The amino acid response to a mixed meal in patients with type 2 diabetes: effect of sitagliptin treatment.

Aims: Amino acid (AA) metabolism is altered in type 2 diabetes (T2D), and fasting levels of alpha-hydroxybutyrate (alpha-HB), a biomarker for insulin resistance, have been suggested to track AA metabolism. We investigated the changes in AA and alpha-HB induced by a mixed-meal tolerance test (MTT) and the effects of sitagliptin treatment. Methods: Forty-seven T2D patients [56 +/- 7 years, body mass index (BMI) 29.9 +/- 4.2 kg/m(2)] were randomized to sitaglip in (100 mg/day, 6 weeks) or placebo. Seven age- and BMI-matched non-diabetic subjects served as control (CT). Results: During a 5-h MIT, branched-chain AA (BCAA) peaked earlier in T2D than CT [75(25) vs. 62(3) mmol(l.h over 2 h, median(interguartile range), p = 0.05], and rose higher [5-h increment: 31(23) vs. 19(24) mmol.h, p =005]. Fasting alpha-HB was higher [7.5(2.7) vs. 5.9(1.3) mu g/ml, p = 0.04 T20 vs. CT], and its meal-induced increments were larger [24(99) vs. 41(86) mu gml, p = a006]. Plasma non-esterified fatty acids (NFFA) declined during MU, but their increments were greater in patients (53 + 16 vs. 35 10 alpha-1E.h, p =0005). Compared to placebo, both BCAA [-6.4(21.11 vs. 0.0(48.0) mmolil.h, p = 0.01] and alpha-HB increments [-114(250) vs. 114(428) mu g/ml.h, p =0002] decreased with sitagliptin, and meal-induced NEFA suppression was improved. Changes in BCAA and alpha-HB were reciprocally related to changes in insulin sensitivity (I) = 0.37 and 0.43, p < 0.01). Conclusions: T20 is associated with a hyperaminoacidaemic response to MIT, which circulating alpha-HB levels track. Sitagliptin-induced glycaem c improvement was associated with reductions in BCAA and rx-HP excursions and better NEFA suppression, in parallel with improved insulin sensitivity, confirming that rx-HB is a readout of metabolic overload.