Targeted overactivity of β cell KATP channels induces profound neonatal diabetes

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.