Desensitization of Insulin Secretion by Depolarizing Insulin Secretagogues

Abstract

Prolonged stimulation of insulin secretion by depolarization and Ca2؉ influx regularly leads to a reversible state of decreased secretory responsiveness to nutrient and nonnutrient stimuli. This state is termed "desensitization." The onset of desensitization may occur within 1 h of exposure to depolarizing stimuli. Desensitization by exposure to sulfonylureas, imidazolines, or quinine produces a marked cross-desensitization against other ATP-sensitive K ؉ channel (K ATP channel)-blocking secretagogues. However, desensitized ␤-cells do not necessarily show changes in K ATP channel activity or Ca 2؉ handling. Care has to be taken to distinguish desensitization-induced changes in signaling from effects due to the persisting presence of secretagogues. The desensitization by depolarizing secretagogues is mostly accompanied by a reduced content of immunoreactive insulin and a marked reduction of secretory granules in the ␤-cells. In vitro recovery from a desensitization by the imidazoline efaroxan was nearly complete after 4 h. At this time point the depletion of the granule content was partially reversed. Apparently, recovery from desensitization affects the whole lifespan of a granule from biogenesis to exocytosis. There is, however, no direct relation between the ␤-cell granule content and the secretory responsiveness. Even though a prolonged exposure of isolated islets to depolarizing secretagogues is often associated with the occurrence of ultrastructural damage to ␤-cells, we could not find a cogent link between depolarization and Ca 2؉ influx and apoptotic or necrotic ␤-cell death. Diabetes 53 (Suppl. 3)

Glibenclamide-Induced Apoptosis Is Specifically Enhanced by Expression of the Sulfonylurea Receptor Isoform SUR1 but Not by Expression of SUR2B or the Mutant SUR1(M1289T)

“…These results are in accordance with previous studies reporting a negative impact of prolonged exposure to some sulfonylureas on islet cell function (Rustenbeck et al, 2004b;Del Guerra et al, 2005). In addition, the sulfonylureas glibenclamide and tolbutamide are known to elicit apoptosis in ␤-cells or pancreatic cell lines (Efanova et al, 1998;Iwakura et al, 2000;Rustenbeck et al, 2004a;Maedler et al, 2004Maedler et al, , 2005.…”

Ca2+-dependent desensitization of insulin secretion by strong potassium depolarization

“…Thus, the insulin secretion by K ϩ depolarization has not only quantitatively but also qualitatively different characteristics, depending on the K ϩ concentration. The virtual inability of 15 mM K ϩ to increase secretion in the presence of basal glucose confirms our recent observation (15) but is in apparent conflict with another report that 15 mM K ϩ was moderately effective in the presence of 5 mM glucose and elicited a desensitization of secretion, a typical feature of a depolarizing secretagogue (30,39). However, in the latter study rat islets were used, which are known to have a higher glucose sensitivity than mouse islets (21,40).…”

Tumour necrosis factor-α-induced glucose-stimulated insulin secretion inhibition in INS-1 cells is ascribed to a reduction of the glucose-stimulated Ca2+ influx

“…The reason that TNF-a did not inhibit KCl-stimulated insulin secretion was not clear, but a lack of impairment of KClstimulated insulin secretion was frequently observed in b-cells that were not responsive to glucose. Several studies have reported that insulin secretion stimulated by membrane-depolarizing agents such as KCl and arginine was not blunted in secretagogueinduced desensitized b-cells or islet b-cells isolated from diabetic patients (Rustenbeck et al 2004, Del Guerra et al 2005 . A recent report that prevention of prenylation of small G-proteins, which may be involved in insulin granule movement, inhibited GSIS but not KCl-stimulated insulin secretion supports the idea that b-cells with functional impairment at the step of Ca 2C influx or insulin exocytosis can respond to KCl (Veluthakal et al 2007).…”