KATP deficiency in hyperinsulinism and diabetes

KATP 缺乏导致高胰岛素血症和糖尿病

• 批准号: 10658504
• 负责人: Colin G Nichols
• 金额: $ 50.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658504
• 关键词: Acute; Address; Animal Model; Animals; Beta Cell; Biological; Calcium; Cations; Cells; Chronic; Climacteric; Collaborations; Coupling; Data; Development; Diabetes Mellitus; Diazoxide; Disease; Down-Regulation; Electrophysiology (science); Exhibits; Exposure to; Failure; Feedback; Gene Expression; Glucose; Glucose Intolerance; Goals; High Fat Diet; Human; Hyperglycemia; Hyperinsulinism; Individual; Insulin; Insulin Resistance; Ions; Joints; Knockout Mice; Link; Measures; Modeling; Molecular; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Patients; Persistent Hyperinsulinemia Hypoglycemia of Infancy; Physiological; Process; Productivity; Publishing; Role; Secretory Cell; Stress; Structure of beta Cell of islet; Sulfonylurea Compounds; TRPM5 gene; Testing; Time; World Health; blind; clinically significant; db/db mouse; density; experimental study; gain of function mutation; genetic approach; glucose tolerance; human disease; improved; inhibitor; insulin secretion; islet; knock-down; loss of function; mouse model; neonatal diabetes mellitus; novel; pharmacologic; response; therapeutic development; transcriptomics

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.

项目总结