Decreasing cx36 gap junction coupling compensates for overactive KATP channels to restore insulin secretion and prevent hyperglycemia in a mouse model of neonatal diabetes.
Mutations to the ATP-sensitive K(+) channel (KATP 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 KATP 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 KATP channels and measured glucose homeostasis and islet metabolic, electrical, and insulin secretion responses. In the normal presence of Cx36, after expression of ATP-insensitive KATP 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 KATP 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.
Department of Bioengineering, University of Colorado, Anschutz Medical Campus, Aurora, CO.
Linda M
LM
Nguyen
Marina
M
Pozzoli
Thomas H
TH
Hraha
Richard K P
RK
Benninger
D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000097004:Gap Junction delta-2 Protein
D001786:Blood Glucose; D002118:Calcium; D017630:Connexins; D007328:Insulin; D054086:KATP Channels; D000097004:Gap Junction delta-2 Protein