Insulin regulation of lysine and α-aminoadipic acid dynamics and amino metabolites in insulin-resistant and control women

<p dir="ltr">Insulin is a key regulator of amino acids (AAs) metabolism. Many plasma AAs, including lysine and its metabolite, α-aminoadipic acid (α-AA), a predictor for developing diabetes, are elevated in insulin resistance. In 18 insulin-resistant (IR) over-weight women with polycystic ovary syndrome compared to 12 lean controls, high physiological insulin during a euglycemic clamp failed to normalize many elevated AA metabolites, including branched-chain and aromatic AA, alpha-amino-butyric acid, and lysine, but normalized α-AA. To understand the underpinning of differential responses of lysine and its metabolic product α-AA to high physiological insulin in IR compared to controls, we developed a kinetic model utilizing [α-¹⁵N₁] lysine and [¹³C₁] <i>α-AA</i> as tracers and measured the two tracers simultaneously in <i>α-AA</i> by innovative mass spectrometry. High insulin increased lysine conversion to <i>α-AA</i> in IR and controls 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 <i>α-AA</i> by high insulin, <i>α-AA</i> concentration decreased in IR because of the sustained greater MCR of <i>α-AA</i>. The abnormal AAs and metabolites, even while on high physiological insulin, could potentially explain many functional derangements in IR.</p>