A NOVEL INSULIN SECRETAGOGUE IS A PHOSPHODIESTERASE INHIBITOR

The arylpiperazine L-686,398 was described as an oral hypoglycemic age nt and is shown to be an insulin secretagogue in vitro. The characteri stics of its activity were similar to those of the incretin glucagon-l ike peptide I (GLP-I). We demonstrate that both the peptide and L-686, 398 increase the accumulation of cAMP in isolated ob/ob mouse pancreat ic islet cells, but by different mechanisms. Although GLP-I activates adenylate cyclase, the arylpiperazine has no effect on this enzyme or on the binding of I-125-labeled GLS-I to its receptor on RINm5F rat in sulinoma cell membranes. However, L-686,398 inhibits the total cAMP ph osphodiesterase (PDE) activity in homogenates of ob/ob mouse pancreati c islets with an EC(50) of similar to 50 mu mol/l. To determine the me chanism of PDE inhibition by the arylpiperazine and to examine its spe cificity, we studied the kinetics of arylpiperazine inhibition of two recombinant PDEs. The arylpiperazine is a competitive inhibitor of bot h a human heart type III PDE and a rat type IV-D PDE. Inhibition of th e type III and IV isozymes are characterized by K-i values of 27 and 5 mu mol/l, respectively. Although not extremely potent, the arylpipera zine does exhibit modest selectivity between these PDEs. The observati on that L-686,398 acts as a PDE inhibitor suggests that exploration fo r beta-cell-specific PDE isoforms may reveal novel PDEs as targets for the development of therapeutically useful glucose-dependent insulin s ecretagogues.