Ion channel regulation of pancreatic islet cell function

离子通道对胰岛细胞功能的调节

• 批准号: 10477248
• 负责人: Rajan Sah
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477248
• 关键词: Adipose tissue; Aging; Anions; Attention; B Cell Proliferation; B-Lymphocytes; Beta Cell; Biology; C-terminal; Cadaver; Cell membrane; Cell physiology; Cellular biology; Chlorides; Closure by clamp; Complex; Coupling; Cryoelectron Microscopy; Data; Diabetes Mellitus; Diabetes prevention; Disease; Equilibrium; Exhibits; FRAP1 gene; Failure; Glucose; Glucose Intolerance; Health; Heart Diseases; Human; Hyperglycemia; Immunoprecipitation; Impairment; In Vitro; Insulin; Ion Channel; Islets of Langerhans; Kidney Diseases; Knowledge; Label; Leucine-Rich Repeat; Long-Term Effects; Mass Spectrum Analysis; Measures; Mediating; Membrane Potentials; Microscopy; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Phase; Population; Protein Family; Proto-Oncogene Proteins c-akt; Reagent; Regulation; Reporting; Research; Retinal Diseases; Signal Pathway; Signal Transduction; Societies; Stroke; Structure of beta Cell of islet; Swelling; Testing; Therapeutic; Time; Vesicle; Veterans; cell growth; experimental study; gain of function; in vivo; innovation; insight; insulin secretion; insulin sensitivity; islet; knowledge base; member; military veteran; mortality; mutant; novel; novel therapeutic intervention; patch clamp; preservation; therapeutic target; trafficking; voltage; voltage clamp

Project Summary/Abstract It is estimated that 1 in 4 Veterans suffer from diabetes, and, in the Veteran population, this is largely Type 2 diabetes. This condition drives heart disease, stroke, retinopathy, nephropathy and neuropathy, all of which are a cause of significant morbidity and mortality among our Veterans. As such, understanding the biology of diabetes, discovering novel molecules that regulate b-cell function and developing innovative therapeutic approaches will have a significant impact on the health of our aging veteran population. Type 2 diabetes is characterized by both a loss of insulin sensitivity and, ultimately, a relative loss of insulin-secretion from the pancreatic b-cell. Insulin secretion from the pancreatic b-cell is triggered by Ca2+ influx through voltage-gated Ca2+ channels (VGCC) to trigger insulin vesicle fusion with the b-cell plasma membrane. We recently reported that SWELL1 (LRRC8a), a member of the Leucine Rich Repeat Containing protein family, is required for ICl,SWELL in β-cells. SWELL1-mediated ICl,SWELL activates upon b-cell swelling induced by glucose import, and this generates a depolarizing current contributing to VGCC activation, thereby regulating insulin secretion and systemic glycemia. Indeed, mice with SWELL1-deficient β-cells exhibit impaired glucose- stimulated insulin secretion and glucose intolerance. Moreover, we find that ICl,SWELL is reduced in both mouse and humans in the context of Type 2 diabetes (T2D) indicating that reduced SWELL1 signaling is associated with impaired b-cell function in T2D. The objective of the current proposal is to delineate the mechanisms by which SWELL1 signaling regulates b-cell function, under basal conditions, and in the setting of Type 2 diabetes. Our central hypothesis is that SWELL1 regulates both glucose-stimulated insulin secretion and PI3K-AKT-mTOR signaling in b-cells to maintain systemic glycaemia, and that impaired SWELL1 signaling contributes to b-cell failure in Type 2 diabetes. The contribution of this proposal is significant because it explores the innovative concept the SWELL1 utilizes dual signaling domains (channel versus LRRD) to regulate b-cell function in health and T2D. Importantly, this proposal will also define the relationship between b-cell SWELL1 and T2D and test the notion that reduced SWELL1 signaling may drive impaired b-cell function in T2D. We propose the following two AIMs: AIM#1: Delineate the mechanism(s) of SWELL1-mediated regulation of excitation-secretion coupling. AIM#2: Dissect the molecular mechanisms of SWELL1 macro-complex regulation of AKT-mTOR signaling in b-cells. The contribution of this proposal is innovative because it delineates a novel SWELL1 signaling pathway that connects glucose-mediated b-cell swelling to b-cell depolarization and insulin-release - a form of b-cell swell- activation or “swell-secretion” coupling. This proposal will enhance our understanding of b-cell biology and help direct novel therapeutic approaches to b-cell failure in Type 2 diabetes. !

项目总结/文摘