Targeted Overactivity of β Cell KATP Channels Induces Profound Neonatal Diabetes

@article{Koster2000TargetedOO,
  title={Targeted Overactivity of $\beta$ Cell KATP Channels Induces Profound Neonatal Diabetes},
  author={Jc. Koster and Barbara Marshall and Nancy J. Ensor and John A. Corbett and Cg. Nichols},
  journal={Cell},
  year={2000},
  volume={100},
  pages={645-654}
}
A paradigm for control of insulin secretion is that glucose metabolism elevates cytoplasmic [ATP]/[ADP] in beta cells, closing K(ATP) channels and causing depolarization, Ca2+ entry, and insulin release. Decreased responsiveness of K(ATP) channels to elevated [ATP]/[ADP] should therefore lead to decreased insulin secretion and diabetes. To test this critical prediction, we generated transgenic mice expressing beta cell K(ATP) channels with reduced ATP sensitivity. Animals develop severe… 
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It is demonstrated that a range of phenotypes can be expected for a reduction in ATP sensitivity of β-cell KATP channels and provide models for the corollary neonatal diabetes in humans.
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The results suggest that incomplete suppression of KATP channel activity can give rise to a maintained hyperinsulinism.
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Mice with KATP channel gain-of-function mutations are hyperglycaemic and have impaired glucose-stimulated insulin secretion, a phenotype that accurately mimics human diabetes.
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This review highlights the important role of the β-cell KATP channel in glucose physiology and provides an introduction to some of the other review articles in this special edition of the Reviews in Endocrine and Metabolic Disorders.
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Defects in beta cell Ca2+ signalling, glucose metabolism and insulin secretion in a murine model of KATP channel-induced neonatal diabetes mellitus
TLDR
The primary defect in KATP-induced neonatal diabetes mellitus is failure of glucose metabolism to elevate [Ca2+]i, which suppresses insulin secretion and mildly alters islet glucose metabolism, which is secondary to the long-term hyperglycaemia and/or hypoinsulinaemia that result from the absence of glucose-dependent insulin secretion.
ATP-sensitive K+ channel signaling in glucokinase-deficient diabetes.
TLDR
The significant abrogation ofnGK(-/-) and nGK(+/-) phenotypes in the absence of K(ATP) demonstrate that a major factor in glucokinase deficiency is indeed altered K( ATP) signaling, and have implications for understanding and therapy of glucokin enzyme-related diabetes.
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