Insulin is a key regulator of amino acid metabolism. Many plasma amino acids, including lysine and its metabolite, α-aminoadipic acid (α-AA), a predictor for developing diabetes, are elevated in insulin resistance (IR). In 18 overweight women with IR and polycystic ovary syndrome compared with 12 lean control women, high physiological insulin during a euglycemic clamp failed to normalize many elevated amino acid metabolites, including branched-chain and aromatic amino acids, α-aminobutyric acid, and lysine, but normalized α-AA. To understand the underpinnings of differential responses of lysine and its metabolic product α-AA to high physiological insulin in IR compared with control participants, we developed a kinetic model using [α-15N1]-lysine and [13C1]-α-AA as tracers and measured the two tracers simultaneously in α-AA by innovative mass spectrometry. High insulin increased lysine conversion to α-AA in the IR and control groups but failed to normalize plasma lysine concentrations in IR due to a decrease in lysine metabolic clearance rate (MCR). In contrast, despite higher conversion rates of lysine to α-AA by high insulin, α-AA concentration decreased in IR because of the sustained greater MCR of α-AA. The abnormal amino acids and metabolites, even while on high physiological insulin, could potentially explain many functional derangements in IR.

Article Highlights
  • This study aimed to determine whether high physiological insulin normalizes abnormal plasma amino metabolites in individuals with insulin resistance.

  • High insulin levels failed to normalize many amino acids, including lysine, but normalized the lysine metabolite α-aminoadipic acid (α-AA) reported to predict future diabetes.

  • A novel kinetic model was developed using two stable isotope tracers to measure lysine and α-AA kinetics simultaneously in humans during a single protocol using innovative mass spectrometry that can be applied to study other amino acid kinetics.

  • High physiological insulin normalized α-AA in insulin resistance by maintaining its higher metabolic clearance, suggesting that high α-AA resulted from insulin resistance.

Clinical trials reg. no. NCT02086526, clinicaltrials.gov

This article contains supplementary material online at https://doi.org/10.2337/figshare.26152849.

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