Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose.
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.
Shiota
Chiyo
C
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Larsson
Olof
O
Shelton
Kathy D
KD
Shiota
Masakazu
M
Efanov
Alexander M
AM
Hoy
Marianne
M
Lindner
Jill
J
Kooptiwut
Suwattanee
S
Juntti-Berggren
Lisa
L
Gromada
Jesper
J
Berggren
Per-Olof
PO
Magnuson
Mark A
MA
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
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