# The Response of Alpha‐Aminoadipic Acid (2‐AAA) to Short Term Lysine Ingestion in Healthy Individuals

## TL;DR

This study shows that lysine intake increases plasma and urine levels of 2-AAA, a metabolite linked to diabetes and heart disease, and that this effect varies among individuals.

## Contribution

The study demonstrates that lysine ingestion leads to inter-individual variation in 2-AAA metabolism and stimulates endocrine responses.

## Key findings

- Orally ingested lysine is metabolized to 2-AAA within hours, with detectable levels in plasma and urine.
- Individuals with higher waist-to-hip ratio excrete more 2-AAA, tryptophan, and kynurenine.
- Lysine ingestion increases plasma insulin, C-peptide, glucagon, and GLP-1 levels.

## Abstract

Higher circulating levels of the metabolite alpha‐aminoadipic acid (2‐AAA) associate with increased risk of diabetes and cardiometabolic disease. 2‐AAA is metabolised from lysine, an essential dietary amino acid. However, the effects of lysine intake on plasma levels of 2‐AAA were unclear. We measured post‐prandial changes in plasma and urine levels of 2‐AAA in healthy individuals in response to oral intake of 13C isotope‐labelled lysine and assessed relationships with markers of glucose homeostasis.

We recruited healthy individuals (N = 16) to an acute lysine challenge. We administered 5 g of 13C Lysine‐HCL in 50 mL water as an oral bolus. We measured the appearance of 13C lysine and 13C 2‐AAA in plasma and urine over a period of 6 h post‐ingestion and assessed changes in insulin, C‐peptide, glucagon, and GLP‐1.

We found that 13C lysine and 13C 2‐AAA were detectable in plasma 30 min post‐ingestion, peaking on average 2 h post‐ingestion. Interestingly, non‐labelled lysine and non‐labelled 2‐AAA also increased. Individuals with higher plasma levels of 13C 2‐AAA post‐ingestion also had higher levels of 13C 2‐AAA in urine. The rate of appearance of 2‐AAA in plasma and excretion in urine differed between individuals and was associated with differences in waist‐to‐hip ratio (WHR). We observed increases in plasma insulin, C‐peptide, glucagon, and GLP‐1 post‐lysine ingestion.

Our data suggest that orally ingested lysine is catabolised to 2‐AAA over several hours. However, lysine ingestion also stimulates an increase in 2‐AAA from endogenous sources. The rate of production and excretion differs between individuals, suggestive of controlled regulation of this metabolic pathway. Individuals with a higher WHR, indicative of greater visceral adiposity, may have increased excretion of 2‐AAA, tryptophan, and kynurenine.

Higher circulating levels of the metabolite alpha‐aminoadipic acid (2‐AAA) associate with increased risk of diabetes and cardiometabolic disease. We found that administration of 13C lysine in healthy volunteers associates with inter‐individual variation in lysine‐2‐AAA metabolism and leads to increases in plasma insulin, C‐peptide, glucagon, and GLP‐1 post‐lysine ingestion.