A stable peroxovanadium compound with insulin-like action in human fat cells.
Aqueous solutions of peroxovanadium (pV) compounds are potent insulin-mimics in various types of cell. Since chemical instability is a problem with these agents, we studied the insulin-like action in human fat cells of a stable pV complex, bpV(pic). It enhanced 14C-U-glucose uptake in a dose-dependent manner by approximately twofold which was slightly less than the effect of insulin (approximately threefold). The pV complex did not alter cell-surface insulin binding and submaximal concentrations did not influence cellular sensitivity to insulin action on glucose uptake. The bpV(pic) inhibited the lipolytic effect of isoprenaline to the same extent as insulin; however, when the cGMP-inhibitable low-K(m) phosphodiesterase (cGI-PDE) was blocked with the specific inhibitor OPC 3911, the antilipolytic effect of insulin, but not that of bpV(pic), was completely prevented. Moreover, when lipolysis was stimulated by the non-hydrolysable cAMP analogue N6-monobutyryl cAMP, bpV(pic), in contrast to insulin, maintained an antilipolytic effect. These findings indicate that bpV(pic) exerts its antilipolytic effect not only through cGI-PDE activation, similar to the effect of insulin, but also by means of other mechanisms. The tyrosine kinase activity of insulin receptors from human placenta was not altered by the pV compound itself, whereas bpV(pic) clearly enhanced insulin-stimulated activity. In contrast, in situ tyrosine phosphorylation of the insulin receptor beta-subunit as well as that of several other proteins was clearly increased in cells which were treated with bpV(pic), whereas vanadate only amplified insulin-stimulated tyrosine phosphorylation. In conclusion, bpV(pic) exerts powerful insulin-like effects in human fat cells and may be a new and potentially useful agent in the management of insulin-resistant states.
Eriksson
J W
JW
Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
Lönnroth
P
P
Posner
B I
BI
Shaver
A
A
Wesslau
C
C
Smith
U P
UP
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D001706:Biopsy; D002250:Carbon Radioisotopes; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008066:Lipolysis / Q000187:drug effects*; D019000:Phosphotyrosine / Q000032:analysis; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011972:Receptor, Insulin / Q000302:isolation & purification / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D012867:Skin; D014638:Vanadates / Q000494:pharmacology*
D002250:Carbon Radioisotopes; D007004:Hypoglycemic Agents; D007328:Insulin; D011994:Recombinant Proteins; C069276:peroxovanadate; D019000:Phosphotyrosine; D014638:Vanadates; D011972:Receptor, Insulin; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D005947:Glucose; D007545:Isoproterenol