Decreasing Cx36 Gap Junction Coupling Compensates for Overactive K(ATP) Channels to Restore Insulin Secretion and Prevent Hyperglycemia in a Mouse Model of Neonatal Diabetes

Mutations to the ATP-sensitive K(+) channel (K(ATP) channel) that reduce the sensitivity of ATP inhibition cause neonatal diabetes mellitus via suppression of β-cell glucose-stimulated free calcium activity ([Ca(2+)](i)) and insulin secretion. Connexin-36 (Cx36) gap junctions also regulate islet electrical activity; upon knockout of Cx36, β-cells show [Ca(2+)](i) elevations at basal glucose. We hypothesized that in the presence of overactive ATP-insensitive K(ATP) channels, a reduction in Cx36 would allow elevations in glucose-stimulated [Ca(2+)](i) and insulin secretion to improve glucose homeostasis. To test this, we introduced a genetic knockout of Cx36 into mice that express ATP-insensitive K(ATP) channels and measured glucose homeostasis and islet metabolic, electrical, and insulin secretion responses. In the normal presence of Cx36, after expression of ATP-insensitive K(ATP) channels, blood glucose levels rapidly rose to >500 mg/dL. Islets from these mice showed reduced glucose-stimulated [Ca(2+)](i) and no insulin secretion. In mice lacking Cx36 after expression of ATP-insensitive K(ATP) channels, normal glucose levels were maintained. Islets from these mice had near-normal glucose-stimulated [Ca(2+)](i) and insulin secretion. We therefore demonstrate a novel mechanism by which islet function can be recovered in a monogenic model of diabetes. A reduction of gap junction coupling allows sufficient glucose-stimulated [Ca(2+)](i) and insulin secretion to prevent the emergence of diabetes.