Development of Metal Complexes with Antidialetic Effect

以高血糖为共同发病机制的糖尿病（DM）分为两类；以胰腺缺乏胰岛素合成和分泌为特征的胰岛素依赖型1型糖尿病和以肥胖引起的胰岛素抵抗为特征的非胰岛素依赖型2型糖尿病。前者只需每天注射胰岛素即可治疗，后者需要运动和控制饮食，同时服用口服合成药物。每日注射胰岛素与身体和精神负担有关，此外，长期注射胰岛素导致一些患者形成自身抗体。口服药物会导致胰腺因胰岛素需求减少而停止胰岛素合成。这反过来又需要注射胰岛素。为了克服胰岛素注射和口服药物的缺陷，我们计划开发具有新作用机制的新型降糖药。为此，我们在实验动物中使用金属配合物治疗两种类型的糖尿病。根据这些结果，我们发现了以下事实。(1)建立了一种新的体外脂肪细胞葡萄糖摄取和抑制游离脂肪酸释放的评价体系；(2)在钒(+4)-吡啶甲酸配合物中，取代基位置比电子效应更能增强配合物的降糖活性。(3)在对钒基和锌-3-羟基吡啶配合物构效关系的研究中，发现了良好的大蒜素相关配合物，不仅能改善抗糖尿病状态，还能改善代谢综合征；(4)这些配合物被发现可作用于胰岛素信号级联，最终在细胞膜上转运葡萄糖转运蛋白4；(5)钒基化合物的一些药物递送系统被提出。根据这些事实，提出了未来临床试验的几种复合物。

Diabetes mellitus (DM) with a common pathogenesis of hyperglycemia is classified into two types; insulin-dependent type 1 DM characterized by the absence of insulin synthesis and secretion in the pancreas, and non-insulin-dependent type 2 DM characterized by insulin resistance due to obesity.The former is treated only by daily insulin injections and the latter needs exercise and diet control along with the administration of oral synthetic medicines. Daily insulin injections are associated with physical and spiritual burden, and, in addition, the long-term insulin injections leads to the formation of self-antibodies in some patients. The administration of oral medicines causes the pancreas to discontinue insulin synthesis because of a reduced insulin demand. This in turn necessitates the need for insulin injections. In order to overcome the defects of insulin injections and oral medicines, we have planed to develop new antidiabetic agents with a novel mechanism of action. For this purpose, we used metal complexes to treat both types of DM in experimental animals. On the basis of the results, we found the followng facts. (1) A new in vitro evaluation system was established in terms of glucose uptake and inhibition of free fatty acid release in the adipocytes, (2) In vanadyl (+4)-picolinate complexes, the importance of the substituent position rather than the electronic effect was conclude to enhance the hypoglycemic activity of the complexes. (3) In the study on structure-activity relationship for vanadyl- and zinc-3-hydroxypyrone complexes, excellent allixin-related complexes, which improve not only antidiabetic state but also anti-metabolic syndromes, were found, (4) The complexes have been revealed to act on the insulin signaling cascade, and finally to transport the glucose transporter 4 in the cell membranes, and (5) Some drug delivery systems were proposed for vanadyl compounds. From these facts, several complexes for clinical trials in the future were proposed.