Effect of insulin sensitizer therapy on amino acids and their metabolites.
OBJECTIVE
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.
Division of Endocrinology, Endocrinology Research Unit, Mayo Clinic College of Medicine, Rochester, MN. Electronic address: bairving@geisinger.edu.
Brian A
BA
Irving
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN.
Rickey E
RE
Carter
Division of Endocrinology, Endocrinology Research Unit, Mayo Clinic College of Medicine, Rochester, MN.
Mattias
M
Soop
Department of Nursing, Mayo Clinic College of Medicine, Rochester, MN.
Audrey
A
Weymiller
Department of Family Medicine, Mayo Clinic College of Medicine, Rochester, MN.
Husnain
H
Syed
Division of Endocrinology, Endocrinology Research Unit, Mayo Clinic College of Medicine, Rochester, MN.
Helen
H
Karakelides
Division of Endocrinology, Endocrinology Research Unit, Mayo Clinic College of Medicine, Rochester, MN.
Sumit
S
Bhagra
Division of Endocrinology, Endocrinology Research Unit, Mayo Clinic College of Medicine, Rochester, MN.
Kevin R
KR
Short
Division of Reproductive Endocrinology, Mayo Clinic College of Medicine, Rochester, MN.
Laura
L
Tatpati
Division of Endocrinology, Endocrinology Research Unit, Mayo Clinic College of Medicine, Rochester, MN.
Rocco
R
Barazzoni
Division of Endocrinology, Endocrinology Research Unit, Mayo Clinic College of Medicine, Rochester, MN. Electronic address: nair@mayo.edu.
K Sreekumaran
KS
Nair
D000328:Adult; D000596:Amino Acids / Q000097:blood*; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D004311:Double-Blind Method; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000819:agonists*; D007333:Insulin Resistance; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D009765:Obesity / Q000378:metabolism; D050177:Overweight / Q000378:metabolism; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use
D000596:Amino Acids; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D008687:Metformin; D000077205:Pioglitazone
Biomarkers; Diabetes; Insulin resistance; Metabolomics; Obesity