1745-P: Voltage-Gated K+ Channel Kv7.1 Is an Important Regulator of Insulin Secretion in Normal and Hyperinsulinemic Islets

Fifty percent of infants with Beckwith-Wiedemann syndrome (BWS), an overgrowth syndrome caused by genetic / epigenetic abnormalities in imprinted genes on chromosome 11p15, have persistent hypoglycemia due to hyperinsulinism (BWS-HI). BWS-HI islets exhibit increased baseline and glucose-stimulated insulin secretion (GSIS) and are responsive to the K_ATP channel inhibitor glyburide, suggesting it is not caused by impaired K_ATP channels. KCNQ1 expression, encoding the pore-forming α subunit of voltage-gated K⁺ channel Kv7.1, is reduced in BWS-HI islets compared to normal islets (3-fold; p = 4.5×10⁻⁷) and KCNQ1 loss-of-function mutations in humans are associated with HI. We used genetic and pharmacologic methods to modify Kv7.1 activity and examined changes to insulin secretion. In response to glucose, Kcnq1^−/− mice had lower plasma glucose and higher plasma insulin than wild-type controls. Perifusion of Kcnq1^−/− pancreatic islets with increasing concentrations of glucose showed that GSIS in these islets was faster and greater than in wild-type islets. The perifusion GSIS responses in normal human, wild-type mouse and Sur1^−/− mouse (K_ATP-HI mouse model) islets with two different Kv7.1 activators (hexachlorophene or ML277) were markedly slower and diminished. In contrast, wild-type mouse islet perifusion with the Kv7.1 inhibitor chromanol 293B strikingly fastened and increased the GSIS response compared to vehicle controls. Membrane potential (V_m) analysis of Kcnq1^−/− islets demonstrated that depolarization occurs more quickly during the initiation of insulin secretion compared to wild-type controls. Treatment with Kv7.1 activators resulted in V_m changes in both wild-type mouse and normal human islets compared to controls. Our results reveal the capacity of Kv7.1 to regulate insulin secretion in pancreatic islets and that Kv7.1 is a viable target for development of therapeutics for HI.