Exenatide, a glucagon-like peptide-1 receptor agonist, acutely inhibits intestinal lipoprotein production in healthy humans.

OBJECTIVE Incretin-based therapies for the treatment of type 2 diabetes mellitus improve plasma lipid profiles and postprandial lipemia, but their exact mechanism of action remains unclear. Here, we examined the acute effect of the glucagon-like peptide-1 receptor agonist, exenatide, on intestinal and hepatic triglyceride-rich lipoprotein production and clearance in healthy humans. METHODS AND RESULTS Fifteen normolipidemic, normoglycemic men underwent 2 studies each (SC 10 μg exenatide versus placebo), 4 to 6 weeks apart, in random order, in which triglyceride-rich lipoprotein particle kinetics were examined with a primed, constant infusion of deuterated leucine and analyzed by multicompartmental modeling under pancreatic clamp conditions. A fed state was maintained during each study by infusing a high-fat, mixed macronutrient, liquid formula at a constant rate directly into the duodenum via a nasoduodenal tube. Exenatide significantly suppressed the plasma concentration and production rate of triglyceride-rich lipoprotein-apolipoprotein B-48, but not of triglyceride-rich lipoprotein-apolipoprotein B-100. CONCLUSIONS These results suggest a possible direct effect of exenatide on intestinal lipoprotein particle production, independent of changes in weight gain and satiety as seen in long-term studies and independent of changes in gastric emptying. This finding expands our understanding of the effects of exenatide in metabolic regulation beyond its primary therapeutic role in regulation of glucose homeostasis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov, NCT01056549.