Mutations to the KATP channel which reduce the sensitivity of ATP-inhibition cause neonatal diabetes mellitus, via suppression of β-cell glucose-stimulated free-calcium activity ([Ca2+]i) and insulin secretion. Connexin-36 (Cx36) gap junctions also regulates islet electrical activity: upon a knockout of Cx36 β-cells show [Ca2+]i elevations at basal glucose. We hypothesized that in the presence of overactive ATP-insensitive KATP channels, a reduction in Cx36 would allow elevations in glucose-stimulated [Ca2+]i and insulin secretion to improve glucose homeostasis. To test this, we introduced a genetic knockout of Cx36 into mice that express ATP-insensitive KATP channels and measured glucose homeostasis and islet metabolic, electrical and insulin secretion responses. In the normal presence of Cx36, following expression of ATP-insensitive KATP channels, blood glucose levels rapidly rose to >500mg/dl. Islets from these mice showed reduced glucose-stimulated [Ca2+]i and no insulin secretion. In mice lacking Cx36 following expression of ATP-insensitive KATP channels, normal glucose levels were maintained. Islets from these mice had near-normal glucose-stimulated [Ca2+]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 [Ca2+]i and insulin secretion to prevent the emergence of diabetes.
2 These authors contributed equally.
- Received July 3, 2013.
- Accepted January 8, 2014.
- © 2014 by the American Diabetes Association.
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