2 + caused small increases in the cyclic AMP content of whole human islets. These studies demonstrated that human -cells express an extracellular CaR and that activation of the receptor inhibits basal and nutrient-stimulated insulin secretion. The transduction mechanism that mediates this inhibitory effect is unknown, but our results suggest that it is unlikely to be through the adenylate cyclase-cyclic AMP pathway or through the phopholipase C-IP 3 p a t h w a y. This CaRmediated inhibitory mechanism may be an important autoregulatory mechanism in the control of insulin secretion. D i a b e t e s 4 9 :4 0 9-417, 2000

The role(s) played by protein tyrosine kinases (PTKs) in the regulation of insulin secretion from pancreatic cells is not clear. We have examined the effects of glucose, the major physiological insulin secretagogue, on the tyrosine phosphorylation state of islet proteins, and assessed cell insulin secretory responses in the presence of PTK inhibitors. Under basal conditions islets contained many proteins phosphorylated on tyrosine residues, and glucose (20 mM; 5-15 min) was without demonstrable effect on the pattern of tyrosine phosphorylation, in either the absence or presence of the protein tyrosine phosphatase (PTP) inhibitor, sodium pervanadate (PV). PV alone (100 µM) increased tyrosine phosphorylation of several islet proteins. The PTK inhibitors genistein (GS) and tyrphostin A47 (TA47) inhibited islet tyrosine kinase activities and glucose-, 4 ketoisocaproic acid (KIC)-and sulphonylurea-stimulated insulin release, without affecting glucose metabolism. GS and TA47 also inhibited protein serine/threonine kinase activities to a limited extent, but had no effect on Ca 2+ , cyclic AMP-or phorbol myristate acetate (PMA)-induced insulin secretion from electrically permeabilised islets. These results suggest that PTK inhibitors exert their inhibitory effects on insulin secretion proximal to Ca 2+ entry and it is proposed that they act at the site of the voltage-dependent Ca 2+ channel which regulates Ca 2+ influx into cells following nutrient-and sulphonylurea-induced depolarisation.

No abstract

No abstract

No abstract