  • eng