The long-term toxicity and hypoglycemic effect of vanadyl complexes on non-diabetic and type Ⅱ diabetic mice

钒化合物对非糖尿病和II型糖尿病小鼠的长期毒性和降糖效果研究（英文）

Vanadium compounds are promising anti-diabetic agents. However, the concern in the toxicity, especially the long-term renal side effect along with diabetic status, is restricting the further development of this metal drug. Recently, we have prepared a bis（（5-hydroxy-4-oxo-4H-pyran-2-yl） methyl 2-hydroxy-benzoatato） oxovanadium（BSOV）, which exhibited excellent hypoglycemic effect with low acute toxicity. In order to facilitate the development of anti-diabetic vanadium complexes, especially BSOV, we studied the long-term toxicity and hypoglycemic effect of BSOV in comparison with bis（maltolato） oxovanadium（BMOV） on both non-diabetic and type II diabetic mice. The experiments confirmed a stable hypoglycemic effect for both the vanadium complexes over the testing period（6–7 months）. However, the chronic administration of vanadium compounds slightly increased oxidative stress in ICR mice and the induced renal interstitial edema（RIE） in a part of the diabetic animals associated with low levels of serum albumin. The use of an antioxidant dietary supplement（a combination of vitamin C and Zinc gluconate） could prevent vanadium-induced oxidative stress but have marginal effect on RIE. However, BSOV caused much lower incidence of RIE than BMOV did, suggesting that BSOV is an important step towards the successful development of anti-diabetic vanadium drugs.

钒化合物作为抗糖尿病药物具有巨大的发展潜力。但是,钒化合物的毒性,尤其是在糖尿病的长期给药中对肾的副作用,限制了其进一步的临床应用。本课题组此前合成了具有良好降血糖作用和低急性毒性的新型抗糖尿病钒化合物BSOV。为了推进BSOV应用和抗糖尿病钒化合物研究的进展,我们以非糖尿病ICR小鼠和II型糖尿病db/db小鼠为对象并以BMOV为对照,对BSOV的长期毒性和降糖效果进行了观察。实验结果确认了两种钒化合物在实验期间(6–7个月)都具有稳定的降糖效果。然而,钒化合物的长期使用在ICR小鼠会轻度增强机体的氧化应激,而在糖尿病小鼠则可能会诱发肾间质水肿,这一作用伴随了明显的血清白蛋白偏低。通过饮食中补充抗氧化剂(维生素C和葡萄糖酸锌)能够消除小鼠的氧化应激现象,但对于肾间质水肿则无明显改善作用。相对于BMOV,BSOV所导致的肾间质水肿发生率明显降低,说明BSOV是向抗糖尿病钒化合物最终成功跨出的重要一步。