详细记录  
题名:Decreasing Cx36 gap junction coupling compensates for overactive KATP channels to restore insulin secretion and prevent hyperglycemia in a mouse model of neonatal diabetes.
作者:NGUYEN LM; POZZOLI M; HRAHA TH; BENNINGER RK;
来源:Diabetes. 2014 Jan 23. [ IF= 7.89 ] ]
URL :10.2337/db13-1048
日期:20140217
摘要:Mutations to the KATP channel which reduce the sensitivity of ATP-inhibition
cause neonatal diabetes mellitus, via suppression of beta-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
beta-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.

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