Heteroleptic oxidovanadium(IV)-malate complex improves glucose uptake in HepG2 and enhances insulin action in streptozotocin-induced diabetic rats.

Abstract

Diabetes mellitus, a complex and heterogeneous disease associated with hyperglycemia, is a leading cause of mortality and reduces life expectancy. Vanadium complexes have been studied for the treatment of diabetes. The effect of complex [VO(bpy)(mal)]·H2O (complex A) was evaluated in a human hepatocarcinoma (HepG2) cell line and in streptozotocin (STZ)-induced diabetic male Wistar rats conditioned in seven groups with different treatments (n = 10 animals per group). Electron paramagnetic resonance and 51V NMR analyses of complex A in high-glucose Dulbecco's Modified Eagle Medium (DMEM) revealed the oxidation and hydrolysis of the oxidovanadium(IV) complex over a period of 24h at 37°C to give low-nuclearity vanadates "V1" (H2VO4-), "V2" (H2V2O72-), and "V4" (V4O124-). In HepG2 cells, complex A exhibited low cytotoxic effects at concentrations 2.5 to 7.5μmol L-1 (IC50 10.53μmol L-1) and increased glucose uptake (2-NBDG) up to 93%, an effect similar to insulin. In STZ-induced diabetic rats, complex A at 10 and 30mgkg-1 administered by oral gavage for 12days did not affect the animals, suggesting low toxicity or metabolic impairment during the experimental period. Compared to insulin treatment alone, complex A (30mgkg-1) in association with insulin was found to improve glycemia (30.6 ± 6.3mmol L-1 vs. 21.1 ± 8.6mmol L-1, respectively; p = 0.002), resulting in approximately 30% additional reduction in glycemia. The insulin-enhancing effect of complex A was associated with low toxicity and was achieved via oral administration, suggesting the potential of complex A as a promising candidate for the adjuvant treatment of diabetes.