Skip to main content
ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Obesity and Metabolism Research » Research » Publications at this Location » Publication #295402
Title: Acylcarnitines: potential implications for skeletal muscle insulin resistance

Author
item AGUER, CELINE - University Of Ottawa
item MCCOIN, COLIN - University Of California
item Knotts, Trina
item MCPHERSON, RUTH - University Of Ottawa
item DENT, ROBERT - University Of Ottawa
item Hwang, Daniel
item Adams, Sean
item HARPER, MARY-ELLEN - University Of Ottawa

Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/30/2014
Publication Date: 10/23/2014
Citation: Aguer, C., Mccoin, C.S., Knotts, T.A., Mcpherson, R., Dent, R., Hwang, D.H., Adams, S.H., Harper, M. 2014. Acylcarnitines: potential implications for skeletal muscle insulin resistance. Journal of Federation of American Societies for Experimental Biology. 29(1):336-345. doi: 10.1096/fj.14-255901.

Interpretive Summary: Insulin resistance is linked to increased acylcarnitine species in a number of tissues including skeletal muscle, due to incomplete fatty acid oxidation (FAO). It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aim of this study was to determine whether acylcarnitines are responsible for muscle insulin resistance and to better understand the link between incomplete muscle FAO, oxidative stress, inflammation and insulin resistance development. Differentiated C2C12 and primary human myotubes were treated with short, medium and long acylcarnitines (C4:0, C14:0, C16:0) or a mix of acylcarnitines. Treatment with C16:0- and C4:0-acylcarnitines resulted in decreased insulin response at the level of Akt phosphorylation and/or glucose uptake. Inhibition of carnitine acyltransferases reversed palmitate-induced insulin resistance. While pro-inflammatory cytokines were not affected under these conditions, oxidative stress was increased by acylcarnitine treatment. C16:0-acylcarnitine-induced oxidative stress and insulin resistance were reversed by treatment with antioxidants. Thus, results are consistent with the conclusion that incomplete muscle FAO causes acylcarnitine accumulation and associated oxidative stress, raising the possibility that these metabolites play a role in muscle insulin resistance. If true, this would represent a paradigm shift in our understanding of the pathology of type 2 diabetes mellitus.

Technical Abstract: Insulin resistance is linked to increased acylcarnitine species in a number of tissues including skeletal muscle, due to incomplete fatty acid oxidation (FAO). It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aim of this study was to determine whether acylcarnitines are responsible for muscle insulin resistance and to better understand the link between incomplete muscle FAO, oxidative stress, inflammation and insulin resistance development. Differentiated C2C12 and primary human myotubes were treated with short, medium and long acylcarnitines (C4:0, C14:0, C16:0) or a mix of acylcarnitines. Treatment with C16:0- and C4:0-acylcarnitines resulted in decreased insulin response at the level of Akt phosphorylation and/or glucose uptake. Inhibition of carnitine acyltransferases reversed palmitate-induced insulin resistance. While pro-inflammatory cytokines were not affected under these conditions, oxidative stress was increased by acylcarnitine treatment. C16:0-acylcarnitine-induced oxidative stress and insulin resistance were reversed by treatment with antioxidants. Thus, results are consistent with the conclusion that incomplete muscle FAO causes acylcarnitine accumulation and associated oxidative stress, raising the possibility that these metabolites play a role in muscle insulin resistance.