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.
abstract: OBJECTIVE
  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 mumol.kg-1.min-1, p < 0.05, respectively), corresponding with a twofold to threefold increase in skeletal muscle glycogenesis and de novo lipogenesis from 3-(3)H-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 mumol.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
  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.
authors.affiliation: ID TNO Animal Nutrition, Institute for Animal Science and Health, Lelystad, The Netherlands.
authors.forename: S J
authors.initials: SJ
authors.lastname: Koopmans
authors.forename: M C
authors.initials: MC
authors.lastname: Jong
authors.forename: I
authors.initials: I
authors.lastname: Que
authors.forename: V E
authors.initials: VE
authors.lastname: Dahlmans
authors.forename: H
authors.initials: H
authors.lastname: Pijl
authors.forename: J K
authors.initials: JK
authors.lastname: Radder
authors.forename: M
authors.initials: M
authors.lastname: Frölich
authors.forename: L M
authors.initials: LM
authors.lastname: Havekes
mesh_terms: D000818:Animals; D053302:Apolipoprotein C-I; D001056:Apolipoproteins C / Q000235:genetics*; D001786:Blood Glucose / Q000378:metabolism*; D001794:Blood Pressure; D002784:Cholesterol / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D015870:Gene Expression; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D015309:Glucose Clamp Technique; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics*; D007328:Insulin / Q000097:blood*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D019308:Palmitic Acid / Q000008:administration & dosage / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D014316:Tritium
chemical_list: D053302:Apolipoprotein C-I; D001056:Apolipoproteins C; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D014280:Triglycerides; D014316:Tritium; D019308:Palmitic Acid; D006003:Glycogen; D002784:Cholesterol; D005947:Glucose