Desensitization of insulin secretion by depolarizing insulin secretagogues.
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 (KATP channel)-blocking secretagogues. However, desensitized beta-cells do not necessarily show changes in KATP channel activity or Ca2+ 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 beta-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 beta-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 beta-cells, we could not find a cogent link between depolarization and Ca2+ influx and apoptotic or necrotic beta-cell death.
Rustenbeck
Ingo
I
Institute of Pharmacology and Toxicology, University of Braunschweig, Mendelssohnstr. 1, D-38106 Braunschweig, Germany. i.rustenbeck@tu-bs.de
Wienbergen
Antje
A
Bleck
Claudia
C
Jörns
Anne
A
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D006801:Humans; D019329:Idazoxan / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*
D001572:Benzofurans; D007093:Imidazoles; D007328:Insulin; D015221:Potassium Channels; C062597:efaroxan; D002118:Calcium; D019329:Idazoxan