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) in plasma, 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~30 kg/m2) adults with impaired fasting glucose or untreated diabetes. Participants 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). 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.

Does Citrulline Sit at the Nexus of Metformin’s Pleotropic Effects on Metabolism and Mediate Its Salutatory Effects in Individuals With Type 2 Diabetes?

“…Of note, metformin also reduced serum concentrations of arginine in their unadjusted model. These results corroborate our prior findings that 3 months of metformin plus pioglitazone therapy reduced plasma concentrations of citrulline and arginine in overweight/obese adults with impaired fasting glucose (9). Likewise, acutely administering metformin reduced plasma citrulline concentrations in African Americans without diabetes (10).…”

“…Indeed, in the "human discovery" study, serum concentrations of citrulline, arginine, ornithine, and urea were all lower (based on the unadjusted model) in the metformin-treated versus untreated participants with T2D (8). Metformininduced reductions in these metabolites likely reflect reductions in urea biosynthesis, secondary to reductions in gluconeogenesis (9). Reductions in serum/plasma amino acids may also result in reduced pressure for the liver and kidneys to perform high rates of urea detoxification secondary to reductions in protein breakdown.…”

“…A hallmark finding of metformin therapy includes reductions in urea cycle metabolites citrulline, arginine, and ornithine (8)(9)(10). Indeed, in the "human discovery" study, serum concentrations of citrulline, arginine, ornithine, and urea were all lower (based on the unadjusted model) in the metformin-treated versus untreated participants with T2D (8).…”

“…The impact of metformin on whole-body urea biosynthesis could be tested using stable isotope methodologies (22). For example, in vivo synthesis of [1][2][3][4][5][6][7][8][9][10][11][12][13] C]urea following administration of [1][2][3][4][5][6][7][8][9][10][11][12][13] C]acetate has been reported as a reliable method for measuring in vivo urea biosynthesis (22). Of interest, in the present "translational" study, metformin did not affect citrulline concentrations in the db/db diabetic mouse liver and metformin's effects on other urea cycle metabolites was not evaluated.…”

Nutrient Transporter Expression in the Jejunum in Relation to Body Mass Index in Patients Undergoing Bariatric Surgery

“…In a subset of patients ( n = 30) with overnight fasted, pre-operative, serum that were stored at −80 °C, we measured serum concentrations of branched-chain amino acids (leucine, isoleucine, and valine) and aromatic amino acids (phenylalanine and tyrosine) by liquid chromatography (LC) mass spectrometry as previously described [13] and concentrations of short-chain fatty acids (isobutyric acid, butyric acid, isovaleric acid, valeric acid, isocaproic acid, and hexanoic acid) by gas chromatography (GC) mass spectrometry as previously described [14]. All measures for isobutyric acid were above the standard curve; due to sample constraints, we were unable to re-run a diluted sample to obtain these values, and therefore we excluded these data from the present analysis.…”