Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women.
Inefficient muscle long-chain fatty acid (LCFA) combustion is associated with insulin resistance, but molecular links between 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 the UCP3 g/a polymorphism (n = 28/genotype: 22 diabetic, 6 nondiabetic/genotype) were conducted. Contrary to our hypothesis, genotype had 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 beta-oxidation in the latter (i.e. summed C10- to C14-carnitine concentrations were approximately 300% of controls; P = 0.004). Across all volunteers (n = 56), acetylcarnitine rose and propionylcarnitine decreased with increasing hemoglobin A1c (r = 0.544, P < 0.0001; and r = -0.308, 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 kappa-B activity (up to 200% of controls) in RAW264.7 cells. These results are consistent with the working hypothesis that inefficient tissue LCFA beta-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.
Adams
Sean H
SH
USDA/Agricultural Research Service Western Human Nutrition Research Center, USA. sean.h.adams@ars.usda.gov
Hoppel
Charles L
CL
Lok
Kerry H
KH
Zhao
Ling
L
Wong
Scott W
SW
Minkler
Paul E
PE
Hwang
Daniel H
DH
Newman
John W
JW
Garvey
W Timothy
WT
D000328:Adult; D001741:Black or African American; D000368:Aged; D000369:Aged, 80 and over; D002331:Carnitine / Q000031:analogs & derivatives* / Q000097:blood; D002952:Citric Acid Cycle / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000208:ethnology / Q000235:genetics; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000150:complications; D010084:Oxidation-Reduction; D011110:Polymorphism, Genetic; D000071247:Uncoupling Protein 3; D055815:Young Adult
D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D016328:NF-kappa B; C000604392:UCP3 protein, human; D000071247:Uncoupling Protein 3; C116917:acylcarnitine; D002331:Carnitine