Chastening the double-edged sword of glucose metabolism in beta-cells

磨练β细胞中葡萄糖代谢的双刃剑

基本信息

批准号：
9296135
负责人：
Richard G Kibbey
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9296135
关键词：
Adipose tissue Anabolism Beta Cell Cadaver Carbon Cell Respiration Cell physiology Cellular Metabolic Process Cessation of life Citric Acid Cycle Coupled Coupling Data Development Diabetes Mellitus Distal Enzyme Activation Erythrocytes Functional disorder Futile Cycling Glucokinase Gluconeogenesis Glucose Glycolysis Health Human In Vitro Inflammation Injury Insulin Isotope Labeling Liver Longevity Measurement Measures Mediator of activation protein Medicine Metabolic Metabolic Pathway Metabolism Metaphor Methods Mitochondria Oranges Pathway interactions Pharmacology Phosphorylation Process Protein Isoforms Pyruvate Pyruvate Carboxylase Pyruvate Kinase Reaction Resolution Signal Transduction Stimulus Structure of beta Cell of islet Technology Toxic effect Translating Work blood glucose regulation diabetic follow-up glucose metabolism human subject improved improved functioning in vivo injured innovation insulin secretion insulin sensitivity islet novel novel strategies novel therapeutic intervention novel therapeutics prevent response small molecule wasting western diet

项目摘要

Abstract: Pancreatic beta-cells are the last line of defense to preserve glucose homeostasis and preventing diabetes. Some past therapies that have enhanced their function are associated with a loss of durability due in part to injury and dedifferentiation of beta-cells. A clear understanding of the metabolic features that are tied improved function as well as those that are detrimental may help in the development of new therapies. Much of the understanding of how glucose is metabolized to generate a signal to release insulin have been obtained in a piecemeal fashion. As a consequence, there has been a surprising divergence, rather than a convergence, on the fundamentals such as metabolism-secretion-coupling as well as metabolic toxicities. New quantitative and comprehensive methods are required to reevaluate the relationship of flux through metabolic pathways in human beta-cells. The Kibbey lab has recently developed such a platform called Mass Isotopomer Multi Ordinate Spectral Analysis (MIMOSA) that can follow the stepwise transfer of mass isotope labeled substrates through glycolysis and the TCA cycle. Here a proposed expansion of this innovation to include additional metabolic flux measurements will assess normal and diabetic human beta-cells. MIMOSA will first be applied to characterize the fundamentals of normal beta-cell metabolism in response to different fuels, metabolic stimuli, and medicines. A second aim will follow up on the observation that glucokinase activators restore insulin secretion in diabetic humans but ultimately loose durability due to toxic metabolism. Here the top-down “pushing” metabolism will be compared to “pulling” metabolism from the bottom using small molecule enzymatic activators. Preliminary data using MIMOSA identifies an import benefit of activating anaplerotic pyruvate carboxylase metabolism in normal, glucolipotoxic, and diabetic human islets. However, top-down pushing leads to overflow of glycolytic metabolites into detrimental metabolic pathways that are relieved by pharmacologically unloading glycolysis. A third aim will translate these findings in vivo, where activation of the allosterically-regulated pyruvate kinase isoforms are anticipated to improve glucose homeostasis both by stimulating insulin secretion but also uncoupling gluconeogenesis via energy wasting futile cycles that improve insulin sensitivity. So taken together, this proposal leverages an innovative metabolic flux platform to identify the mechanistic fundamentals of how beta-cells work and how they fail and translates this information in vivo to validate a potential novel therapeutic approach to treat diabetes.

抽象的：胰腺β细胞是维持葡萄糖稳态和预防糖尿病的最后一道防线。过去一些增强其功能的疗法与耐久性的丧失有关，部分原因是对β细胞损伤和去分化的相关代谢特征的清晰了解得到了改善。功能以及那些困扰的可能有助于开发新疗法。对葡萄糖如何代谢以产生释放胰岛素的信号的理解已经在结果，时尚出现了惊人的分歧，而不是趋同。代谢-分泌-耦合以及代谢毒性等基础知识。需要综合方法来重新评估代谢途径的通量关系 Kibbey 实验室最近开发了一个名为 Mass Isotopomer Multi 的平台。纵坐标光谱分析 (MIMOSA)，可以跟踪质量同位素标记底物的逐步转移通过糖酵解和 TCA 循环，这里提出了对这一创新的扩展，以包括额外的内容。代谢通量测量将首先应用 MIMOSA 来评估正常和糖尿病人类 β 细胞。表征正常 β 细胞代谢响应不同燃料、代谢的基本原理第二个目标是观察葡萄糖激酶激活剂恢复情况。糖尿病人的胰岛素分泌，但最终由于有毒代谢而失去耐久性。将“推”代谢与使用小分子从底部“拉”代谢进行比较使用 MIMOSA 的酶激活剂的初步数据确定了激活回补的重要益处。然而，正常、糖脂毒性和糖尿病人胰岛中的丙酮酸羧化酶代谢是自上而下的。推动会导致糖酵解代谢途径溢出到代谢途径中，而这些代谢途径可以通过以下方式缓解：第三个目标是将这些发现转化为体内糖酵解的药理学卸载，其中激活糖酵解。变构调节的丙酮酸激酶亚型预计可通过以下方式改善葡萄糖稳态：刺激胰岛素分泌，但也通过能量浪费无效循环来解偶联糖异生，从而改善综上所述，该提案利用创新的代谢流平台来识别胰岛素敏感性。 β 细胞如何工作以及它们如何失效的机制基础，并将这些信息在体内转化为验证治疗糖尿病的潜在新治疗方法。