Decreasing Cx36 gap junction coupling compensates for overactive KATP channels to restore insulin secretion and prevent hyperglycemia in a mouse model of neonatal diabetes

  1. Richard K.P. Benningera,b,1
  1. aDepartment of Bioengineering, University of Colorado, Anschutz Medical campus, Aurora, CO.
  2. bBarbara Davis center for childhood diabetes, University of Colorado, Anschutz Medical campus, Aurora, CO.
  1. 1Corresponding author: richard.benninger{at}


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.

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