Targeted overactivity of beta cell K-ATP channels induces profound neonatal diabetes

A paradigm for control of insulin secretion is that glucose metabolism elev ates cytoplasmic [ATP]/[ADP] in beta cells, closing K-ATP channels and caus ing depolarization, Ca2+ entry, and insulin release. Decreased responsivene ss of K-ATP channels to elevated [ATP]/[ADP] should therefore lead to decre ased insulin secretion and diabetes. To test this critical prediction, we g enerated transgenic mice expressing beta cell K-ATP channels with reduced A TP 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 wer e normal (before day 3), pointing to reduced insulin secretion as causal. T he data indicate that normal K-ATP channel activity is critical for mainten ance of euglycemia and that overactivity can cause diabetes by inhibiting i nsulin secretion.