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Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance.
J Clin Endocrinol Metab. 2019 02 01; 104(2):359-368.JC

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.

Authors+Show Affiliations

Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.Diabetes Modelling Group, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30215735

Citation

Whyte, Martin B., et al. "Lixisenatide Reduces Chylomicron Triacylglycerol By Increased Clearance." The Journal of Clinical Endocrinology and Metabolism, vol. 104, no. 2, 2019, pp. 359-368.
Whyte MB, Shojaee-Moradie F, Sharaf SE, et al. Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance. J Clin Endocrinol Metab. 2019;104(2):359-368.
Whyte, M. B., Shojaee-Moradie, F., Sharaf, S. E., Jackson, N. C., Fielding, B., Hovorka, R., Mendis, J., Russell-Jones, D., & Umpleby, A. M. (2019). Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance. The Journal of Clinical Endocrinology and Metabolism, 104(2), 359-368. https://doi.org/10.1210/jc.2018-01176
Whyte MB, et al. Lixisenatide Reduces Chylomicron Triacylglycerol By Increased Clearance. J Clin Endocrinol Metab. 2019 02 1;104(2):359-368. PubMed PMID: 30215735.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance. AU - Whyte,Martin B, AU - Shojaee-Moradie,Fariba, AU - Sharaf,Sharaf E, AU - Jackson,Nicola C, AU - Fielding,Barbara, AU - Hovorka,Roman, AU - Mendis,Jeewaka, AU - Russell-Jones,David, AU - Umpleby,A Margot, PY - 2018/05/29/received PY - 2018/09/06/accepted PY - 2018/9/15/pubmed PY - 2019/12/18/medline PY - 2018/9/15/entrez SP - 359 EP - 368 JF - The Journal of clinical endocrinology and metabolism JO - J Clin Endocrinol Metab VL - 104 IS - 2 N2 - 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. SN - 1945-7197 UR - https://www.unboundmedicine.com/medline/citation/30215735/Lixisenatide_Reduces_Chylomicron_Triacylglycerol_by_Increased_Clearance_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2018-01176 DB - PRIME DP - Unbound Medicine ER -