Development of Metal Complexes with Antidialetic Effect

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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.