Endogenous Glucagon-Like Peptide 1 Enhanced by Vildagliptin Reduces Triglyceride Appearance During Intraduodenal Fat Infusion in Type 2 Diabetes

Glucagon-like peptide 1 (GLP-1) receptor agonists improve dyslipidemia and reduce cardiovascular risk in type 2 diabetes (T2D), but the role of endogenous GLP-1 in lipid metabolism remains unclear. We evaluated the effect of dipeptidyl peptidase 4 (DPP-4) inhibition on the response of plasma triglycerides (TGs) to intraduodenal lipid and a mixed meal, and the impact of GLP-1 receptor blockade with exendin(9-39) in T2D. Fifteen participants with T2D, managed by diet and/or metformin, were studied on three occasions in a double-blind, randomized, crossover design. Vildagliptin (50 mg) or placebo was administered orally (t = −60 min), followed by intravenous exendin(9-39) from t = −60 to 150 min on one of the two vildagliptin days or 0.9% saline on two other days. A lipid emulsion was infused intraduodenally (2 kcal/min, t = 0–120 min), followed by a mixed meal (t = 120–150 min). Plasma TG levels, quantified by liquid chromatography– tandem mass spectrometry, increased after lipid and meal, with most individual TGs corresponding to those in the lipid emulsion. Vildagliptin reduced TG(54:4) and TG(54:5) concentrations (each P < 0.01), without affecting total TGs. Blocking endogenous GLP-1 during vildagliptin treatment increased plasma total TGs (P < 0.001), associated with elevations of 10 individual TG species (P < 0.05 each). These outcomes suggest that endogenous GLP-1 contributes to the physiological modulation of postprandial TG appearance in T2D.