Iterative Stimulation of Pancreatic Islets by Glipizide

Abstract

Iterative administrations of glipizide (2 μmol/l) for 10 min each to perifused rat pancreatic islets provoked at low glucose concentration (2.8 mmol/l) rapid and rapidly reversible decreases in ⁸⁶Rb outflow, rapid and rapidly reversible increases in ⁴⁵Ca outflow and modest stimulations of insulin release. In the presence of Ca²⁺, the reascension in ⁸⁶Rb outflow was preceded by a transient fall in effluent radioactivity upon withdrawal of the sulfonylurea. At a higher concentration of D-glucose (8.3 mmol/l), glipizide provoked, each time, biphasic and rapidly reversible increases in both ⁸⁶Rb and ⁴⁵Ca outflow, as well as in insulin release. These results are compatible with the view that glipizide decreases K⁺ conductance, leading to depolarization of the B-cell plasma membrane and gating of voltage-sensitive Ca²⁺ channels. In the presence of 8.3 mmol/l D-glucose, however, the inhibitory effect of glipizide on effluent K⁺ permeability may be masked by activation of Ca²⁺-sensitive K⁺ channels. The present data also indicate that glipizide is able to evoke, at the occasion of iterative administrations, biphasic ionic and secretory responses, without evidence of tachyphylaxis.

Repaglinide, a new oral antidiabetic agent: a review of recent preclinical studies

“…This increase in 86 Rb outflow is less marked when the islets are perifused in the absence of extracellular Ca 2þ [17]. It could thus correspond, as expected from comparable studies performed with hypoglycaemic sulphonylureas [21,22], to the activation of voltage-and/or Ca 2þ -responsive K þ channels in the islets already stimulated by D-glucose. Incidentally, the secretory response to KAD-1229 was reversed rapidly in the presence or absence of hexose, while this was not the case in the islets exposed to repaglinide [10,17].…”

Insulin Secretagogues, But Not Glucose, Stimulate an Increase in [Ca2+]i in the Fetal Rat β-cell

“…Glipizide is a K + ATP channel blocker that can lead to insulin secretion in adult rat islets (37). In fetal rat islets, glipizide (50 jxmol/1) caused a rapid increase in [Ca 2+ ]j of 42 ± 6 nmol/1 above resting levels (n = 13) (Table 1), presumably by depolarization-induced Ca 2+ influx.…”

“…Identical results were obtained when a lower concentration of glipizide (2 |xmol/l) was used (n = 8). Typically, higher concentrations of glipizide have been used in studies with whole islets to allow the drug to permeate the islet (37,38).…”