Effect of insulin sensitizer therapy on amino acids and their metabolites

Abstract

Aims: Prior studies have reported that elevated concentrations of several plasma amino acids (AA), particularly branched chain (BCAA) and aromatic AA predict the onset of type 2 diabetes. We sought to test the hypothesis that circulating BCAA, aromatic AA and related AA metabolites decline in response to the use of insulin sensitizing agents in overweight/obese adults with impaired fasting glucose or untreated diabetes.

Methods: We performed a secondary analysis of a randomized, double-blind, placebo, controlled study conducted in twenty five overweight/obese (BMI ~30kg/m(2)) adults with impaired fasting glucose or untreated diabetes. Participants were randomized to three months of pioglitazone (45mg per day) plus metformin (1000mg twice per day, N=12 participants) or placebo (N=13). We measured insulin sensitivity by the euglycemic-hyperinsulinemic clamp and fasting concentrations of AA and AA metabolites using ultra-pressure liquid chromatography tandem mass spectrometry before and after the three-month intervention.

Results: Insulin sensitizer therapy that significantly enhanced insulin sensitivity reduced 9 out of 33 AA and AA metabolites measured compared to placebo treatment. Moreover, insulin sensitizer therapy significantly reduced three functionally clustered AA and metabolite pairs: i) phenylalanine/tyrosine, ii) citrulline/arginine, and iii) lysine/α-aminoadipic acid.

Conclusions: Reductions in plasma concentrations of several AA and AA metabolites in response to three months of insulin sensitizer therapy support the concept that reduced insulin sensitivity alters AA and AA metabolites.

Trial registration: ClinicalTrials.gov NCT00443755.

Keywords: Biomarkers; Diabetes; Insulin resistance; Metabolomics; Obesity.

Conflict of interest statement

Disclosure Summary

We have no conflicts of interest to disclose.

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Fig. 1

Effects of three months of insulin sensitizer therapy on amino acids and amino acid metabolites. Twenty five overweight/obese (BMI~30 kg/m2) adults with impaired fasting glucose or untreated diabetes were randomized to three months of pioglitazone (45 mg per day) plus metformin (1000 mg twice per day, N = 12 participants) or placebo (n=13). Compared to placebo, insulin sensitizer therapy increased fasting plasma concentrations of phenylalanine (A), tyrosine (B), glutamic acid (C), arginine (D), citrulline (E), aspartic acid (F), lysine (G), α-aminoadipic acid (H), and ethanolamine (I). The values represent the individual percent changes for the insulin sensitizer (open circles) and placebo (closed circles) groups. In addition, the median percent change and interquartile ranges are also provided. P-Values are from the Wilcoxon Rank Sum Test for the difference between the absolute change scores using the normal approximation.

Fig. 2

Venn diagram for plasma amino acid and amino acid metabolites that were reduced in response to an acute or chronic increase in insulin action. Compared to saline, 22 amino acids and amino acid metabolites were reduced in response to an acute infusion of insulin in healthy young adults (n = 9 per group) (grey circle). Compared to placebo, nine amino acids and amino acid metabolites were reduced in response to three months of insulin sensitizer therapy in overweight/obese (BMI~30 kg/m2) adults with impaired fasting glucose or untreated diabetes (n = 13, placebo; n = 12 insulin sensitizer) (white circle). Three functional pairs of amino acids and amino acid metabolites (phenylalanine/tyrosine, lysine/α-aminoadipic acid, and arginine/citrulline) were reduced in response to both the acute infusion of insulin as well as three months of insulin sensitizer therapy. Finally, serine concentrations were reduced in response to the acute infusion of insulin, while it was increased in response to three months of insulin sensitizer therapy.