Hyperlipidaemia is associated with increased insulin-mediated glucose metabolism, reduced fatty acid metabolism and normal blood pressure in transgenic mice overexpressing human apolipoprotein C1

Aims/hypothesis. Insulin resistance for glucose metabolism is associated wi th hyperlipidaemia and high blood pressure. In this study we investigated t he effect of primary hyperlipidaemia on basal and insulin-mediated glucose and on non-esterified fatty acid (NEFA) metabolism and mean arterial pressu re in hyperlipidaemic transgenic mice overexpressing apolipoprotein C1 (APO C1). Previous studies have shown that APOC1 transgenic mice develop hyperli pidaemia primarily because of an impaired hepatic uptake of very low densit y lipoprotein (VLDL). Methods. Basal and hyperinsulinaemic (6 mU . kg(-1) . min(-1)), euglycaemic (7 mmol/l) clamps with 3-H-3-glucose or 9,10-H-3-palmitic acid infusions a nd in situ freeze clamped tissue collection were carried out. Results. The APOC1 mice showed increased basal plasma cholesterol, triglyce ride, NEFA and decreased glucose concentrations compared with wild-type mic e (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 com pared 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 (H2O)-H-3) and glucose storage increased in APOC1 mice compared with wildt ype mice (339 +/- 28 vs 200 +/- 11; 183 +/- 39 vs 128 +/- 17 and 156 +/- 44 vs 72 +/- 17 mu mol . kg(-1) . min(-1), p < 0.05, respectively), correspon ding with a twofold to threefold increase in skeletal muscle glycogenesis a nd de novo lipogenesis from 3-3H-glucose in skeletal muscle and adipose tis sue (p<0.05). Basal whole body NEFA clearance was decreased threefold in AP OC1 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 oxidati on (generation of (H2O)-H-3) 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 <mu>mol . kg(-1) . min(-1), p < 0.05) in the face of higher pla sma NEFA concentrations (1.3 +/- 0.3 vs 0.5 +/- 0.1 mmol/l, p < 0.05), resp ectively. Mean arterial pressure and heart rate were similar in APOC1 vs wi ld-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 con ditions, suggesting an intrinsic defect in NEFA metabolism. Primary hyperli pidaemia alone in APOC1 mice does not lead to insulin resistance for glucos e metabolism and high blood pressure.