Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose

Chiyo Shiota, Olof Larsson, Kathy D. Shelton, Masakazu Shiota, Alexander M. Efanov, Marianne Høy, Jill Lindner, Suwattanee Kooptiwut, Lisa Juntti-Berggren, Jesper Gromada, Per Olof Berggren, Mark A. Magnuson

Research output: Contribution to journalArticle

165 Scopus citations

Abstract

The ATP-sensitive potassium channel is a key molecular complex for glucose-stimulated insulin secretion in pancreatic β cells. In humans, mutations in either of the two subunits for this channel, the sulfonylurea type 1 receptor (Sur1) or Kir6.2, cause persistent hyperinsulinemic hypoglycemia of infancy. We have generated and characterized Sur1 null mice. Interestingly, these animals remain euglycemic for a large portion of their life despite constant depolarization of membrane, elevated cytoplasmic free Ca2+ concentrations, and intact sensitivity of the exocytotic machinery to Ca2+. A comparison of glucose- and meal-stimulated insulin secretion showed that, although Sur1 null mice do not secrete insulin in response to glucose, they secrete nearly normal amounts of insulin in response to feeding. Because Sur1 null mice lack an insulin secretory response to GLP-1, even though their islets exhibit a normal rise in cAMP by GLP-1, we tested their response to cholinergic stimulation. We found that perfused Sur1 null pancreata secreted insulin in response to the cholinergic agonist carbachol in a glucose-dependent manner. Together, these findings suggest that cholinergic stimulation is one of the mechanisms that compensate for the severely impaired response to glucose and GLP-1 brought on by the absence of Sur1, thereby allowing euglycemia to be maintained.

Original languageEnglish (US)
Pages (from-to)37176-37183
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number40
DOIs
StatePublished - Oct 4 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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