Bis(α-furancarboxylato)oxovanadium(IV) Exerts Durable Antidiabetic Effects and Suppresses Matrix Metalloproteinase-2 Activity in Spontaneous Type 2 Diabetic KKAy Mice

Abstract

Vanadium compounds maintain euglycemic effects in diabetic rats long after drug withdrawal and bis(α-furancarboxylato)oxovanadium(IV) (BFOV) possesses potent antidiabetic effects in diabetic rats. Here, we investigated the treatment and posttreatment effects of BFOV in diabetic Kuo Kondo [1, 2] with Ay gene (KKAy) mice, and whether these effects were associated with changes in matrix metalloproteinases (MMPs). KKAy mice received normal saline or BFOV initially at 70μmol/kg/day for 1month, which was tapered to 17μmol/kg/day in the next 2months and discontinued thereafter. Compared to diabetic controls, fasting plasma glucose (FPG) was reduced by 46 and 19% in KKAy mice after 70μmol/kg BFOV for 1month and 3months after BFOV withdrawal, respectively. OGTT and ITT showed improved glucose tolerance and a better response of FPG to insulin with a significant decrease in HOMA-IR and a marked rise in the insulin sensitivity index after 70μmol/kg BFOV for 1month and 4months after BFOV withdrawal (P <0.05 in all vs. diabetic controls). BFOV treatment resulted in a moderate but significant reduction in body weight and systolic blood pressure (SBP) at 1month of treatment and 4months following BFOV withdrawal (P <0.05 in all vs. diabetic controls). Gelatin zymography showed that serum MMP2 activity was significantly reduced and immunoblotting assays further showed that MMP2 expression was markedly downregulated in the liver after 1month of treatment with 70μmol/kg and 4months after BFOV withdrawal (P <0.05 in all vs. diabetic controls). These results suggested that BFOV possessed potent treatment and posttreatment effects in KKAy mice with improved metabolic profile and reduced body weight and SBP. Furthermore, these effects were associated with decreased MMP2 expression and activity in diabetic KKAy mice.