Abstract
ContextGlucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear.ObjectiveTo determine the mechanisms of postprandial lipid and glucose control with lixisenatide (GLP-1 analog) in type 2 diabetes.DesignRandomized, double-blind, cross-over study.SettingCentre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom.PatientsEight obese men with type 2 diabetes [age, 57.3 ± 1.9 years; body mass index, 30.3 ± 1.0 kg/m2; glycosylated hemoglobin, 66.5 ± 2.6 mmol/mol (8.2% ± 0.3%)].InterventionsTwo metabolic studies, 4 weeks after lixisenatide or placebo, with cross-over and repetition of studies.Main Outcome MeasuresStudy one: very-low-density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with an IV bolus of [2H5]glycerol in a 12-hour study, with hourly feeding. Oral [13C]triolein, in a single meal, labeled enterally derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable IV [6,6-2H2]glucose infusion.ResultsStudy one: CM-TAG (but not VLDL-TAG) pool-size was lower with lixisenatide (P = 0.046). Lixisenatide reduced CM [13C]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 AUC0–240min 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 AUC0–360min (P = 0.006) were lower with lixisenatide than with placebo.ConclusionsLixisenatide reduced [13C]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.
Highlights
Postprandial hypertriglyceridaemia is an independent risk factor for cardiovascular disease (1-4)
The novel finding of this study was that the chronic effect of lixisenatide was to reduce CM TAG concentration through increased clearance
Our experimental protocol was designed to examine postprandial TAG metabolism by a) the appearance of [13C]oleate in plasma TAG after a high-fat 80kcal single meal, given 150 minutes after injection of the investigational medicinal product (IMP); b) hourly feeding of high-fat 80kcal single meals for twelve hours to achieve a steadystate in plasma TAG and measurement of CM and very-low density lipoprotein (VLDL) TAG kinetics, and c) the plasma TAG response to a standard 500 kcal liquid meal, in study two
Summary
Postprandial hypertriglyceridaemia is an independent risk factor for cardiovascular disease (1-4). This may occur via the generation of small, dense low-density lipoproteins, oxidative stress, inflammation, and/or endothelial dysfunction. Postprandial hypertriglyceridaemia is due to an excess of triglyceride-rich lipoproteins (TRL) and may result from: the overproduction of very low-density lipoproteins (VLDL) synthesised by the liver, which contain the higher molecular weight form of apolipoprotein (apo)B, apoB100; chylomicrons (CM) synthesised in the enterocytes, in response to dietary fat, which contain the lower molecular weight form of apoB, apoB48; impaired TRL clearance; or a combination of these processes. GLP-1 receptor agonists (RA) lower postprandial hypertriglyceridaemia (5-7), which may contribute to their cardiovascular benefit, but the mechanism has not been elucidated.
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