Unexpected potentiation of insulin release by the calcium store blocker TMB-8

Insulin release from rat pancreatic islets, stimulated by cAMP, 3-isobutyl-1-methylxanthine, or forskolin, is potentiated by TMB-8 [8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate], a drug that blocks the efflux of calcium from intracellular calcium stores without affecting influx. There is a short latent period before the potentiation occurs which can be reduced by preincubation with the drug. TMB-8 alone neither stimulates nor inhibits insulin release. The results suggest that an intracellular store fills with calcium because of the blocked efflux and unchanged influx, and loses its ability to regulate the cytosol Ca++ concentration. Under basal conditions, in the presence or absence of TMB-8, the plasma membrane is able to regulate the cytosol Ca++ concentration at low levels so that no change in insulin release occurs. However, when 3-isobutyl-1-methylxanthine, cAMP, or forskolin add an additional Ca++ load to the cytosol, the regulator capacity of the plasma membrane is overwhelmed, and cytosol Ca++ rises to higher levels than in the absence of TMB-8 because the filled store is no longer regulating. Thus, insulin release is potentiated.