title: The amino acid response to a mixed meal in patients with type 2 diabetes: effect of sitagliptin treatment.
abstract: OBJECTIVE
  Amino acid (AA) metabolism is altered in type 2 diabetes (T2D), and fasting levels of α-hydroxybutyrate (α-HB), a biomarker for insulin resistance, have been suggested to track AA metabolism. We investigated the changes in AA and α-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 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 α-HB was higher [7.5(2.7) vs. 5.9(1.3) µg/ml, p = 0.04 T2D vs. CT], and its meal-induced increments were larger [24(99) vs. -41(86) µg/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 α-HB increments [-114(250) vs. 114(428) µg/ml · h, p = 0.002] decreased with sitagliptin, and meal-induced NEFA suppression was improved. Changes in BCAA and α-HB were reciprocally related to changes in insulin sensitivity (ρ = -0.37 and -0.43, p ≤ 0.01).
  
  
  CONCLUSIONS
  T2D is associated with a hyperaminoacidaemic response to MTT, which circulating α-HB levels track. Sitagliptin-induced glycaemic improvement was associated with reductions in BCAA and α-HB excursions and better NEFA suppression, in parallel with improved insulin sensitivity, confirming that α-HB is a readout of metabolic overload.
authors.affiliation: Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Muscelli
authors.forename: S
authors.initials: S
authors.lastname: Frascerra
authors.forename: A
authors.initials: A
authors.lastname: Casolaro
authors.forename: S
authors.initials: S
authors.lastname: Baldi
authors.forename: A
authors.initials: A
authors.lastname: Mari
authors.forename: W
authors.initials: W
authors.lastname: Gall
authors.forename: J
authors.initials: J
authors.lastname: Cobb
authors.forename: E
authors.initials: E
authors.lastname: Ferrannini
mesh_terms: D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000187:drug effects* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage*; D005215:Fasting; D005260:Female; D006801:Humans; D006885:Hydroxybutyrates / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D062407:Meals; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000008:administration & dosage*
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006885:Hydroxybutyrates; D007328:Insulin; D011719:Pyrazines; D014230:Triazoles; C031570:2-hydroxybutyric acid; D000068900:Sitagliptin Phosphate
keywords: 1-linoleoyl-glycerophosphocholine; T2D; branched-chain aminoacids; sitagliptin; α-hydroxybutyrate