AJP - Endocrinology and Metabolism, Vol 268, Issue 1 E60-E66, Copyright © 1995 by American Physiological Society

ARTICLES

In vivo insulin mimetic effects of pV compounds: role for tissue targeting in determining potency

A. P. Bevan, J. W. Burgess, J. F. Yale, P. G. Drake, D. Lachance, G. Baquiran, A. Shaver and B. I. Posner
Polypeptide Hormone Laboratory, McGill Nutrition and Food Science Centre, Montreal, Quebec, Canada.

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.

This article has been cited by other articles:

				G. R. Ehring, H. H. Kerschbaum, C. M. Fanger, C. Eder, H. Rauer, and M. D. Cahalan Vanadate Induces Calcium Signaling, Ca2+ Release-Activated Ca2+ Channel Activation, and Gene Expression in T Lymphocytes and RBL-2H3 Mast Cells Via Thiol Oxidation J. Immunol., January 15, 2000; 164(2): 679 - 687. [Abstract] [Full Text] [PDF]

				M. Olivier, B.-J. Romero-Gallo, C. Matte, J. Blanchette, B. I. Posner, M. J. Tremblay, and R. Faure Modulation of Interferon-gamma -induced Macrophage Activation by Phosphotyrosine Phosphatases Inhibition. EFFECT ON MURINE LEISHMANIASIS PROGRESSION J. Biol. Chem., May 29, 1998; 273(22): 13944 - 13949. [Abstract] [Full Text] [PDF]

				A. P. Bevan, A. Krook, J. Tikerpae, P. J. Seabright, K. Siddle, and G. D. Smith Chloroquine Extends the Lifetime of the Activated Insulin Receptor Complex in Endosomes J. Biol. Chem., October 24, 1997; 272(43): 26833 - 26840. [Abstract] [Full Text] [PDF]

				C. M. Krejsa, S. G. Nadler, J. M. Esselstyn, T. J. Kavanagh, J. A. Ledbetter, and G. L. Schieven Role of Oxidative Stress in the Action of Vanadium Phosphotyrosine Phosphatase Inhibitors. REDOX INDEPENDENT ACTIVATION OF NF-kappa B J. Biol. Chem., April 25, 1997; 272(17): 11541 - 11549. [Abstract] [Full Text] [PDF]

				M. K. Tikkanen, D. J. Carter, A. M. Harris, H. M. Le, D. O. Azorsa, P. S. Meltzer, and F. E. Murdoch Endogenously expressed estrogen receptor and coactivator AIB1 interact in MCF-7 human breast cancer cells PNAS, November 7, 2000; 97(23): 12536 - 12540. [Abstract] [Full Text] [PDF]

				C. Lavoie, E. Chevet, L. Roy, N. K. Tonks, A. Fazel, B. I. Posner, J. Paiement, and J. J. M. Bergeron Tyrosine phosphorylation of p97 regulates transitional endoplasmic reticulum assembly in vitro PNAS, December 5, 2000; 97(25): 13637 - 13642. [Abstract] [Full Text] [PDF]