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 24 h 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 7.5 μmol L⁻¹ (IC₅₀ 10.53 μmol 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 30 mg kg⁻¹ administered by oral gavage for 12 days did not affect the animals, suggesting low toxicity or metabolic impairment during the experimental period. Compared to insulin treatment alone, complex A (30 mg kg⁻¹) in association with insulin was found to improve glycemia (30.6 ± 6.3 mmol L⁻¹ vs. 21.1 ± 8.6 mmol 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.