Endogenous Glucagon-Like Peptide 1 Enhanced by Vildagliptin Reduces Triglyceride Appearance During Intraduodenal Fat...

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.

The contribution of endogenous glucagon-like peptide 1 (GLP-1) to postprandial lipid metabolism in type 2 diabetes (T2D) is poorly defined. The specific questions we wanted to answer were what is the effect of dipeptidyl peptidase 4 (DPP-4) inhibition on plasma triglyceride (TG) profiles during an intraduodenal lipid infusion and following a mixed meal in T2D, and how does blockage of endogenous GLP-1 signaling affect these responses? We found that plasma TGs increased after intraduodenal lipid infusion and the meal, with most species reflecting the infused lipid emulsion. Vildagliptin selectively reduced TG(54:4) and TG(54:5) species, whereas exendin(9-39) increased total TGs and 10 individual TG species. The implications of our finding are that endogenous GLP-1 plays a physiological role in the regulation of postprandial lipid handling in T2D.