Adiels M, Westerbacka J, Soro-Paavonen A, Häkkinen A M, Vehkavaara S, Caslake M J, Packard C, Olofsson S O, Yki-Järvinen H, Taskinen M R, Borén J
Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Göteborg University, Gothenburg, Sweden.
Diabetologia. 2007 Nov;50(11):2356-65. doi: 10.1007/s00125-007-0790-1. Epub 2007 Sep 12.
AIMS/HYPOTHESIS: Overproduction of VLDL(1) seems to be the central pathophysiological feature of the dyslipidaemia associated with type 2 diabetes. We explored the relationship between liver fat and suppression of VLDL(1) production by insulin in participants with a broad range of liver fat content.
A multicompartmental model was used to determine the kinetic parameters of apolipoprotein B and TG in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol during a hyperinsulinaemic-euglycaemic clamp in 20 male participants: eight with type 2 diabetes and 12 control volunteers. The participants were divided into two groups with low or high liver fat. All participants with diabetes were in the high liver-fat group.
The results showed a rapid drop in VLDL(1)-apolipoprotein B and -triacylglycerol secretion in participants with low liver fat during the insulin infusion. In contrast, participants with high liver fat showed no significant change in VLDL(1) secretion. The VLDL(1) suppression following insulin infusion correlated with the suppression of NEFA, and the ability of insulin to suppress the plasma NEFA was impaired in participants with high liver fat. A novel finding was an inverse response between VLDL(1) and VLDL(2) secretion in participants with low liver fat: VLDL(1) secretion decreased acutely after insulin infusion whereas VLDL(2) secretion increased.
CONCLUSIONS/INTERPRETATION: Insulin downregulates VLDL(1) secretion and increases VLDL(2) secretion in participants with low liver fat but fails to suppress VLDL(1) secretion in participants with high liver fat, resulting in overproduction of VLDL(1). Thus, liver fat is associated with lack of VLDL(1) suppression in response to insulin.
目的/假设：极低密度脂蛋白1（VLDL(1)）过度生成似乎是2型糖尿病相关血脂异常的核心病理生理特征。我们在肝脏脂肪含量范围广泛的参与者中探究了肝脏脂肪与胰岛素对VLDL(1)生成的抑制作用之间的关系。
在20名男性参与者（8名2型糖尿病患者和12名对照志愿者）进行高胰岛素-正糖钳夹试验期间，静脉注射[³H]亮氨酸和[⁵H]甘油后，使用多室模型来确定VLDL(1)和VLDL(2)中载脂蛋白B和甘油三酯（TG）的动力学参数。参与者被分为肝脏脂肪含量低或高的两组。所有糖尿病参与者都在肝脏脂肪含量高的组中。
结果显示，在胰岛素输注期间，肝脏脂肪含量低的参与者中，VLDL(1)载脂蛋白B和甘油三酯分泌迅速下降。相比之下，肝脏脂肪含量高的参与者中，VLDL(1)分泌无显著变化。胰岛素输注后VLDL(1)的抑制与非酯化脂肪酸（NEFA）的抑制相关，并且肝脏脂肪含量高的参与者中胰岛素抑制血浆NEFA的能力受损。一个新发现是肝脏脂肪含量低的参与者中VLDL(1)和VLDL(2)分泌之间存在反向反应：胰岛素输注后VLDL(1)分泌急剧下降，而VLDL(2)分泌增加。
结论/解读：胰岛素可下调肝脏脂肪含量低的参与者中VLDL(1)的分泌并增加VLDL(2)的分泌，但无法抑制肝脏脂肪含量高的参与者中VLDL(1)的分泌，从而导致VLDL(1)过度生成。因此，肝脏脂肪与胰岛素刺激下VLDL(1)抑制不足有关。
