IN-VIVO INSULIN MIMETIC EFFECTS OF PV COMPOUNDS - ROLE FOR TISSUE TARGETING IN DETERMINING POTENCY

Peroxovanadium (pV) compounds activate the insulin receptor kinase in hepatocytes and inhibit the dephosphorylation of insulin receptors in hepatic endosomes with highly correlated potencies (Posner, B. I., R. Faure, J. W. Burgess, A. P. Bevan, D. Lachance, G. Zhang-Sun, J. B. Ng , D. A. Hall, B. S. Lum, and A. Shaver J. Biol. Chem. 269: 4596-4604, 1994). After intravenous administration, K-2[VO(O-2)(2)(picolinato)].2 H(2)O [bpV(pic)], VO(O-2) (picolinato) (H2O)(2) [mpV(pic)], K[VO(O-2)2 (picolinato)].3H(2)O [bpV(phen)], and -2)(2)(4,7-dimethyl-1,10-phenant hroline)].1/2H(2)O [bpV(Me(2)phen)] produced 50% of their maximal hypo glycemic effect at doses of 0.04, 0.04, 0.32, and 0.65 mu mol/100 g bo dy wt, respectively. In contrast, their potencies as inhibitors of dep hosphorylation were bpV(pic) = bpV(phen) > mpV(pic) = bpV(Me(2)phen). bpV(pic) stimulated [C-14]glucose incorporation into rat diaphragm gly cogen in vivo, and its effect was dose dependent, synergistic with ins ulin, and evident in other skeletal muscles. In contrast, bpV(phen) di splayed no effect on glycogen synthesis in skeletal muscle. mpV(pic) s timulated and bpV(Me(2)phen) had no effect on glycogen synthesis in th e diaphragm. bpV(pic) augmented rat diaphragm insulin receptor kinase 2.2-fold with a time-integrated response 70% that of insulin. In contr ast, the effect of bpV(phen) was delayed and much reduced. Thus, the i n vivo potencies of pV compounds reflect differing capacities to act o n skeletal muscle. The ancillary ligand within the pV complex may targ et one tissue in preference to another.