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, K2[VO(O2)2(picolinato)].2H2O [bpV(pic)], VO(O2) (picolinato) (H2O)2 [mpV(pic)], K[VO(O2)2(picolinato)].3H2O [bpV(phen)], and K[VO(O2)2(4,7-dimethyl-1,10-phenanthroline)].1/2H2O [bpV(Me2phen)] produced 50% of their maximal hypoglycemic effect at doses of 0.04, 0.04, 0.32, and 0.65 mumol/100 g body wt, respectively. In contrast, their potencies as inhibitors of dephosphorylation were bpV(pic) = bpV(phen) > mpV(pic) = bpV(Me2phen). bpV(pic) stimulated [14C]glucose incorporation into rat diaphragm glycogen in vivo, and its effect was dose dependent, synergistic with insulin, and evident in other skeletal muscles. In contrast, bpV(phen) displayed no effect on glycogen synthesis in skeletal muscle. mpV(pic) stimulated and bpV(Me2phen) had no effect on glycogen synthesis in the diaphragm. bpV(pic) augmented rat diaphragm insulin receptor kinase 2.2-fold with a time-integrated response 70% that of insulin. In contrast, the effect of bpV(phen) was delayed and much reduced. Thus, the in vivo potencies of pV compounds reflect differing capacities to act on skeletal muscle. The ancillary ligand within the pV complex may target one tissue in preference to another.
Bevan
A P
AP
Polypeptide Hormone Laboratory, McGill Nutrition and Food Science Centre, Montreal, Quebec, Canada.
Burgess
J W
JW
Yale
J F
JF
Drake
P G
PG
Lachance
D
D
Baquiran
G
G
Shaver
A
A
Posner
B I
BI
D000818:Animals; D003964:Diaphragm / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014638:Vanadates / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D007328:Insulin; C069276:peroxovanadate; D014638:Vanadates; D006003:Glycogen; D017027:Protein Tyrosine Phosphatases; D005947:Glucose