Muscelli, E, et al. The Amino Acid Response to a Mixed Meal in Patients with Type 2 Diabetes: Effect of Sitagliptin Treatment. Diabetes Obes Metab, 2014.

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/m2 ] were randomized to sitagliptin (100 mg/day, 6 weeks) or placebo. Seven age- and BMI-matched non-diabetic subjects served as control (CT). RESULTS: During a 5-h MTT, branched-chain AA (BCAA) peaked earlier in T2D than CT [75(25) vs. 62(3) mmol/l.h over 2 h, median(interquartile range), p = 0.05], and rose higher [5-h increment: 31(23) vs. 19(24) mmol/l.h, p = 0.05]. Fasting alpha-HB was higher [7.5(2.7) vs. 5.9(1.3) microg/ml, p = 0.04 T2D vs. CT], and its meal-induced increments were larger [24(99) vs. -41(86) microg/ml.h, p = 0.006]. Plasma non-esterified fatty acids (NEFA) declined during MTT, but their increments were greater in patients (53 +/- 16 vs. 35 +/- 10 mEq/l.h, p = 0.005). Compared to placebo, both BCAA [-6.4(21.1) vs. 0.0(48.0) mmol/l.h, p = 0.01] and alpha-HB increments [-114(250) vs. 114(428) microg/ml.h, p = 0.002] decreased with sitagliptin, and meal-induced NEFA suppression was improved. Changes in BCAA and alpha-HB were reciprocally related to changes in insulin sensitivity (rho = -0.37 and -0.43, p </= 0.01). CONCLUSIONS: T2D is associated with a hyperaminoacidaemic response to MTT, which circulating alpha-HB levels track. Sitagliptin-induced glycaemic improvement was associated with reductions in BCAA and alpha-HB excursions and better NEFA suppression, in parallel with improved insulin sensitivity, confirming that alpha-HB is a readout of metabolic overload.

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