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Randomized Controlled Trial
. 2019 Feb 1;104(2):359-368.
doi: 10.1210/jc.2018-01176.

Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance

Martin B Whyte  1 , Fariba Shojaee-Moradie  1 , Sharaf E Sharaf  1 , Nicola C Jackson  1 , Barbara Fielding  1 , Roman Hovorka  2 , Jeewaka Mendis  1 , David Russell-Jones  1 , A Margot Umpleby  1
Affiliations
Randomized Controlled Trial

Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance

Martin B Whyte et al. J Clin Endocrinol Metab. .

Abstract

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/m2; 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 [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.

Results: Study 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.

Conclusions: Lixisenatide 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.

Trial registration: ClinicalTrials.gov NCT02049034.

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Figures

Figure 1.
Figure 1.
(A) Plasma TAG, (B) TRL-TAG, (C) VLDL-TAG, and (D) CM-TAG concentrations (mmol/L) at fasting (−240 minutes) and after meal drinks at 1-hour intervals (−240 to 480 minutes) at the end of 4 weeks of treatment with either lixisenatide (white circles) or placebo (black circles) (study one). Lixisenatide or placebo injection was self-administered at −270 minutes. The results are presented as mean ± SEM. Black arrows indicate hourly meals; narrow gray arrows, the meal labeled with [1,1,1 13C3]triolein; and wide gray arrows, the bolus of [1,1,2,3,3 2H5]glycerol administered at the start of steady-state. *P < 0.05.
Figure 2.
Figure 2.
(A) CM [13C]oleate concentration (µmol/L) at fasting (−240 minutes) and after meal drinks at 1-hour intervals (−240 to 480 minutes) at the end of 4 weeks of treatment with either lixisenatide (white circles) or placebo (black circles) (study one). [13C]oleate was mixed with the third meal (−120 minutes). The lixisenatide or placebo injection was self-administered at −270 minutes. (B) FCR of VLDL-TAG and CM-TAG (pools per day). (C) Production rate of VLDL-TAG and CM-TAG (mg/d/kg body weight). The results are presented as mean ± SEM. *P < 0.05.
Figure 3.
Figure 3.
(A) Plasma glucose, (B) glucagon, (C) TAG, (D) NEFA, (E) acetaminophen, and (F) insulin (pmol/L) at fasting (−120 to 0 minutes) and in response to a mixed meal and acetaminophen (consumed at 0 minutes) at the end of 4 weeks of treatment with either lixisenatide (white circles) or placebo (black circles) (study two). The lixisenatide or placebo injection was self-administered at −30 minutes. The results are presented as mean ± SEM. *P < 0.05.
Figure 4.
Figure 4.
(A) Total glucose Ra, (B) meal glucose Ra, (C) EGP, and (D) Rd (µmol/kg/min) at fasting (−40 to 0 minutes) and in response to a mixed meal (consumed at 0 minutes) at the end of 4 weeks of treatment with either lixisenatide (white circles) or placebo (black circles) (study two). The lixisenatide or placebo injection was self-administered at −30 minutes. The results are presented as mean ± SEM. *P < 0.05.
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References

    1. Patsch JR, Miesenböck G, Hopferwieser T, Mühlberger V, Knapp E, Dunn JK, Gotto AM Jr, Patsch W. Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state. Arterioscler Thromb. 1992;12(11):1336–1345. - PubMed
    1. Sharrett AR, Chambless LE, Heiss G, Paton CC, Patsch W. Association of postprandial triglyceride and retinyl palmitate responses with asymptomatic carotid artery atherosclerosis in middle-aged men and women. The Atherosclerosis Risk in Communities (ARIC) study. Arterioscler Thromb Vasc Biol. 1995;15(12):2122–2129. - PubMed
    1. Eberly LE, Stamler J, Neaton JD; Multiple Risk Factor Intervention Trial Research Group . Relation of triglyceride levels, fasting and nonfasting, to fatal and nonfatal coronary heart disease. Arch Intern Med. 2003;163(9):1077–1083. - PubMed
    1. Schrezenmeir J, Keppler I, Fenselau S, Weber P, Biesalski HK, Probst R, Laue C, Zuchhold HD, Prellwitz W, Beyer J. The phenomenon of a high triglyceride response to an oral lipid load in healthy subjects and its link to the metabolic syndrome. Ann N Y Acad Sci. 1993;683:302–314. - PubMed
    1. Meier JJ, Gethmann A, Götze O, Gallwitz B, Holst JJ, Schmidt WE, Nauck MA. Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans. Diabetologia. 2006;49(3):452–458. - PubMed

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