title: Desensitization of insulin secretion.
abstract: Desensitization of insulin secretion describes a reversible state of decreased secretory responsiveness of the pancreatic beta-cell, induced by a prolonged exposure to a multitude of stimuli. These include the main physiological stimulator, glucose, but also other nutrients like free fatty acids and practically all pharmacological stimulators acting by depolarization and Ca2+ influx into the beta-cell. Desensitization of insulin secretion appears to be an important step in the manifestation of type 2 diabetes and in the secondary failure of oral antidiabetic treatment. In this commentary, the basic concepts and the controversial issues in the field will be outlined. With regard to glucose-induced desensitization, two fundamentally opposing concepts have emerged. The first is that desensitization is the consequence of functional changes in the beta-cell that impair glucose-recognition. The second is that long-term increased secretory activity leads to a depletion of releasable insulin, often in spite of increased insulin synthesis. The latter concept is more appropriately termed beta-cell exhaustion. The same dichotomy applies to the desensitization evoked by pharmacological stimuli: again the relative contributions of a decreased insulin content versus alterations in signal transduction are in dispute. The action of tolbutamide on beta-cells may be an example of desensitization caused by a lack of releasable insulin since the signaling mechanisms are nearly unchanged, whereas the action of phentolamine, an imidazoline, induces a strong desensitization without reducing insulin content or secretory granules, apparently by abolishing Ca2+ influx. With pharmacological agents it seems that both, alterations in signal transduction and decreased availability of releasable insulin, can contribute to the desensitized state of the beta-cell, the relative contribution being variable depending upon the exact nature of the secretory stimulus.
authors.affiliation: Institute of Pharmacology and Toxicology, Technical University of Braunschweig, Mendelssohnstr. 1, D-38106, Braunschweig, Germany. i.rustenbeck@tu-bs.de
authors.forename: Ingo
authors.initials: I
authors.lastname: Rustenbeck
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004734:Energy Metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D013453:Sulfonylurea Compounds / Q000494:pharmacology
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D013453:Sulfonylurea Compounds; D005947:Glucose