Pace-Asciak C R, Demin P M, Estrada M, Liu G
Programme in Integrative Biology, Research Institute, Hospital for Sick Children, 555 University Avenue, Toronto, Ont., Canada.
FEBS Lett. 1999 Nov 19;461(3):165-8. doi: 10.1016/s0014-5793(99)01460-x.
We have demonstrated over a decade ago that hepoxilins cause the release of insulin from isolated pancreatic islets of Langerhans in vitro. However, no studies are available so far to indicate whether these compounds are active in vivo. The present study is the first to our knowledge which demonstrates that hepoxilins administered intra-arterially in the anaesthetized rat cause the release of insulin in the circulation. This release is dependent on the glucose status of the rat. Hence, animals fasted overnight do not respond to hepoxilin administration, while animals that have had free access to food respond to hepoxilins with a rise in insulin concentrations in blood. The hepoxilin effect is rapid and varies with different hepoxilins, the most potent of which is hepoxilin A(3) (HxA(3)) (both the 8S and the 8R enantiomers). Administration of 100 microg HxA(3) produces a rise in blood insulin equivalent to that caused by the administration of 5 mg glucose. In view of earlier evidence showing that these compounds cause a rise in intracellular calcium levels in vitro at a <1 microg/ml concentration through a receptor-mediated mechanism, we speculate that the actions of hepoxilins in causing the release of insulin from the pancreas may be due to alterations in calcium levels within the beta-cell. We believe that hepoxilins may represent new lead compounds as therapeutics in type II diabetes mellitus.
十多年前我们就已证明，肝氧杂环素可在体外诱导分离的胰岛朗格汉斯细胞释放胰岛素。然而，目前尚无研究表明这些化合物在体内是否具有活性。据我们所知，本研究首次证实，在麻醉大鼠中动脉内给予肝氧杂环素可导致循环中胰岛素的释放。这种释放取决于大鼠的血糖状态。因此，禁食过夜的动物对肝氧杂环素给药无反应，而自由进食的动物对肝氧杂环素给药的反应是血液中胰岛素浓度升高。肝氧杂环素的作用迅速，且因不同的肝氧杂环素而异，其中最有效的是肝氧杂环素A(3)（HxA(3)）（8S和8R对映体）。给予100微克HxA(3)可使血液胰岛素水平升高，相当于给予5毫克葡萄糖所引起的升高。鉴于早期证据表明，这些化合物在体外通过受体介导的机制，在浓度<1微克/毫升时可使细胞内钙水平升高，我们推测肝氧杂环素促使胰腺释放胰岛素的作用可能是由于β细胞内钙水平的改变。我们认为，肝氧杂环素可能代表了作为II型糖尿病治疗药物的新先导化合物。
