Development of Metal Complexes with Antidialetic Effect

糖尿病（DM）以高血糖为共同发病机制，分为两种类型;胰岛素依赖型1型DM，特征为胰腺中缺乏胰岛素合成和分泌，非胰岛素依赖型2型糖尿病的特点是由于肥胖引起的胰岛素抵抗。前者仅通过每日注射胰岛素治疗，后者需要运动和饮食控制以及口服合成药物沿着。每日注射胰岛素会带来身体和精神负担，此外，长期注射胰岛素会导致部分患者形成自身抗体。口服药物的管理导致胰腺停止胰岛素合成，因为减少胰岛素的需求。这反过来又需要胰岛素注射。为了克服胰岛素注射剂和口服药物的缺点，我们计划开发具有新作用机制的新型抗糖尿病药物。为此，我们使用金属配合物来治疗实验动物中的两种类型的DM。根据这些结果，我们发现了以下事实。(1)（2）在（+4）-吡啶甲酸氧钒配合物中，取代基的位置而不是电子效应对配合物的降血糖活性有重要影响。(3)在对钒氧和锌-3-羟基吡喃酮配合物构效关系的研究中，发现了具有良好抗糖尿病和抗代谢综合征作用的大蒜素类配合物。（4）这些配合物作用于胰岛素信号级联反应，并最终在细胞膜上转运葡萄糖转运蛋白4，（5）提出了钒氧化合物的药物传递体系。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.