游离脂肪酸在体内会损害肝脏对胰岛素的摄取。

Free fatty acids impair hepatic insulin extraction in vivo.

作者信息

Wiesenthal S R, Sandhu H, McCall R H, Tchipashvili V, Yoshii H, Polonsky K, Shi Z Q, Lewis G F, Mari A, Giacca A

机构信息

Department of Physiology, University of Toronto, Ontario, Canada.

出版信息

Diabetes. 1999 Apr;48(4):766-74. doi: 10.2337/diabetes.48.4.766.

DOI:10.2337/diabetes.48.4.766

PMID:10102693

Abstract

Hyperinsulinemia is a common finding in obesity and results from insulin hypersecretion and impaired hepatic insulin extraction. In vitro studies have shown that free fatty acids (FFAs), which are often elevated in obesity, can impair insulin binding and degradation in isolated rat hepatocytes. To investigate whether FFAs impair hepatic insulin extraction (E(H)) in vivo, either saline (SAL) or 10% Intralipid (0.03 ml x kg(-1) x min(-1)) plus heparin (0.44 U x kg(-1) x min(-1)) (IH) was infused into normal dogs to elevate FFA levels. Insulin was infused intraportally at 18 pmol x kg(-1) x min(-1) for 150 min (period A, high insulin dose), and then at 2.4 pmol x kg(-1) x min(-1) for another 150 min (period B, low insulin dose). After the low portal insulin dose, additional insulin was infused peripherally at 8.4 pmol x kg(-1) x min(-1) for 120 min (period C) to assess the clearance of insulin from the peripheral plasma. In 16 paired experiments, FFA levels were 1,085 +/- 167, 1,491 +/- 240, 1,159 +/- 221 micromol/l (IH) and 221 +/- 44, 329 +/- 72, 176 +/- 44 micromol/l (SAL) in periods A, B, and C, respectively. Peripheral insulin levels were greater with IH (P < 0.001) than with SAL in all periods (1,620 +/- 114, 126 +/- 12, 1,050 +/- 72 pmol/l for IH vs. 1,344 +/- 168, 96 +/- 4.2, 882 +/- 60 pmol/l for SAL). Glucose clearance was impaired by IH in all periods (P < 0.05), whereas glucose production was slightly increased by IH during period B. Peripheral insulin clearance (Cl) and E(H) were calculated from the insulin infusion rate and insulin concentration data in each period by taking into account the nonlinearity of insulin kinetics. Cl was lower (P < 0.01) with IH (9.6 +/- 0.6, 12.0 +/- 0.9, 10.2 +/- 0.6 ml x kg(-1) x min(-1)) than with SAL (11.2 +/- 1, 13.6 +/- 0.7, 11.9 +/- 0.9 ml x kg(-1) x min(-1)) in periods A, B, and C. E(H) was also lower (P < 0.05) with IH (25 +/- 4, 40 +/- 5, 32 +/- 5%) than with SAL (30 +/- 2.8, 47 +/- 3, 38 +/- 3%). We conclude that FFAs can impair hepatic insulin extraction in vivo at high and low insulin levels, an effect that may contribute to the peripheral hyperinsulinemia of obesity.

摘要

高胰岛素血症在肥胖症中很常见，是胰岛素分泌过多和肝脏胰岛素摄取受损的结果。体外研究表明，肥胖症中常常升高的游离脂肪酸（FFA）可损害分离的大鼠肝细胞中的胰岛素结合和降解。为了研究FFA在体内是否会损害肝脏胰岛素摄取（E(H)），将生理盐水（SAL）或10%脂肪乳剂（0.03 ml·kg⁻¹·min⁻¹）加肝素（0.44 U·kg⁻¹·min⁻¹）（IH）注入正常犬体内以提高FFA水平。以18 pmol·kg⁻¹·min⁻¹的速率经门静脉输注胰岛素150分钟（A期，高胰岛素剂量），然后以2.4 pmol·kg⁻¹·min⁻¹的速率再输注150分钟（B期，低胰岛素剂量）。在低门静脉胰岛素剂量后，以8.4 pmol·kg⁻¹·min⁻¹的速率经外周静脉额外输注胰岛素120分钟（C期），以评估胰岛素从外周血浆中的清除情况。在16组配对实验中，A、B和C期的FFA水平分别为1085±167、1491±240、1159±221 μmol/L（IH）和221±44、329±72、176±44 μmol/L（SAL）。在所有时期，IH组的外周胰岛素水平均高于SAL组（P<0.001）（IH组为1620±114、126±12、1050±72 pmol/L，SAL组为1344±168、96±4.2、882±60 pmol/L）。在所有时期，IH均损害葡萄糖清除（P<0.05），而在B期IH使葡萄糖生成略有增加。根据每个时期的胰岛素输注速率和胰岛素浓度数据，并考虑胰岛素动力学的非线性，计算外周胰岛素清除率（Cl）和E(H)。在A、B和C期，IH组的Cl低于SAL组（P<0.01）（IH组为9.6±0.6、12.0±0.9、10.2±0.6 ml·kg⁻¹·min⁻¹，SAL组为11.2±1、13.6±0.7、11.9±0.9 ml·kg⁻¹·min⁻¹）。IH组的E(H)也低于SAL组（P<0.05）（IH组为25±4、40±5、32±5%，SAL组为30±2.8、47±3、38±3%）。我们得出结论，FFA在高胰岛素水平和低胰岛素水平时均可在体内损害肝脏胰岛素摄取，这种作用可能导致肥胖症的外周高胰岛素血症。