Glucagon release is regulated by tyrosine phosphatase and PI3-kinase activity.

Since inhibition of protein tyrosine phosphatase (PTPase) activity by peroxovanadate (pV) affects insulin release and phosphorylation of pancreatic islet proteins in the insulin signaling pathway, we studied whether pV also modulates glucagon release. At 3.3mM glucose, pV (0.1-1mM) enhanced glucagon release in a dose-dependent manner in islets of normal Wistar and diabetic GK rats. Arginine-stimulated glucagon responses were higher in GK than in Wistar islets. These responses were inhibited by pV (0.01-0.1mM), also after islet exposure to pertussis toxin (PTX), but were abolished by 1 microM wortmannin. Moreover, in GK but not Wistar islets, wortmannin significantly stimulated basal glucagon secretion (p<0.05) and inhibited arginine-induced glucagon secretion (p<0.001). In In-R1-G9 glucagonoma cells, the inhibitory effect of pV (0.01 mM) on glucagon response to arginine was also observed and paralleled by increased IRS-1 and IRS-2 associated PI3-kinase activity. In conclusion, inhibition of PTPase activity by pV stimulates basal and inhibits arginine-induced glucagon release. The inhibitory effect of 0.01-0.1mM pV seems not to be accounted for by islet peptides acting on PTX sensitive G(i)-proteins. PI3-kinase activity seems to play an important role in pV-induced inhibition of glucagon release.