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.
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.