the Effect of Insulin on α-Aminoadipic Acid Metabolism – Stable Isotope-Based Approach with High Resolution Mass Spectrometry

Presentation Number: SUN 591
Date of Presentation: April 2nd, 2017

Alice Y Chang*1, Dhanajay Sakrikar2, Antigoni Z Lalia1, Xuan-Mai T Persson1, Michele Schiavon3, Ian R Lanza2, Claudio Cobelli3 and K. Sreekumaran Nair1
1Mayo Clinic, Rochester, MN, 2Mayo Clinic College of Medicine, Rochester, MN, 3University of Padova, Padova, Italy

Abstract

Plasma concentrations of α-aminoadipic acid (AAA) are higher with insulin resistance and decrease on insulin sensitizer treatment, and this metabolite of lysine has been reported to predict the development of type 2 diabetes in population-based cohorts. In order to determine whether AAA concentrations are determined by insulin, we used stable isotopes to measure AAA kinetics and appearance rate from lysine.

Methods: We used intravenous [α-15N1]-lysine and [13C1]-AAA as tracers in 12 healthy participants (mean age 32.5±9.2 years, BMI 21.9±1.6 kg/m2) to measure lysine and AAA kinetics. After a baseline study of 4 hours we infused regular insulin (1.55 mU/kg Fat Free Mass (FFM)/min) and maintained blood glucose between 85 and 95 with dextrose infusion. Insulin sensitivity (SI) was estimated from a 3-hr 75 gm oral glucose tolerance test using the oral glucose and C-peptide minimal models. We measured single isotopic (15N or 13C) enrichment of lysine and AAA and double isotopic (15N and 13C ) enrichment of AAA in plasma samples by a novel high resolution mass spectrometry approach.

Results: Endogenous plasma concentrations of lysine and AAA decreased with insulin (Lysine:146.4±4.5 to 120.6±4.9 µM, p < 0.01; AAA: 0.66± 0.05 to 0.51±0.03 µM, p=0.02). Steady state baseline lysine flux was positively correlated with SI (R2= 0.4, p=0.04) and significantly decreased with insulin (lysine: 109.0±6.0 to 91.2±4.7 µmol/kgFFM/hr, p =0.03). Although AAA flux did not change with insulin (0.41±0.03 to 0.35±0.02 µmol/kgFFM/hr, p=0.23), the conversion rate of lysine to AA significantly increased with insulin (0.12±0.01 to 0.15±0.01 µmol/kgFFM/hr, p =0.04). There were no correlations of AAA flux or conversion rate with SI.

Conclusion: Lysine flux is associated with insulin sensitivity and decreases with insulin administration. The insulin-induced fall in lysine flux is related to accelerated conversion of lysine to AAA. Therefore, it appears that insulin primarily drives lysine metabolism causing changes in AAA concentrations. We propose that insulin resistance might differentially affect lysine and AAA flux to explain increased AAA in insulin resistant states.

 

Nothing to Disclose: AYC, DS, AZL, XMTP, MS, IRL, CC, KSN