Rapid Ca2+ influx and diacylglycerol synthesis in growth hormone-mediated islet beta-cell mitogenesis

Growth hormone (GH) is an important mitogenic stimulus for the insulin-prod ucing beta-cell. We investigated the effects of GH on Ca2+ handling and dia cylglycerol (DAG) and cAMP formation in the beta-cell. GH elicited a rapid increase in the cytoplasmic free [Ca2+], which required extracellular Ca2and was also blocked by pertussis toxin or protein kinase C (PKC) inhibitio n. GH also elevated islet DAG content, which should lead to PKC activation. Pertussis toxin and PKC inhibitors obliterated the mitogenicity of GH, sug gesting involvement of GTP-binding proteins. PKC activation stimulated beta -cell proliferation, and it also activated phospholipase D. Islet cAMP cont ent was not elevated by GH. Addition of a specific protein kinase A antagon ist failed to influence the mitogenicity of GH, whereas a stimulatory cAMP agonist stimulated beta-cell replication. We conclude that GH rapidly incre ases the beta-cell cytoplasmic free [Ca2+] and also evokes a similar increa se in DAG content via a phosphatidylcholine-specific phospholipase C, but d oes not affect mitogen-activated protein kinases, phospholipase D, or the c AMP signaling pathway. This rise in DAG may be of importance in translation of the stimulatory signal of GH into a proliferative response by the beta- cell, which seems to occur through GTP-binding proteins and PKC-dependent m echanisms.