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

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.