Interaction of glucagon-like peptide-I (7–37) and somatostatin-14 on signal transduction and proinsulin gene expression in βTC-1 cells

Abstract

The interactions of glucagon-like peptide-I(7–37) (7–36)amide (GLP-I) and somatostatin-14 were characterized on the cyclic adenosine monophosphate (cAMP)-dependent signal transduction pathway and on proinsulin gene expression using mouse insulinoma βTC-1 cells. GLP-I stimulated the activity of adenylate cyclase maximally at 1 μmol/L (151%). This effect was inhibited by 1 μmol/L somatostatin (119%). Forskolin also stimulated adenylate cyclase activity (10 μmol/L forskolin, 265%), and this action was inhibited by somatostatin (220%). Somatostatin alone left the basal adenylate cyclase activity unaltered. Somatostatin reduced the GLP-I-stimulated increase of intracellular cAMP levels (100 nmol/L GLP-I, 141%; 100 nmol/L GLP-I + 1 μmol/L somatostatin, 110%). GLP-I stimulated concentration-dependently the activity of protein kinase A (PKA), with a maximum at 10 nmol/L (181%). This action was inhibited by 100 nmol/L somatostatin (118%), but somatostatin did not influence the basal PKA activity. Furthermore, somatostatin reduced the GLP-I-induced stimulation of proinsulin gene expression (10 nmol/L GLP-I, 176%; 10 nmol/L GLP-I + 1 μmol/L somatostatin, 77%). Somatostatin itself inhibited concentration-dependently proinsulin gene expression (1 μmol/L somatostatin, 53%). These data demonstrate that GLP-I increases the activities of both adenylate cyclase and cAMP-dependent PKA, whereas somatostatin counteracts the stimulatory effect of GLP-I on adenylate cyclase activity, cAMP generation, PKA activity, and proinsulin gene expression. The interaction of both hormones occurs at the level of adenylate cyclase. Therefore, the interaction of both peptide hormones regulates downstream events, including gene expression.