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.

BackgroundPolycystic ovary syndrome (PCOS) is characterized by a hyperandrogenic state and frequently develops skeletal muscle insulin resistance. We determined whether testosterone adversely affects insulin action by increasing serine phosphorylation of IRS-1636/639 in differentiated rat skeletal muscle myotubes. The phosphorylation of Akt, mTOR, and S6K, downstream targets of the PI3-kinase-IRS-1 complex were also studied.MethodsPrimary differentiated rat skeletal muscle myotubes were subjected to insulin for 30 min after 16-hour pre-exposure to either low (20 ng/ml) or high (200 ng/ml) doses of testosterone. Protein phosphorylation of IRS-1 Ser636/639, Akt Ser473, mTOR-Ser2448, and S6K-Thr389 were measured by Western blot with signal intensity measured by immunofluorescence.ResultsCells exposed to 100 nM of insulin had increased IRS-1 Ser636/639 and Akt Ser473 phosphorylation. Cells pre-exposed to low-dose testosterone had significantly increased insulin-induced mTOR-Ser2448 and S6K-Thr389 phosphorylation (p<0.05), and further increased insulin-induced IRS-1 Ser636/639 phosphorylation (p = 0.042) compared to control cells. High-dose testosterone pre-exposure attenuated the insulin-induced mTOR-Ser2448 and S6K-Thr389 phosphorylation.ConclusionsThe data demonstrated an interaction between testosterone and insulin on phosphorylation of intracellular signaling proteins, and suggests a link between a hyperandrogenic, hyperinsulinemic environment and the development of insulin resistance involving serine phosphorylation of IRS-1 Ser636/639. These results may guide further investigations of potential mechanisms of PCOS-related insulin resistance.

BCAA increased skeletal muscle MAPR in the young participants in comparison with saline, but this effect was not seen in the elderly participants indicating, that unlike in the young, BCAA does not increase muscle mitochondrial function in the elderly.

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Objective: To determine whether targeted pharmacological improvement of insulin sensitivity will normalize the associated elevations of thrombotic and inflammatory cardiovascular disease (CVD) biomarkers in individuals with insulin resistance. Patients and Methods: Study 1 was a cross-sectional study of Asian Indians with and without diabetes mellitus and Northern European Americans without diabetes (nϭ14 each) conducted between December 11, 2003, and July 14, 2006. Study 2 was a secondary analysis of a double-blind randomized controlled study conducted between August 19, 2005, and August 24, 2010, that included 25 individuals with untreated diabetes or impaired fasting glucose who were randomized to receive placebo (nϭ13) or a combination of metformin, 1000 mg twice daily, and pioglitazone, 45 mg daily (nϭ12), for 3 months. In both studies, measurements of insulin sensitivity (euglycemic-hyperinsulinemic clamp) and plasma inflammatory and thrombotic factor concentrations were obtained on enrollment (studies 1 and 2) and after intervention (study 2). Results: Study 1 demonstrated significant correlations between insulin sensitivity and plasma adiponectin, highdensity lipoprotein cholesterol, plasminogen activator inhibitor 1, interleukin 6, tumor necrosis factor ␣, and triglycerides. Insulin sensitizer therapy significantly improved insulin sensitivity, inflammatory cytokines except interleukin 6, and thrombotic factors except fibrinogen, without concomitant changes in weight, blood pressure, or body composition. Conclusion: Insulin sensitizer therapy ameliorates inflammatory and thrombotic factors implicated in developing CVD. Interventions to improve insulin sensitivity may thus be considered as therapeutic options to reduce CVD burden in insulin-resistant states, although further research is needed to determine long-term effects on morbidity and mortality. Trial Registration: clinicaltrials.gov identifier: NCT00443755 (study 2)