Raman P, Judd R L
Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, AL 36849-5518, USA.
Eur J Pharmacol. 2000 Dec 1;409(1):19-29. doi: 10.1016/s0014-2999(00)00806-2.
Previous studies from our laboratory as well as from others have suggested that the thiazolidinediones have the capacity to act as insulinomimetic agents, especially in the liver. In order to further characterize this insulinomimetic action, we evaluated the effect of troglitazone, a representative thiazolidinedione, on lactate- and glucagon-stimulated gluconeogenesis, in the presence or absence of insulin (10 nM) in isolated rat hepatocytes. The antigluconeogenic effect of troglitazone under basal (lactate-stimulated) conditions was found to be due to an elevation in the fructose 2,6-bisphosphate content, which was, however, not mediated by an activation of 6-phosphofructo 2-kinase. Troglitazone (125 and 250 microM) in the absence of insulin, produced a dose-dependent reduction in glucagon-stimulated gluconeogenesis, thereby suggesting an insulinomimetic effect. In addition, troglitazone (125 and 250 microM), in combination with insulin, produced an additive inhibition of gluconeogenesis during glucagon-stimulated conditions. However, unlike insulin, the metabolic mechanism responsible for these effects (in the presence or absence of insulin) does not involve fructose 2,6-bisphosphate.
我们实验室以及其他机构之前的研究表明，噻唑烷二酮类药物有能力充当胰岛素模拟剂，尤其是在肝脏中。为了进一步明确这种胰岛素模拟作用，我们评估了曲格列酮（一种具有代表性的噻唑烷二酮类药物）在分离的大鼠肝细胞中，在有或没有胰岛素（10 nM）存在的情况下，对乳酸和胰高血糖素刺激的糖异生作用的影响。发现在基础（乳酸刺激）条件下，曲格列酮的抗糖异生作用是由于果糖2,6 - 二磷酸含量升高所致，然而，这并不是由6 - 磷酸果糖 - 2 - 激酶的激活介导的。在没有胰岛素的情况下，曲格列酮（125和250 microM）对胰高血糖素刺激的糖异生作用产生了剂量依赖性的降低，从而表明其具有胰岛素模拟作用。此外，曲格列酮（125和250 microM）与胰岛素联合使用时，在胰高血糖素刺激的条件下对糖异生作用产生了相加性抑制。然而，与胰岛素不同的是，导致这些作用（无论有无胰岛素）的代谢机制并不涉及果糖2,6 - 二磷酸。
