Calcium and pancreatic beta-cell function. The mechanism of insulin secretion studied with the aid of lanthanum.
La3+ was used to study the involvement of Ca2+ in insulin secretion in beta-cell-rich pancreatic islets micro-dissected from non-inbred ob/ob mice. Ultrastructural studies revealed that the localization of La3+ was entirely restricted to the exterior of the cells. Consistent with a membrane action, exposure to La3+ failed to affect glucose oxidation and either the sucrose space or the general ultrastructure of the islets. In contrast, La3+ had marked effects on insulin release and 45Ca fluxes. Exposure to La3+ resulted in pronounced inhibition of insulin release irrespective of the presence or absence of Ca2+, 3-isobutyl-1-methylxanthine or glucose. Perifusion experiments revealed that the inhibitory action was prompt, sustained and readily reversible. Removal of La3+ was associated with a subsequent prolonged stimulatory phase of insulin release even in medium deficient in Ca2+. This action could not be attributed to an increase in cyclic AMP, but was potentiated by 3-isobutyl-1-methylxanthine and abolished by L-adrenaline. La3+ displaced 45Ca from superficially located binding sites and inhibited the uptake and efflux of 45Ca. The stimulatory and inhibitory actions of glucose on 45Ca efflux were also abolished in the presence of 2 mM-La3+ Removal of La3+ was associated with the preferential mobilization of 45Ca incorporated in response to glucose. The results indicate that binding of La3+ to superficial sites in the plasma membrane leads to inhibition of insulin release by suppression of transmembrane Ca2+ fluxes. It is suggested that accumulation of Ca2+ in the cytoplasm accounts for the stimulation of insulin release seen after removal of La3+ from inhibitory binding sites in the beta-cell plasma membrane.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D007811:Lanthanum / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D013395:Sucrose / Q000378:metabolism
D007328:Insulin; D013395:Sucrose; D007811:Lanthanum; D000242:Cyclic AMP; D005947:Glucose; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine