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

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posted on 2024-07-05, 19:03 authored by Alice Y Chang, Aneesh K Asokan, Antigoni Z. Lalia, Dhananjay Sakrikar, Ian R. Lanza, Xuan-Mai Petterson, K. Sreekumaran Nair

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] 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 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 α-AA by high insulin, α-AA concentration decreased in IR because of the sustained greater MCR of α-AA. The abnormal AAs and metabolites, even while on high physiological insulin, could potentially explain many functional derangements in IR.

Funding

This publication was made possible by Mayo Clinic Metabolomics Resource Core through grant number U24DK100469 from the National Institute of Diabetes and Digestive and Kidney Diseases, Building Interdisciplinary Careers in Women's Health Award K12HD065987, CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences, and R01AG062859.

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