Print Email Facebook Twitter Hyperlipidaemia is associated with increased insulin-mediated glucose metabolism, reduced fatty acid metabolism and normal blood pressure in transgenic mice overexpressing human apolipoprotein C1 Title Hyperlipidaemia is associated with increased insulin-mediated glucose metabolism, reduced fatty acid metabolism and normal blood pressure in transgenic mice overexpressing human apolipoprotein C1 Author Koopmans, S.J. Jong, M.C. Que, I. Dahlmans, V.E.H. Pijl, H. Radder, J.K. Frölich, M. Havekes, L.M. Gaubius Instituut TNO Publication year 2001 Abstract Aims/hypothesis. Insulin resistance for glucose metabolism is associated with hyperlipidaemia and high blood pressure. In this study we investigated the effect of primary hyperlipidaemia on basal and insulin-mediated glucose and on non-esterified fatty acid (NEFA) metabolism and mean arterial pressure in hyperlipidaemic transgenic mice overexpressing apolipoprotein C1 (APOC1). Previous studies have shown that APOC1 transgenic mice develop hyperlipidaemia primarily because of an impaired hepatic uptake of very low density lipoprotein (VLDL). Methods. Basal and hyperinsulinaemic (6 mU · kg-1 · min-1), euglycaemic (7 mmol/l) clamps with 3-3H-glucose or 9,10-3H-palmitic acid infusions and in situ freeze clamped tissue collection were carried out. Results. The APOC1 mice showed increased basal plasma cholesterol, triglyceride, NEFA and decreased glucose concentrations compared with wild-type mice (7.0 ± 1.2 vs 1.6 ± 0.1, 9.1 ± 2.3 vs 0.6 ± 0.1, 1.9 ± 0.2 vs 0.9 ± 0.1 and 7.0 ± 1.0 vs 10.0 ± 1.1 mmol/l, respectively, p < 0.05). Basal whole body glucose clearance was increased twofold in APOC1 mice compared with wild-type mice (18 ± 2 vs 10 ± 1 ml · kg-1 · min-1, p < 0.05). Insulin-mediated whole body glucose uptake, glycolysis (generation of 3H2O) and glucose storage increased in APOC1 mice compared with wild-type mice (339 ± 28 vs 200 ± 11; 183 ± 39 vs 128 ± 17 and 156 ± 44 vs 72 ± 17 μmol · kg-1 · min-1, p < 0.05, respectively), corresponding with a twofold to three-fold increase in skeletal muscle glycogenesis and de novo lipogenesis from 3-3H-glucose in skeletal muscle and adipose tissue (p < 0.05). Basal whole body NEFA clearance was decreased threefold in APOC1 mice compared with wild-type mice (98 ± 21 vs 314 ± 88 ml · kg-1 · min-1, p < 0.05). Insulin-mediated whole body NEFA uptake, NEFA oxidation (generation of 3H2O) and NEFA storage were lower in APOC1 mice than in wild-type mice (15 ± 3 vs 33 ± 6; 3 ± 2 vs 11 ± 4 and 12 ± 2 vs 22 ± 4 μmol · kg-1· min-1, p < 0.05) in the face of higher plasma NEFA concentrations (1.3 ± 0.3 vs 0.5 ± 0.1 mmol/l, p < 0.05), respectively. Mean arterial pressure and heart rate were similar in APOC1 vs wild-type mice (82 ±4 vs 85 ± 3 mm Hg and 459 ± 14 vs 484 ± 11 beats, min-1). Conclusions/interpretation. 1) Hyperlipidaemic APOC1 mice show reduced NEFA and increased glucose metabolism under both basal and insulin-mediated conditions, suggesting an intrinsic defect in NEFA metabolism. Primary hyperlipidaemia alone in APOC1 mice does not lead to insulin resistance for glucose metabolism and high blood pressure. Chemicals/CAS: Apolipoprotein C-I; Apolipoproteins C; Blood Glucose; Cholesterol, 57-88-5; Fatty Acids, Nonesterified; Glucose, 50-99-7; Glycogen, 9005-79-2; Insulin, 11061-68-0; Palmitic Acid, 57-10-3; Triglycerides; Tritium, 10028-17-8 Subject BiologyAPOC1HypertensionInsulin resistanceInsulin resistance syndromeLipoproteinNEFAFatty acidPalmitic acidTriacylglycerolTritiumVery low density lipoproteinAdipose tissueAnimal modelAnimal tissueBlood pressureCholesterol blood levelClearanceControlled studyFatty acid metabolismGene overexpressionGlucose blood levelGlucose clamp techniqueGlucose metabolismGlycogen synthesisGlycolysisHeart rateHyperinsulinemiaHyperlipidemiaHypertensionIn vivo studyInfusionInsulin resistanceLipid transportLipogenesisMean arterial pressureMouseNonhumanSkeletal muscleTransgenic mouseAnimalsApolipoprotein C-IApolipoproteins CBlood GlucoseBlood PressureCholesterolFatty Acids, NonesterifiedGene ExpressionGlucoseGlucose Clamp TechniqueGlycogenHumansHyperlipidemiasInsulinLipid MetabolismLiverMiceMice, TransgenicMuscle, SkeletalPalmitic AcidTriglyceridesTritium To reference this document use: http://resolver.tudelft.nl/uuid:9d4e4ae0-5069-4f4a-b84e-86e0b7f02868 DOI https://doi.org/10.1007/s001250051641 TNO identifier 236048 Source Diabetologia, 44 (4), 437-443 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.