KATP deficiency in hyperinsulinism and diabetes

项目摘要 这个联合项目的长期目标是了解电的机制、作用和意义。 控制高胰岛素血症和糖尿病中的胰岛素分泌。以往的努力表明， 胰腺β细胞电活动中的KATP通道，并揭示了缺陷的通道活性 可对胰岛素分泌产生深远影响，并引起高胰岛素血症和新生儿糖尿病。这 现在的理解是使用KATP通道激活剂和抑制剂，分别作为第一线， 治疗然而，一个矛盾的，基本上无法解释的，交叉到葡萄糖不足，或直接 糖尿病，见于动物和人的高胰岛素血症。在2型糖尿病中， 从最初的分泌过多到分泌衰竭，可能反映了类似的进展。拟议的研究将利用新的 诱导型KATP通道敲低模型和2型糖尿病模型，以全面探讨 这一逆转的机制基础，从而提高理解和管理HI和其他形式的 长期β-细胞分泌衰竭。

Project Summary The long-term goals of this joint project are to understand the mechanisms, role and significance of electrical control of insulin secretion in hyperinsulinism and diabetes. Previous efforts demonstrated the central role of the KATP channel in electrical activity of the pancreatic beta-cell and revealed how defective channel activity can have profound effects on insulin secretion, and cause hyperinsulinism and neonatal diabetes. This understanding now underlies the use of KATP channel activators and inhibitors, respectively, as first line therapies. However, a paradoxical, essentially unexplained, crossover to glucose-insufficiency, or outright diabetes, is seen in both animals and humans with hyperinsulinism. In Type 2 diabetes, a parallel crossover from initial hypersecretion to secretory failure, may reflect a similar progression. Proposed studies will utilize novel inducible KATP channel knockdown models and models of type 2 diabetes to comprehensively probe the mechanistic basis of this reversal, and thereby improve understanding and management of HI and other forms of long-term -cell secretory failure.