Plasma Acylcarnitine Profiles Suggest Incomplete Long-Chain Fatty Acid b-Oxidation and Altered Tricarboxylic Acid Cycle Activity in Type 2 Diabetic African-American Women

Inefficientmuscle long-chain fatty acid (LCFA) combustion is associatedwith insulin resistance, butmolecular linksbetween mitochondrial fat catabolism and insulin action remain controversial. We hypothesized that plasma acylcarnitine profiling would identify distinct metabolite patterns reflective of muscle fat catabolism when comparing individuals bearing a missense G304A uncoupling protein 3 (UCP3 g/a) polymorphism to controls, because UCP3 is predominantly expressed in skeletal muscle and g/a individuals have reduced whole-body fat oxidation. MS analyses of 42 carnitine moieties in plasma samples from fasting type 2 diabetics (n= 44) and nondiabetics (n= 12)with or without theUCP3 g/a polymorphism (n= 28/ genotype: 22diabetic, 6 nondiabetic/genotype)were conducted. Contrary to our hypothesis, genotypehad a negligible impact on plasma metabolite patterns. However, a comparison of nondiabetics vs. type 2 diabetics revealed a striking increase in the concentrations of fatty acylcarnitines reflective of incomplete LCFA b-oxidation in the latter (i.e. summed C10to C14carnitine concentrations were ~300% of controls; P = 0.004). Across all volunteers (n = 56), acetylcarnitine rose and propionylcarnitine decreasedwith increasinghemoglobinA1c (r=0.544,P,0.0001; and r=20.308,P,0.05, respectively) and with increasing total plasma acylcarnitine concentration. In proof-of-concept studies, we made the novel observation that C12-C14 acylcarnitines significantly stimulated nuclear factor k-B activity (up to 200% of controls) in RAW264.7 cells. These results are consistentwith theworking hypothesis that inefficient tissue LCFA b-oxidation, due in part to a relatively low tricarboxylic acid cycle capacity, increases tissue accumulation of acetyl-CoA and generates chain-shortened acylcarnitine molecules that activate proinflammatory pathways implicated in insulin resistance. J. Nutr. 139: 1073–1081, 2009.