Low plasma carnosinase activity promotes carnosinemia after carnosine ingestion in humans

Abstract

A polymorphism in the carnosine dipeptidase-1 gene (CNDP1), resulting in decreased plasma carnosinase activity, is associated with a reduced risk for diabetic nephropathy. Because carnosine, a natural scavenger/suppressor of ROS, advanced glycation end products, and reactive aldehydes, is readily degraded in blood by the highly active carnosinase enzyme, it has been postulated that low serum carnosinase activity might be advantageous to reduce diabetic complications. The aim of this study was to examine whether low carnosinase activity promotes circulating carnosine levels after carnosine supplementation in humans. Blood and urine were sampled in 25 healthy subjects after acute supplementation with 60 mg/kg body wt carnosine. Precooled EDTA-containing tubes were used for blood withdrawal, and plasma samples were immediately deproteinized and analyzed for carnosine and beta-alanine by HPLC. CNDP1 genotype, baseline plasma carnosinase activity, and protein content were assessed. Upon carnosine ingestion, 8 of the 25 subjects (responders) displayed a measurable increase in plasma carnosine up to 1 h after supplementation. Subjects with no measurable increment in plasma carnosine (nonresponders) had approx. 2-fold higher plasma carnosinase protein content and approx. 1.5-fold higher activity compared with responders. Urinary carnosine recovery was 2.6-fold higher in responders versus nonresponders and was negatively dependent on both the activity and protein content of the plasma carnosinase enzyme. In conclusion, low plasma carnosinase activity promotes the presence of circulating carnosine upon an oral challenge. These data may further clarify the link among CNDP1 genotype, carnosinase, and diabetic nephropathy

Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity

“…Unlike rodents, humans have considerable serum CN1 activity which may even be higher in particular disease states, e.g., in diabetic individuals compared to healthy controls (Riedl et al 2010). Thus, as observed in healthy volunteers, carnosine supplementation only leads to a moderate increase in plasma carnosine for a limited period of time between 1 and 2 h because of its rapid degradation by CN1 (Everaert et al 2012) that may markedly limit carnosine's beneficial effects in humans.…”

Beta-alanine supplementation, muscle carnosine and exercise performance

“…However, in humans, circulating carnosine is readily degraded by the highly active serum carnosinase enzyme (CN1), mostly resulting in a low or even nonmeasurable plasma carnosine concentrations after supplementation or dietary ingestion. Though, Everaert et al [45] found that people with low CN1 activity and content show measurable increases in carnosinemia following carnosine ingestion in a dose (60 mg/kg body weight) far exceeding the normal dietary intake [36 & ]. Thereupon, the relevance of low serum CN1 activity toward athletic populations was demonstrated, as it was shown that explosive athletes at an elite level have lower serum CN1 activity and content, possibly resulting from genetic selection [46 & ].…”

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“…In diabetic patients with microvascular complications, non-invasive measurement of tissue carnosine concentrations by proton magnetic resonance spectroscopy (1H-MRS) shows a significant reduction of carnosine concentrations in skeletal muscles of patients with type 2 diabetes, but not in patients with type 1 diabetes [36]. Oral administration of β-alanine, the rate limiting amino acid for the biosynthesis of carnosine [48], to healthy volunteers during 4 weeks resulted in reduced fatigue after physical exercise and in 30-50% increase of carnosine storage in peripheral muscle tissue, as determined again by proton-MRS [52]. Interestingly, this accumulation is followed by a slow clearance of carnosine during 3-6 months, suggesting a prolonged efficacy of short-term intervention [49,53].…”