Desensitization of Insulin Secretion by Depolarizing Insulin Secretagogues

  1. Ingo Rustenbeck1,
  2. Antje Wienbergen1,
  3. Claudia Bleck1 and
  4. Anne Jörns2
  1. 1Institute of Pharmacology and Toxicology, University of Braunschweig, Braunschweig, Germany
  2. 2Institute of Anatomy, Hannover Medical School, Hannover, Germany
  1. Address correspondence and reprint requests to Dr. I. Rustenbeck, Institute of Pharmacology and Toxicology, University of Braunschweig, Mendelssohnstr. 1, D-38106 Braunschweig, Germany. E-mail: i.rustenbeck{at}tu-bs.de

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 (KATP channel)-blocking secretagogues. However, desensitized β-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 β-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 β-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 β-cells, we could not find a cogent link between depolarization and Ca2+ influx and apoptotic or necrotic β-cell death.

Footnotes

  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    • Accepted June 3, 2004.
    • Received March 12, 2004.
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