Acute effects of insulin in the control of VLDL production in humans - Implications for the insulin-resistant state
Acute effects of insulin in the control of VLDL production in humans - Implications for the insulin-resistant state
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DOI：
10.2337/diacare.19.4.390
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发表时间：
1996-04-01
期刊：
影响因子：
16.2
通讯作者：
Steiner, G
中科院分区：
文献类型：
--
作者：
Lewis, GF;Steiner, G
高胰岛素血症在胰岛素抵抗状态下甘油三酯(TG)和极低密度脂蛋白(VLDL)过度生成的发病机制中所起的作用仍存在争议。虽然在人类和动物身上的研究普遍表明，慢性高胰岛素血症促进VLDL的产生，特别是在合成VLDL的底物充足的情况下，但大多数使用培养的肝细胞和肝癌细胞进行的体外研究都证明了胰岛素的急性抑制作用。利用放射性标记的极低密度脂蛋白示踪剂，我们研究了高胰岛素血症对人类极低密度脂蛋白生成的急性影响。我们发现胰岛素对血浆游离脂肪酸(FFA)水平的快速抑制作用以及胰岛素对VLDLTG和VLDL载脂蛋白B(Apo B)的抑制作用在瘦型胰岛素敏感者中持续存在。高胰岛素血症时注入肝素和Intralipid可显著提高血浆FFA水平，显著增加VLDLTG和VLDLapoB的产生。当高胰岛素血症时胰岛素对血浆FFA水平的抑制被阻断时，VLDLTG的产生仍然受到抑制，尽管程度比单独使用胰岛素要小。根据这些发现，我们得出结论，胰岛素抑制胰岛素敏感者极低密度脂蛋白的产生，部分是通过抑制血浆FFA水平，部分是通过非FFA介导的(可能是直接的肝脏)机制。此外，我们发现长期胰岛素抵抗的高胰岛素血症肥胖者对胰岛素对极低密度脂蛋白apoB产生的这种抑制作用具有抵抗力，这与其他人使用从胰岛素抵抗或高胰岛素血症大鼠分离的培养肝细胞进行体外实验的类似发现一致。这些发现与人类慢性胰岛素抵抗状态相关的高甘油三酯血症机制的相关性仍然是一个推测问题。一种假设是，对正常胰岛素抑制作用的抵抗，以及与胰岛素抵抗相关的其他代谢异常，可能会导致餐后和吸收后高甘油三酯血症。
The role of hyperinsulinemia in the pathogenesis of triglyceride (TG) and VLDL overproduction in insulin-resistant states remains controversial. While studies in humans and animals have generally suggested that chronic hyperinsulinemia facilitates VLDL production, particularly in the presence of an abundant supply of substrate for VLDL synthesis, the majority of in vitro studies using cultured hepatocytes and hepatoma cell lines have demonstrated an acute inhibitory effect of insulin. Using radiolabeled VLDL tracers we have examined the acute effect of hyperinsulinemia on VLDL production in humans. We found a rapid suppression of plasma free fatty acid (FFA) levels in response to insulin and a consistent 50-60% insulin-induced suppression of both VLDL TG and VLDL apolipoprotein (apo) B in lean insulin-sensitive individuals. Elevation of plasma FFA levels by infusing heparin and Intralipid without hyperinsulinemia resulted in a marked increase in VLDL TG and VLDL apoB production When the insulin-induced suppression of plasma FFA levels was prevented during hyperinsulinemia, VLDL TG production was still inhibited, although to a lesser extent than with insulin alone. We concluded from these findings that insulin suppresses VLDL production in insulin-sensitive humans partly by suppressing plasma FFA levels and partly by a non-FFA-mediated (perhaps direct hepatic) mechanism. In addition, we found that chronically insulin-resistant hyperinsulinemic obese individuals were resistant to this suppressive effect of insulin on VLDL apoB production, in keeping with similar findings by others performing in vitro experiments using cultured hepatocytes isolated from insulin-resistant or hyperinsulinemic rats. The relevance of these findings to the mechanism of hypertriglyceridemia associated with chronic insulin-resistant states in humans remains a matter of speculation. One hypothesis is that resistance to the normal suppressive effect of insulin, in association with other metabolic abnormalities associated with insulin resistance, may contribute to postprandial and postabsorptive hypertriglyceridemia.