Insulinomimetic Activity of Vanadyl-Porphyrin Complexes
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概要
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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(S<SUB>2</SUB>N<SUB>2</SUB>) 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(O<SUB>4</SUB>), VO(S<SUB>4</SUB>), VO(S<SUB>2</SUB>O<SUB>2</SUB>), VO(S<SUB>2</SUB>N<SUB>2</SUB>) and VO(N<SUB>2</SUB>O<SUB>2</SUB>) have been proposed, however, few complexes with the VO(N<SUB>4</SUB>) coordination mode have been examined. Recently, we found that meso-tetrakis({1-methylpyridinium-4-yl}porphyrinato)oxovanadium(IV), VOTMPyP, with the VO(N<SUB>4</SUB>) 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 <I>in vitro</I> 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 IC<SUB>50</SUB> value, which is a 50% inhibitory concentration of the complex for FFA-release from the adipocytes, was estimated to be 488.3 ± 49.1 <I>μ</I>M for VOTMPyP and 18.6 ± 13.0 <I>μ</I>M for VOTPPS, respectively. The EC<SUB>50</SUB> 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 <I>μ</I>M. The complex VOPP, which is insoluble in water, exhibited no <I>in vitro</I> 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.
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