MODULATION OF TYROSINE KINASE-ACTIVITY HAS MULTIPLE ACTIONS ON INSULIN RELEASE FROM THE PANCREATIC BETA-CELL - STUDIES WITH LAVENDUSTIN-A

We investigated the role of tyrosine kinases in the regulation of insu lin release from a hamster beta-cell line, HIT T15, using selective ty rosine kinase inhibitors. Genistein increased the insulin release indu ced by glucose, but herbimycin A, tyrphostins and the erbstatin analog ue failed to change the release. Lavendustin A at 0.1 nM-1 mu M caused a concave-shaped inhibition of the insulin release stimulated by 7 mM glucose. The inhibitory effect of lavendustin A was overcome by highe r concentrations of glucose. Lavendustin B, the negative control analo gue, had no effect on the release. Lavendustin A at a nanomolar range progressively inhibited insulin release by high K+ (50 mM)-depolarizat ion whereas the inhibitor did not change the insulin release by Ca2+ i onophore (A23187). On the contrary, lavendustin A at 10 nM significant ly increased insulin release when glucose-induced insulin release was enhanced by either 5 mu M forskolin or 162 nM 12-O-tetradecanoylphorbo l 13-acetate. Lavendustin A failed to influence the Ca2+ induced insul in release from HIT cells permeabilized with streptolysin-O. These fin dings suggest that tyrosine kinases may play versatile roles in the co ntrol of insulin release from the pancreatic beta-cell.