Fuel Metabolism and insulin secretion in KATP-hyperinsulinism human islets

KATP-高胰岛素血症人胰岛的燃料代谢和胰岛素分泌

基本信息

  • 批准号:
    8630007
  • 负责人:
  • 金额:
    $ 37.88万
  • 依托单位:
  • 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 2018-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Inactivating mutations in KATP channels cause the most common and severe form of congenital hyperinsulinism (KATPHI). Children with KATPHI are usually unresponsive to medical therapy and require pancreatectomy to control the hypoglycemia and prevent permanent brain damage. The goal of this proposal is to elucidate the ¿-cell pathophysiology in KATPHI through the examination of fuel metabolism and stimulus-secretion coupling in islets isolated from children with KATPHI. Our overall hypothesis is that disturbances in KATP channels function result not only in dysregulation of the triggering pathway of insulin release, but also have secondary consequences that drastically disturb glucose and amino acid metabolism and alter fuel-stimulated insulin secretion through both the triggering and the amplification pathway. This hypothesis will be examined in three related and overlapping specific aims: Aim 1 characterizes fuel metabolism and fuel-mediated insulin release in human islets with inactivating mutations in KATP channels and examines the role that elevated cytosolic calcium plays in determining the fate of metabolic fuels in these islets. Aim 2 focuses on examining the metabolic and cAMP-mediated amplification of insulin secretion within the framework of energy production in human KATPHI islets. Aim 3 examines the differences in gene expression between KATPHI islets and normal islets and integrates the metabolic and transcriptional profile of these islets to understand the mechanisms underlying the differences in fuel metabolism and insulin secretion. KATPHI is a severe genetic disorder associated with high rates of neurodevelopmental impairment. It has been almost 20 years since the discovery of the molecular basis of this condition. However, the incomplete understanding of the pathophysiology underlying the dysregulated insulin secretion has precluded the development of effective therapies. Thus, outcomes with current treatment approaches continue to be suboptimal for children carrying the most severe mutations. Our study aims at examining the pathophysiology within the framework of the energy production/insulin secretion relationship to identify new targets for therapy. This study will improve our understanding of the mechanisms and second messengers mediating the amplifying pathway of insulin secretion, which in turn, will be helpful for understanding the mechanisms implicated in the progressive ¿-cell failure that leads to type 2 diabetes. Thus, these studies may lead to the identification of novel targets for therapy not only for hyperinsulinism but also for diabetes.
描述(由申请人证明):KATP渠道中的灭活突变导致最常见和严重的现状形式)Katphi儿童对医疗,胰腺切除术无反应,以控制低血糖症和预期的永久性AIN损害。 » - 通过检查K. atphi的儿童的燃料代谢和刺激 - 验证耦合,但也具有次要奉献,但也有二次促进葡萄糖和氨基酸酸性葡萄糖和燃料的燃料,途径和燃料介导的胰岛素在人类的胰岛中释放,在KATP通道中释放了胞质钙在确定这些小岛中的Metabo LIC燃料的命运中。正常的胰岛并整合了机制的代谢和分析型,与胰岛素分泌相关的差异差异已近20年。对于携带最严重的突变的儿童,目前的治疗方法的结果继续是最严重的。涉及到的机制» - 导致2型糖尿病的细胞衰竭可能导致鉴定新的治疗靶标的糖尿病。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Diva D. De Leon其他文献

Diva D. De Leon的其他文献

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{{ truncateString('Diva D. De Leon', 18)}}的其他基金

Phase 2A Study of Exendin for the Treatment of Congenital Hyperinsulinism
Exendin 治疗先天性高胰岛素血症的 2A 期研究
  • 批准号:
    8568402
  • 财政年份:
    2013
  • 资助金额:
    $ 37.88万
  • 项目类别:
Insulin Secretion in Hyperinsulinism Human Islets
高胰岛素血症人类胰岛的胰岛素分泌
  • 批准号:
    9885218
  • 财政年份:
    2013
  • 资助金额:
    $ 37.88万
  • 项目类别:
Fuel Metabolism and insulin secretion in KATP-hyperinsulinism human islets
KATP-高胰岛素血症人胰岛的燃料代谢和胰岛素分泌
  • 批准号:
    9057027
  • 财政年份:
    2013
  • 资助金额:
    $ 37.88万
  • 项目类别:
Phase 2A Study of Exendin for the Treatment of Congenital Hyperinsulinism
Exendin 治疗先天性高胰岛素血症的 2A 期研究
  • 批准号:
    8839669
  • 财政年份:
    2013
  • 资助金额:
    $ 37.88万
  • 项目类别:
Fuel Metabolism and insulin secretion in KATP-hyperinsulinism human islets
KATP-高胰岛素血症人胰岛的燃料代谢和胰岛素分泌
  • 批准号:
    8852609
  • 财政年份:
    2013
  • 资助金额:
    $ 37.88万
  • 项目类别:
Insulin Secretion in Hyperinsulinism Human Islets
高胰岛素血症人类胰岛的胰岛素分泌
  • 批准号:
    10348708
  • 财政年份:
    2013
  • 资助金额:
    $ 37.88万
  • 项目类别:
Fuel Metabolism and insulin secretion in KATP-hyperinsulinism human islets
KATP-高胰岛素血症人胰岛的燃料代谢和胰岛素分泌
  • 批准号:
    8734412
  • 财政年份:
    2013
  • 资助金额:
    $ 37.88万
  • 项目类别:
Phase 2A Study of Exendin for the Treatment of Congenital Hyperinsulinism
Exendin 治疗先天性高胰岛素血症的 2A 期研究
  • 批准号:
    8653839
  • 财政年份:
    2013
  • 资助金额:
    $ 37.88万
  • 项目类别:
Insulin Secretion in Hyperinsulinism Human Islets
高胰岛素血症人类胰岛的胰岛素分泌
  • 批准号:
    10553133
  • 财政年份:
    2013
  • 资助金额:
    $ 37.88万
  • 项目类别:
Role of GLP-1 in Congenital Hyperinsulinism
GLP-1 在先天性高胰岛素血症中的作用
  • 批准号:
    7912924
  • 财政年份:
    2009
  • 资助金额:
    $ 37.88万
  • 项目类别:

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