Insulin Secretion in Hyperinsulinism Human Islets

高胰岛素血症人类胰岛的胰岛素分泌

基本信息

批准号：
10553133
负责人：
Diva D. De Leon
金额：
$ 62.95万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10553133
关键词：
Address Affect Beckwith-Wiedemann Syndrome Beta Cell Calcium Child Chronic Complex Defect Disease Electrophysiology (science)Failure Functional disorder Funding Gene Expression Genetic Genetic Diseases Genomics Health Human Hyperinsulinism Infant Insulin Ion Channel Knock-in Knock-out Long QT Syndrome Membrane Potentials Metabolism Modeling Molecular Mus Mutation Neurodevelopmental Impairment Non-Insulin-Dependent Diabetes Mellitus Outcome Study Pancreas Pathway interactions Persistent Hyperinsulinemia Hypoglycemia of Infancy Phenotype Physiological Play Potassium Channel Rest Risk Role Secondary to Stimulus Testing Up-Regulation Variant Withdrawal basal insulin blood glucose regulation differential expression genetic approach genetic manipulation improved in vivo insulin regulation insulin secretion interest islet metabolomics mouse model new therapeutic target novel pharmacologic response

项目摘要

PROJECT SUMMARY The study of human islets isolated from the pancreas of infants with congenital hyperinsulinism (HI) during the previous funding cycle has afforded us the unique opportunity to examine the islet phenotype in KATPHI integrating function, metabolomics, and genomics. Our findings revealed a complex pathophysiology in which the primary KATP channel defect leads to secondary consequences affecting gene expression, fuel metabolism, and both the triggering and amplifying pathways of insulin secretion. However, many critical questions for addressing unmet needs for the treatment of HI and for the understanding of normal physiological mechanisms of insulin secretion remain unanswered. We are particularly interested in examining the role of two ion channels that are differentially expressed in HI islets in the normal regulation of insulin secretion and their potential role in the pathophysiology of HI: TMEM16A, a Ca2+-activated Cl– channel encoded by ANO1 which is markedly upregulated in KATPHI islets, and Kv7.1, encoded by KCNQ1, whose expression is markedly decreased in islets isolated from the pancreases of children with Beckwith Wiedemann syndrome and HI. In preliminary studies we found that pharmacological modulation of these channels alters insulin secretion. Our overall hypothesis is that both Kv7.1 and TMEM16A play critical roles in the termination of insulin secretion by keeping β-cell Vm hyperpolarized at rest and facilitating β-cell Vm repolarization after stimulation. To test this hypothesis, we propose two aims to examine the role of Kv7.1 and TMEM16A in the regulation of insulin secretion in normal and HI islets. To accomplish these aims we will use genetic and pharmacological approaches to modulate the activity of these channels in normal and HI human and mouse islets. We will examine: 1) the contribution of TMEM16A and Kv7.1 to β-cell Vm at resting and stimulated states; 2) the effect of TMEM16A and Kv7.1 activation and inhibition on cytosolic calcium and insulin secretion in normal human and mouse islets; 3) the effect of genetic inactivation of TMEM16A and Kv7.1 on glucose homeostasis in vivo and fuel-stimulated insulin secretion in vivo and in isolated islets using genetically modified mouse models. This study will expand our understanding of the pathophysiology of HI and will facilitate the identification of new genetic causes and potential new therapeutic targets for this devastating disease. The study may also have implications for the understanding of the mechanisms implicated in the progressive β-cell failure that leads to type 2 diabetes.

项目摘要从先天性高胰岛素（HI）的胰腺中分离出的人类胰岛的研究以前的资金周期为我们提供了检查Katphi胰岛表型的独特机会整合功能，代谢组学和基因组学。我们的发现揭示了一种复杂的病理生理学主要的KATP通道缺陷会导致影响基因表达，燃料代谢的次要后果，以及胰岛素分泌的触发和放大途径。但是，许多关键问题满足对HI治疗的未满足需求和理解正常生理机制的需求胰岛素的分泌仍未得到答复。我们对检查两个离子的作用特别感兴趣在胰岛素分泌的正常调节中，在HI胰岛中表达不同的通道及其 HI：TMEM16A的病理生理学中的潜在作用在Katphi Islet和KV7.1中明显更新，由KCNQ1编码，其表达式是明显的从贝克维斯·威德曼综合征和HI的儿童的胰腺中分离出来的胰岛减少。在初步研究我们发现，这些通道的药物调节改变了胰岛素的分泌。我们的总体假设是KV7.1和TMEM16A在胰岛素的终止中起关键作用通过保持β细胞VM超极性在静止状态并支撑β细胞VM复制后的分泌。刺激。为了检验这一假设，我们提出了两个目的，以检查KV7.1和TMEM16A在调节正常和HI小岛中胰岛素分泌。为了实现这些目标，我们将使用遗传和在正常和HI人和小鼠中调节这些通道活性的药理方法胰岛。我们将检查：1）TMEM16A和KV7.1对β细胞VM在静止和刺激时的贡献国家2）TMEM16A和KV7.1激活和抑制对胞质钙和胰岛素分泌的影响在正常的人类和小鼠胰岛中； 3）TMEM16A和KV7.1遗传失活对葡萄糖的影响体内体内和燃料刺激的胰岛素分泌在体内和孤立的胰岛中使用一般修饰鼠标模型。这项研究将扩大我们对HI的病理生理学的理解，并将促进确定这种毁灭性疾病的新遗传原因和潜在的新治疗靶标。这研究也可能对理解进行性β细胞中隐含的机制有影响导致2型糖尿病的失败。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mitochondrial regulation of β-cell function: maintaining the momentum for insulin release.

DOI：
10.1016/j.mam.2015.01.004
发表时间：
2015-04
期刊：
MOLECULAR ASPECTS OF MEDICINE
影响因子：
10.6
作者：
Kaufman, Brett A.;Li, Changhong;Soleimanpour, Scott A.
通讯作者：
Soleimanpour, Scott A.

Case Report: Two Distinct Focal Congenital Hyperinsulinism Lesions Resulting From Separate Genetic Events.

DOI：
10.3389/fped.2021.699129
发表时间：
2021
期刊：
Frontiers in pediatrics
影响因子：
2.6
作者：
Rosenfeld E;Mitteer L;Boodhansingh K;Becker SA;McKnight H;Boyajian L;Ackermann AM;Kalish JM;Bhatti TR;States LJ;Adzick NS;Lord K;De León DD
通讯作者：
De León DD

Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes.