Is diabetes mellitus-linked amino acid signature associated with β-blocker-induced impaired fasting glucose?

Abstract

Background: The 5-amino acid (AA) signature, including isoleucine, leucine, valine, tyrosine, and phenylalanine, has been associated with incident diabetes mellitus and insulin resistance. We investigated whether this same AA signature, single-nucleotide polymorphisms in genes in their catabolic pathway, was 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 isoleucine, leucine, valine, tyrosine, and phenylalanine, as well as single-nucleotide polymorphisms in branched-chain amino-acid transaminase 1 (BCAT1) and phenylalanine hydroxylase (PAH) with development of IFG. All baseline AA levels were strongly associated with IFG development. Each increment in standard deviation of the 5 AAs was associated with the following odds ratio and 95% confidence interval for IFG based on a fully adjusted model: isoleucine 2.29 (1.31-4.01), leucine 1.80 (1.10-2.96), valine 1.77 (1.07-2.92), tyrosine 2.13 (1.20-3.78), and phenylalanine 2.04 (1.16-3.59). The composite P value was 2×10(-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- http://www.clinicaltrials.gov; Unique Identifier: NCT00246519.

Keywords: amino acids; metabolomics; pharmacogenetics.

Conflict of interest statement

Conflict of Interest Disclosures: RK-D holds patents in the metabolomics field. All others have none.

Figures

Figure 1

Odds ratio and 95% Confidence Intervals (per standard deviation) for baseline amino acid level and development of impaired fasting glucose (IFG) from logistic regressions adjusted for age, gender, BMI, baseline fasting glucose and insulin and HOMA-IR (model 4), n=122. BMI = Body Mass Index, HOMA-IR=Homeostatic Model Assessment – Insulin Resistance, Ile=isoleucine, Leu=leucine, Val=valine, Tyr=tyrosine, Phe=phenylalanine

Figure 2

From the genotyped population, incidence of impaired fasting glucose according to the top PAH SNP, n=184. IFG=impaired fasting glucose.