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Chylomicron-remnant clearance in homozygote and heterozygote Watanabe-heritable-hyperlipidaemic rabbits is defective. Lack of evidence for an independent chylomicron-remnant receptor.

ABSTRACT: Lymph chylomicrons radiolabelled in triacylglycerol and cholesteryl ester were injected into control and Watanabe heritable-hyperlipidaemic (WHHL) rabbits. Clearance of chylomicrons was slower in heterozygote and homozygote WHHL rabbits. Slower remnant clearance in WHHL rabbits was confirmed by monitoring the clearance from plasma of preformed chylomicron remnants. Use of chylomicron-like lipid emulsions injected into control and WHHL rabbits also confirmed the defect in remnant clearance in heterozygote WHHL and homozygote WHHL groups. Clearance from plasma of emulsion triolein was delayed in both WHHL groups compared with controls, owing to slower remnant clearance. The clearance from plasma of radioiodinated rabbit low-density lipoproteins (LDL) in heterozygote WHHL rabbits was the same as control rabbits. Defective chylomicron-remnant removal but normal LDL clearance in the heterozygote WHHL corresponded to elevated concentrations of plasma triacylglycerol and normal concentrations of plasma cholesterol. Receptor versus non-receptor clearances of chylomicron remnants were studied by comparing the clearance of emulsions with and without unesterified cholesterol respectively. Unlike control rabbits, there were no significant differences in the clearances of the two emulsion types in either the homozygote or heterozygote WHHL rabbits, indicating that the apolipoprotein-B100/E receptor is the primary route for clearance of chylomicron remnants from plasma.

SUBMITTER: Bowler A

PROVIDER: S-EPMC1151102 | biostudies-other | 1991 Jun

REPOSITORIES: biostudies-other

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Project description: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.

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Chylomicron-remnant clearance in homozygote and heterozygote Watanabe-heritable-hyperlipidaemic rabbits is defective. Lack of evidence for an independent chylomicron-remnant receptor.

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