The effects of macronutrients composition on hormones and substrates during a meal tolerance test in drugnaive and sitagliptin-treated individuals with type 2 diabetes: a randomized crossover study

Cristina da Silva Schreiber, Alex Rafacho, Renata Silverio, Roberto Betti, Antonio Carlos Lerário, Ana Maria Pita Lotenberg, Klara Rahmann, Carolina Piras de Oliveira, Bernardo Léo Wajchenberg, Protásio Lemos da Luz, Cristina da Silva Schreiber, Alex Rafacho, Renata Silverio, Roberto Betti, Antonio Carlos Lerário, Ana Maria Pita Lotenberg, Klara Rahmann, Carolina Piras de Oliveira, Bernardo Léo Wajchenberg, Protásio Lemos da Luz

Abstract

Objective: To evaluate the effect of sitagliptin treatment in early type 2 diabetes mellitus (T2DM) and the impact of different macronutrient compositions on hormones and substrates during meal tolerance tests (MTT).

Methods: Half of the drug-naive patients with T2DM were randomly assigned for treatment with 100 mg of sitagliptin, q.d., or placebo for 4 weeks and then submitted to 3 consecutive MTT intercalated every 48 h. The MTTs differed in terms of macronutrient composition, with 70% of total energy from carbohydrates, proteins, or lipids. After 4 weeks of washout, a crossover treatment design was repeated. Both patients and researchers were blinded, and a repeated-measures ANOVA was employed for statistical analysis.

Results: Sitagliptin treatment reduced but did not normalize fasting and post-meal glucose values in the three MTTs, with lowered area-under-glucose-curve values varying from 7% to 15%. The sitagliptin treatment also improved the insulinogenic index (+86%) and the insulin/glucose (+25%), glucagon-like peptide-1/glucose (+46%) incremental area under the curves. Patients with early T2DM maintained the lowest glucose excursion after a protein- or lipid-rich meal without any major change in insulin, C-peptide, glucagon, or NEFA levels.

Conclusion: We conclude that sitagliptin treatment is tolerable and contributes to better control of glucose homeostasis in early T2DM, irrespective of macronutrient composition. The blood glucose excursion during meal ingestion is minimal in protein- or fat-rich meals, which can be a positive ally for the management of T2DM. Clinical trial no: NCT00881543.

Keywords: Diabetes; diet; glucose tolerance; glycemia; incretins; meal tolerance test.

Conflict of interest statement

Disclosure: the CPO has been an employee of Eli Lilly and Company since 2010 and an owner of stock in Eli Lilly and Company. The remaining authors have no relevant conflict of interest to disclose.

Figures

Figure 1. Flow chart and gender-specific sitagliptin…
Figure 1. Flow chart and gender-specific sitagliptin effect. In (A) the flow chart of study participants used in the analysis. In (B and C) the lack of correlation between plasma insulin and plasma GLP-1 or NEFA, after 4 weeks of 100 mg sitagliptin treatment, q.d. In (D) the delta (Δ) values for the Adipo-IR (obtained in relation to the respective gender-placebo values) after sitagliptin treatment separated by gender. In (E) the Δ IGI (obtained in relation to the respective gender-placebo values) after sitagliptin treatment grouped by gender. A Pearson correlation test was applied in (B, C). Data are mean ± SD in (D, E). The statistical difference was obtained with an unpaired t-test (D, E). n = 16 for (B, C) and 6-7 (female) and 8-9 (male) for (D, E). GLP-1, glucagon-like peptide-1; NEFA, non-esterified fatty acids; q.d. derives from Latin quaque die and means once daily; Adipo-IR, adipose tissue insulin resistance index, IGI, insulinogenic index.
Figure 2. Effect of sitagliptin treatment on…
Figure 2. Effect of sitagliptin treatment on hormones and substrates during different MTTs. In (A, F, K) the plasma glucose, insulin and C-peptide values during a carbohydrate-rich meal tolerance test in placebo- and sitagliptin-treated (100 mg, q.d., for 4 weeks) patients with early T2D and the respective AUCs. In (B, G, L) the plasma glucose, insulin and C-peptide values and their respective AUCs during a protein-rich meal tolerance test 48 h after the carbohydrate-rich meal tolerance test (same participants). In (C, H, M) the plasma glucose, insulin and C-peptide values and their respective AUCs during a lipid-rich meal tolerance test 48 h after the protein-rich meal tolerance test (same participants). In (D, I, N) the iAUC for plasma glucose, insulin and C-peptide, respectively, separated per macronutrient predominance. In (E, J, O) the Δ (0-60 min) values for plasma glucose, insulin and C-peptide, respectively, separated per macronutrient predominance. Data are mean ± SD. The statistical difference was obtained with 2-way RM for line graphs, paired Student t-test for AUC graphs (A-C, F-H, K-M), and 1-way ANOVA with Tukey post hoc test for scatter graphs (D, E, I, J, N, O). * Means significantly different from baseline values and # means significantly different from placebo group being * or # = p < 0.05, ** = p < 0.01, *** or ### = p < 0.001 and **** or #### = p < 0.0001. n = 16 for all graphs. AUC, area-under-the-curve; iAUC, incremental AUC, MTT, meal tolerance test; T2DM, type 2 diabetes mellitus; q.d., from Latin quaque die, means once daily; CHO, carbohydrate-rich meal; PTN, protein-rich meal; LIP, lipid-rich meal.
Figure 3. Effect of sitagliptin treatment on…
Figure 3. Effect of sitagliptin treatment on hormones and substrates during different MTTs. In (A, E, I) the plasma GLP-1, glucagon and NEFA values during a carbohydrate-rich meal tolerance test in placebo- and sitagliptin-treated (100 mg, q.d., for 4 weeks) patients with early T2D and the respective AUCs. In (B, F, J) the plasma GLP-1, glucagon and NEFA values and their respective AUCs during a protein-rich meal tolerance test 48 h after the carbohydrate-rich meal tolerance test (same participants). In (C, H, M) the plasma GLP-1, glucagon and NEFA values and their respective AUCs during a lipid-rich meal tolerance test 48 h after the protein-rich meal tolerance test (same participants). In (D, H, L) the Δ (0-60 min) values for plasma GLP-1, glucagon and NEFA, respectively, separated per macronutrient predominance. Data are mean ± SD. The statistical difference was obtained with a 2-way RM for line graphs (A-C, E-G, I-K), and 1-way ANOVA with Tukey post hoc test for scatter graphs (D, H, L). * means significantly different from baseline values being * = p < 0.05, ** = p < 0.01, *** = p < 0.001 and **** = p < 0.0001. n = 16 for all graphs. AUC: area-under-the-curve; iAUC: incremental AUC; MTT: meal tolerance test; T2DM: type 2 diabetes mellitus; q.d.: from Latin quaque die, means once daily; GLP-1: glucagon-like peptide-1; NEFA: non-esterified fatty acids; CHO: carbohydrate-rich meal; PTN: protein-rich meal; LIP: lipid-rich meal.

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