Is a Diabetes-Linked Amino Acid Signature associated with Beta Blocker-Induced Impaired Fasting Glucose?
Background—The five amino acid (AA) signature including isoleucine (Ile), leucine (Leu), valine (Val), tyrosine (Tyr), and phenylalanine (Phe) has been associated with incident diabetes and insulin resistance. We investigated whether this same AA signature, single nucleotide polymorphisms (SNPs) in genes in their catabolic pathway, were associated with development of impaired fasting glucose (IFG) after atenolol treatment.
Methods and Results—Among 234 European American participants enrolled in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study and treated with atenolol for 9 weeks, we prospectively followed a nested cohort that had both metabolomics profiling and genotype data available, for the development of IFG. We assessed the association between baseline circulating levels of Ile, Leu, Val, Tyr and Phe, as well as SNPs in BCAT1 and PAH with development of IFG. All baseline AA levels were strongly associated with IFG development. Each increment in standard deviation of the five AAs was associated with the following odds ratio and 95% confidence interval for IFG based on fully adjusted model: Ile 2.29 (1.31-4.01), Leu 1.80 (1.10-2.96), Val 1.77 (1.07-2.92), Tyr 2.13 (1.20-3.78) and Phe 2.04 (1.16-3.59). The composite p value was 2x10-5. Those with PAH (rs2245360) AA genotype had the highest incidence of IFG (p for trend=0.0003).
Conclusions—Our data provide important insight into the metabolic and genetic mechanisms underlying atenolol associated adverse metabolic effects.
Clinical Trial Registration—clinicaltrials.gov; Unique Identifier: NCT00246519
- Received August 22, 2013.
- Revision received February 28, 2014.
- Accepted March 13, 2014.