Targeted Overactivity of β Cell KATP Channels Induces Profound Neonatal Diabetes

AbstractA paradigm for control of insulin secretion is that glucose metabolism elevates cytoplasmic [ATP]/[ADP] in β cells, closing KATP channels and causing depolarization, Ca2+ entry, and insulin release. Decreased responsiveness of KATP 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 KATP 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 KATP channel activity is critical for maintenance of euglycemia and that overactivity can cause diabetes by inhibiting insulin secretion