Desensitization of insulin secretion

Biochem Pharmacol. 2002 Jun 1;63(11):1921-35. doi: 10.1016/s0006-2952(02)00996-6.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / metabolism
  • Energy Metabolism
  • Fatty Acids, Nonesterified / metabolism
  • Glucose / metabolism*
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Sulfonylurea Compounds / pharmacology


  • Fatty Acids, Nonesterified
  • Insulin
  • Sulfonylurea Compounds
  • Glucose