Defects in beta cell Ca  + signalling, @entity413 metabolism and insulin secretion in a @entity19 model of @entity3529 ( XXXX ) channel-induced @entity6 .

@entity3529 @entity6 @entity19 @entity10406 @entity5002 @entity5736 @entity460 @entity972 @entity141 @entity413 @entity855 @entity2383
AIMS/HYPOTHESIS: Mutations that render @entity855 -sensitive @entity972 ( @entity3529 ( @entity855 )) channels insensitive to @entity855 inhibition @entity6 . In @entity19 , these mutations cause insulin secretion to be lost initially and, as the disease progresses, beta cell mass and insulin content also disappear. We investigated whether defects in @entity460 signalling alone are sufficient to explain short-term and long-term islet dysfunction. METHODS: We examined the metabolic, electrical and insulin secretion response in islets from @entity19 that become @entity6 after induction of @entity855 -insensitive @entity5002 expression. To separate direct effects of @entity3529 ( @entity855 ) overactivity on beta cell function from indirect effects of prolonged hyperglycaemia, normal glycaemia was maintained by protective exogenous islet transplantation. RESULTS: In endogenous islets from protected animals, @entity413 -dependent elevations of intracellular free- @entity460 activity ([ @entity141 ](i)) were severely blunted. Insulin content of these islets was normal, and @entity5736 and @entity10406 stimulated increased [ @entity141 ](i). In the absence of transplant protection, [ @entity141 ](i) responses were similar, but @entity413 metabolism and redox state were dramatically altered; @entity5736 - and @entity10406 -stimulated insulin secretion was also lost, because of systemic effects induced by long-term hyperglycaemia and/or hypoinsulinaemia. In both cases, [ @entity141 ](i) dynamics were synchronous across the islet. After reduction of gap-junction coupling, @entity413 -dependent [ @entity141 ](i) and insulin secretion was partially restored, indicating that excitability of weakly expressing cells is suppressed by cells expressing mutants, via gap-junctions. CONCLUSIONS/INTERPRETATION: The primary defect in @entity3529 ( @entity855 )-induced @entity6 is failure of @entity413 metabolism to elevate [ @entity141 ](i), which suppresses insulin secretion and mildly alters islet @entity413 metabolism. @entity2383 are secondary to the long-term hyperglycaemia and/or hypoinsulinaemia that result from the absence of @entity413 -dependent insulin secretion.
