ATTENUATION OF INSULIN-SECRETION BY INSULIN-LIKE-GROWTH-FACTOR-1 IS MEDIATED THROUGH ACTIVATION OF PHOSPHODIESTERASE-3B

Both insulin and insulin-like growth factor 1 (IGF-1) are known to red uce glucose-dependent insulin secretion from the beta cells of pancrea tic islets, In this paper we show that the mechanism by which IGF-1 me diates this effect is in large part through activation of a specific c yclic nucleotide phosphodiesterase, phosphodiesterase 3B (PDE3B), More specifically, in both isolated pancreatic islets and insulin-secretin g HIT-T15 cells, IGF-1 inhibits insulin secretion that has been increa sed by glucose and glucagonlike peptide 1 (GLP-1), Moreover, IGF-1 dec reases cAMP levels in parallel to the reduction of insulin secretion, Insulin secretion stimulated by cAMP analogs that activate protein kin ase A and also are substrates for PDE3B is also inhibited by IGF-1, Ho wever, IGF-1 does not inhibit insulin secretion stimulated by nonhydro lyzable cAMP analogs, In addition, selective inhibitors of PDE3B compl etely block the ability of IGF-1 to inhibit insulin secretion, Finally , PDE3B activity measured in vitro after immunoprecipitation from cell s treated with IGF-1 is higher than the activity from control cells, T aken together with the fact that pancreatic beta cells express little or no insulin receptor but large amounts of IGF-1 receptor, these data strongly suggest a new regulatory feedback loop model for the control of Insulin secretion, In this model, increased insulin secretion in v ivo will stimulate IGF-1 synthesis by the liver, and the secreted IGF- 1 in turn feedback inhibits insulin secretion from the beta cells thro ugh an IGF-1 receptor-mediated pathway, This pathway is likely to be p articularly important when levels of both glucose and secretagogues su ch as GLP-1 are elevated.