Alterations of insulin secretion from mouse islets treated with sulphonylureas: perturbations of Ca 2+ regulation prevail over changes in insulin content

To determine how pretreatment with sulphonylureas alters the β cell function, mouse islets were cultured (18–20 h) without (controls) or with (test) 0.01 μ M glibenclamide. Acute responses to glucose were then determined in the absence of glibenclamide. Test islets were insensitive to drugs (sulphonylureas and diazoxide) acting on K + ‐ATP channels, and their [Ca 2+ ] i was already elevated in the absence of stimulation. Insulin secretion was increased in the absence of glucose, and mainly stimulated between 0–10 instead of 7–20 m M glucose in controls. The maximum response was halved, but this difference disappeared after correction for the 45% decrease in the islet insulin content. The first phase of glucose‐induced insulin secretion was abrogated because of a paradoxical decrease of the high basal [Ca 2+ ] i in β cells. The second phase was preserved but occurred with little rise of [Ca 2+ ] i . These abnormalities did not result from alterations of glucose metabolism (NADPH fluorescence). In islets cultured with 50 μ M tolbutamide, glucose induced biphasic increases in [Ca 2+ ] i and insulin secretion. The decrease in the secretory response was matched by the decrease in insulin content (45%) except at maximal glucose concentrations. Islets pretreated with tolbutamide, however, behaved like those cultured with glibenclamide if tolbutamide was also present during the acute functional tests. In conclusion, treatment with a low glibenclamide concentration causes long‐lasting blockade of K + ‐ATP channels and rise of [Ca 2+ ] i in β cells. Glucose‐induced insulin secretion occurs at lower concentrations, is delayed and is largely mediated by a modulation of Ca 2+ action on exocytosis. It is suggested that glucose regulation of insulin secretion mainly depends on a K + ‐ATP channel‐independent pathway during in vivo sulphonylurea treatment.British Journal of Pharmacology (1999) 127 , 1883–1891; doi: 10.1038/sj.bjp.0702731