Excessive Free Fatty Acid Oxidation in Non‐obese Healthy Asian Men with Insulin Resistance is Associated with Impaired Branched‐chain Amino Acid Oxidation

Abstract

BackgroundBranched‐chain Amino Acids (BCAA) are elevated in insulin resistant (IR) states and may be involved in the pathogenesis of IR in non‐obese individuals. It remains unclear whether this could be secondary to impairment in clearance from oxidation or increased rate of appearance (Ra) because of IR.ObjectivesOur study compared leucine and palmitate kinetics between 14 insulin sensitive (IS) and 12 IR non‐obese healthy Asian men. We hypothesized that greater free fatty acid (FFA) availability for oxidation in IR impairs BCAA oxidation leading to higher blood BCAA concentration.MethodsSubjects underwent oral glucose tolerance testing for measurement of their whole body insulin sensitivity index (WBISI) and body composition measured using the 2H2O method. [U‐13C16] palmitate and [U‐13C6] leucine were infused at least 1‐week apart for quantification of their rates of oxidation and Ra. Kinetic data are expressed as μmol/kgFFM/h.ResultsCompared to IS subjects, IR subject had significantly lower WBISI (3.30 ± 0.26 vs. 8.03 ± 0.92), higher body mass index (24.4 ± 0.6 vs. 23.0 ± 0.3 kg/m2), body fat % (29.8 ± 2.4 vs. 23.7 ± 1.3) and total blood BCAA (438.1 ± 21.7 vs. 385.0 ± 14.5 umol/L, p = 0.048). Palmitate Ra was much higher in IR subjects (189.0 ± 13.5 vs. 151.8 ± 8.5, p = 0.027) indicating greater exposure of skeletal tissue to circulatory FFA. This was accompanied by greater palmitate oxidation (60.6 ± 4.3 vs. 46.2 ± 3.5, p = 0.016) such that plasma concentration was not significantly different between the comparator groups (124.7 ± 5.7 vs. 108.9 ± 13.1, p = 0.295). Leucine Ra (152.8 ± 5.5 vs. 144.6 ± 3.2, p = 0.067) and oxidation (19.2 ± 0.4 vs. 16.3 ± 0.7, p = 0.028) were also higher in IR but leucine oxidative capacity, defined as percentage leucine flux oxidized, was significantly lower (11.9 ± 0.4 vs. 10.6 ± 0.4, p = 0.028).ConclusionsElevated blood BCAA in healthy non‐obese but IR men is a consequence of both greater Ra and impaired BCAA oxidative capacity and this is associated with excessive FFA oxidation.Support or Funding InformationSupported by SingHealth Medicine Academic Clinical Program (03/FY2014/P1/06‐A16)