Insulinomimetic Activity of Vanadyl-Porphyrin Complexes

Abstract

Diabetes mellitus (DM) is one of the life style-related diseases as well as one of the widespread diseases in the world. DM is classified mainly into two types; type 1 insulin-dependent DM is associated with absolute insulin deficiency and type 2 non-insulin dependent DM is associated with lowering of insulin sensitivity in all organs, which ultimately follows absolute insulin deficiency. We first reported that vanadyl-cysteinemethylester complex with the VO(S₂N₂) coordination mode is very useful in the treatment of streptozotocin (STZ)-induced type 1 diabetic rats by daily oral administrations in 1990. Since then, many types of insulinomimetic vanadyl complexes with different coordination modes around vanadyl, such as VO(O₄), VO(S₄), VO(S₂O₂), VO(S₂N₂) and VO(N₂O₂) have been proposed, however, few complexes with the VO(N₄) coordination mode have been examined. Recently, we found that meso-tetrakis({1-methylpyridinium-4-yl}porphyrinato)oxovanadium(IV), VOTMPyP, with the VO(N₄) coordination mode, is a potential insulinomimetic vanadyl complex for the treatment of type 1 diabetic model STZ-rats in the presence of sodium ascorbate. This important finding promoted us to find more active insulinomimetic vanadyl-porphyrin complexes. In this study, we have synthesized, characterized and estimated in vitro insulinomimetic activity of the (protoporphyrinato IX)oxovanadium(IV), VOPP, and meso-tetrakis({4-sulfonatophenyl}porphyrinato)oxovanadium(IV), VOTPPS, complexes, comparing with those of previously proposed insulinomimetic VOTMPyP. VOTPPS was very stable in both 4% bovine serum albumin (BSA) and rat blood serum (RBS) for 48 h without ascorbate. The IC₅₀ value, which is a 50% inhibitory concentration of the complex for FFA-release from the adipocytes, was estimated to be 488.3 ± 49.1 μM for VOTMPyP and 18.6 ± 13.0 μM for VOTPPS, respectively. The EC₅₀ value, which is a 50% enhancing concentration of the compound with respect to the maximal glucose-uptake concentration in epinephrine-treated adipocytes, was not detected for VOTMPyP, but found for VOTPPS as 46.3 ± 6.4 μM. The complex VOPP, which is insoluble in water, exhibited no in vitro insulinomimetic activity in the concentration range examined. Based on these observations, VOTPPS was proposed to be an insulinomimetic vanadyl porphyrin complex having a potential for treating insulin-dependent and noninsulin-dependent diabetic mellitus.