Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes. Cell 2000 Mar 17;100(6):645-54
Date
04/13/2000Pubmed ID
10761930DOI
10.1016/s0092-8674(00)80701-1Scopus ID
2-s2.0-0034677634 (requires institutional sign-in at Scopus site) 263 CitationsAbstract
A paradigm for control of insulin secretion is that glucose metabolism elevates cytoplasmic [ATP]/[ADP] in beta cells, closing K(ATP) channels and causing depolarization, Ca2+ entry, and insulin release. Decreased responsiveness of K(ATP) channels to elevated [ATP]/[ADP] should therefore lead to decreased insulin secretion and diabetes. To test this critical prediction, we generated transgenic mice expressing beta cell K(ATP) channels with reduced ATP sensitivity. Animals develop severe hyperglycemia, hypoinsulinemia, and ketoacidosis within 2 days and typically die within 5. Nevertheless, islet morphology, insulin localization, and alpha and beta cell distributions were normal (before day 3), pointing to reduced insulin secretion as causal. The data indicate that normal K(ATP) channel activity is critical for maintenance of euglycemia and that overactivity can cause diabetes by inhibiting insulin secretion.
Author List
Koster JC, Marshall BA, Ensor N, Corbett JA, Nichols CGAuthor
John A. Corbett PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
3-Hydroxybutyric AcidAnimals
Animals, Newborn
Blood Glucose
Diabetes Mellitus, Type 1
Gene Expression
Genes, Reporter
Green Fluorescent Proteins
Hyperglycemia
Indicators and Reagents
Insulin
Islets of Langerhans
Luminescent Proteins
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Transgenic
Patch-Clamp Techniques
Phenotype
Potassium Channels
Potassium Channels, Inwardly Rectifying
Transgenes
