Targeted overactivity of β cell K(ATP) channels induces profound neonatal diabetes

J. C. Koster, B. A. Marshall, N. Ensor, J. A. Corbett, C. G. Nichols

Research output: Contribution to journalArticlepeer-review

236 Scopus citations

Abstract

A paradigm for control of insulin secretion is that glucose metabolism elevates cytoplasmic [ATP]/[ADP] in β 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 β 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 α and β 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.

Original languageEnglish
Pages (from-to)645-654
Number of pages10
JournalCell
Volume100
Issue number6
DOIs
StatePublished - Mar 17 2000

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