Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance

摘要

Context Glucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear. Objective To determine the mechanisms of postprandial lipid and glucose control with lixisenatide (GLP-1 analog) in type 2 diabetes. Design Randomized, double-blind, cross-over study. Setting Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom. Patients Eight obese men with type 2 diabetes [age, 57.3 ± 1.9 years; body mass index, 30.3 ± 1.0 kg/m ~(2); glycosylated hemoglobin, 66.5 ± 2.6 mmol/mol (8.2% ± 0.3%)]. Interventions Two metabolic studies, 4 weeks after lixisenatide or placebo, with cross-over and repetition of studies. Main Outcome Measures Study one: very-low-density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with an IV bolus of [ ~(2)H _(5)]glycerol in a 12-hour study, with hourly feeding. Oral [ ~(13)C]triolein, in a single meal, labeled enterally derived TAG. Study two: glucose kinetics were measured with [U- ~(13)C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable IV [6,6- ~(2)H _(2)]glucose infusion. Results Study one: CM-TAG (but not VLDL-TAG) pool-size was lower with lixisenatide ( P = 0.046). Lixisenatide reduced CM [ ~(13)C]oleate area under the curve (AUC) _(60–480min) concentration ( P = 0.048) and increased CM-TAG clearance, with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC _(0–240min) were reduced with lixisenatide ( P = 0.0051; P & 0.05). Total glucose production ( P = 0.015), rate of glucose appearance from the meal ( P = 0.0098), and acetaminophen AUC _(0–360min) ( P = 0.006) were lower with lixisenatide than with placebo. Conclusions Lixisenatide reduced [ ~(13)C]oleate concentrations, derived from a single meal in CM-TAG and glucose rate of appearance from the meal through delayed gastric emptying. However, day-long CM production, measured with repeated meal feeding, was not reduced by lixisenatide and decreased CM-TAG concentration resulted from increased CM-TAG clearance. Using stable isotopes, lixisenatide acutely slowed gastric emptying, lowering postprandial TAG levels. A more prolonged effect of reduced chylomicron TAG was from increased clearance.