Impaired Succinate Response to a Mixed Meal in Obesity and Type 2 Diabetes Is Normalized After Metabolic Surgery

Abstract

Objective: To explore the meal response of circulating succinate in patients with obesity and type 2 diabetes undergoing bariatric surgery and to examine the role of gastrointestinal glucose sensing in succinate dynamics in healthy subjects.

Research design and methods: Cohort I comprised 45 patients with morbid obesity and type 2 diabetes (BMI 39.4 ± 1.9 kg/m²) undergoing metabolic surgery. Cohort II was a confirmatory cohort of 13 patients (BMI 39.3 ± 1.4 kg/m²) undergoing gastric bypass surgery. Cohort III comprised 15 healthy subjects (BMI 26.4 ± 0.5 kg/m²). Cohorts I and II completed a 2-h mixed-meal tolerance test (MTT) before the intervention and at 1 year of follow-up, and cohort II also completed a 3-h lipid test (LT). Cohort III underwent a 3-h oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion (IIGI) study.

Results: In cohort I, succinate response to MTT at follow-up was greater than before the intervention (P < 0.0001). This response was confirmed in cohort II with a greater increase after 1 year of surgery (P = 0.009). By contrast, LT did not elicit a succinate response. Changes in succinate response were associated with changes in the area under the curve of glucose (r = 0.417, P < 0.0001) and insulin (r = 0.204, P = 0.002). In cohort III, glycemia, per se, stimulated a plasma succinate response (P = 0.0004), but its response was greater in the OGTT (P = 0.02; OGTT versus IIGI).

Conclusions: The meal-related response of circulating succinate in patients with obesity and type 2 diabetes is recovered after metabolic surgery.

Figure 1

Succinate response to a MTT. A and D: Fasting values of succinate before and 1 year after bariatric surgery for cohort I (A) and II (D). B and E: Time curves of plasma succinate response during an MTT (fold increase over basal values) for cohort I (B) and II (E). C and F: AUC of the succinate time curves normalized for fat mass (kg) for cohort I (C) and II (F). Data are mean ± SEM. Comparisons were tested using the Wilcoxon signed rank test (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001), and time curves were compared using repeated measures ANOVA (P values refer to the interaction between treatment and time). FM, fat mass; LGCP, laparoscopic greater curvature plication; RYGB, Roux-en-Y gastric bypass; SG, sleeve gastrectomy.

Figure 2

Cohort III, metabolic response to an OGTT and an IIGI study. A: The overlay of plasma glucose curves during OGTT and IIGI. B–E: The response of plasma insulin (B), C-peptide (C), GLP-1 (D), and succinate (E) during the OGTT and IIGI. Data are mean ± SEM. Time curves were compared using repeated measures ANOVA (P values refer to the interaction between treatment and time).