title: Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose.
abstract: The ATP-sensitive potassium channel is a key molecular complex for glucose-stimulated insulin secretion in pancreatic beta 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 Ca(2+) concentrations, and intact sensitivity of the exocytotic machinery to Ca(2+). 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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Chiyo
authors.initials: C
authors.lastname: Shiota
authors.forename: Olof
authors.initials: O
authors.lastname: Larsson
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Shelton
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shiota
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Efanov
authors.forename: Marianne
authors.initials: M
authors.lastname: Hoy
authors.forename: Jill
authors.initials: J
authors.lastname: Lindner
authors.forename: Suwattanee
authors.initials: S
authors.lastname: Kooptiwut
authors.forename: Lisa
authors.initials: L
authors.lastname: Juntti-Berggren
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D003001:Cloning, Molecular; D004435:Eating / Q000502:physiology; D005089:Exocytosis; D005838:Genotype; D015309:Glucose Clamp Technique; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010477:Perfusion; D015221:Potassium Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D064233:Sulfonylurea Receptors
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; D001786:Blood Glucose; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D011994:Recombinant Proteins; D064233:Sulfonylurea Receptors; D002217:Carbachol