GLP-1 (Glucagon-Like Peptide-1) Is Physiologically Relevant for Chylomicron Secretion Beyond Its Known Pharmacological Role

Objective: GLP-1R (glucagon-like peptide-1 receptor) agonists are increasingly used for the treatment of hyperglycemia in type 2 diabetes, with additional body weight reducing effects. Long-term administration of GLP-1R agonists has demonstrated cardioprotective effects, but the mechanism of cardiovascular protection is not currently known. Several studies in humans and animal models have shown suppression of intestinal CM (chylomicron) secretion and plasma TG (triglyceride) levels by pharmacological doses of GLP-1R agonists. The objective of this study was to assess the physiological role of endogenously secreted GLP-1 on CM secretion in rats. Approach and Results: Lymph flow, TG concentration, and TG output were assessed in mesenteric lymph duct-cannulated rats in response to an intraduodenal lipid bolus, preceded by an intraperitoneal injection of GLP-1R antagonist Ex (9-39; exendin 9-39) or vehicle. TG output was significantly enhanced in the presence of Ex (9-39) compared with vehicle over a 4-hour period post-lipid bolus (P=0.007). Total lymph volume (P=0.005) and TG mass (P<0.0001) cumulatively collected by the end of the 4-hour period were significantly increased by GLP-1R antagonist. Conclusions: GLP-1R antagonism enhanced intestinal TG output in rats through stimulation of lymph flow and increased lymph TG concentration. Endogenously secreted GLP-1 after a lipid bolus is sufficient to modulate CM secretion in the rat, with GLP-1 physiologically restraining CM secretion through the GLP-1R. It remains to be determined whether the lipid lowering actions of GLP-1R agonists play a role in the cardiovascular protective effects of these therapeutic agents.