Lewis G F, Steiner G
Department of Medicine, University of Toronto, Canada.
Diabetes Care. 1996 Apr;19(4):390-3. doi: 10.2337/diacare.19.4.390.
The role of hyperinsulinemia in the pathogenesis of triglyceride (TG) and VLDL over-production 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.
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）过度产生的发病机制中的作用仍存在争议。虽然对人类和动物的研究普遍表明，慢性高胰岛素血症促进VLDL的产生，特别是在存在丰富的VLDL合成底物供应的情况下，但大多数使用培养的肝细胞和肝癌细胞系的体外研究表明胰岛素具有急性抑制作用。我们使用放射性标记的VLDL示踪剂研究了高胰岛素血症对人类VLDL产生的急性影响。我们发现，在瘦的胰岛素敏感个体中，胰岛素可使血浆游离脂肪酸（FFA）水平迅速降低，并且胰岛素可使VLDL TG和VLDL载脂蛋白（apo）B持续受到50%-60%的抑制。在无高胰岛素血症的情况下，通过输注肝素和脂肪乳剂使血浆FFA水平升高，导致VLDL TG和VLDL apoB产生显著增加。当在高胰岛素血症期间阻止胰岛素诱导的血浆FFA水平降低时，VLDL TG产生仍受到抑制，尽管程度小于单独使用胰岛素时。我们从这些发现中得出结论，胰岛素在胰岛素敏感的人类中抑制VLDL产生，部分是通过抑制血浆FFA水平，部分是通过非FFA介导的（可能是直接肝脏的）机制。此外，我们发现慢性胰岛素抵抗的高胰岛素血症肥胖个体对胰岛素对VLDL apoB产生的这种抑制作用具有抗性，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有待推测。一种假设是，对胰岛素正常抑制作用的抵抗，与胰岛素抵抗相关的其他代谢异常一起，可能导致餐后和吸收后高甘油三酯血症。
