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

• 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
• 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

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细胞是保持葡萄糖稳态和预防糖尿病的最后防御线。 某些过去提高其功能的过去疗法与耐久性丧失有关，部分原因是 β细胞的损伤和去分化。清楚地理解了被绑定的代谢特征的改进 功能以及有害的功能可能有助于开发新疗法。大部分 了解如何将葡萄糖代谢以生成信号以释放胰岛素 零碎时尚。结果，出乎意料的分歧，而不是融合 诸如代谢 - 分泌耦合以及代谢毒性之类的基本面。新的定量和 需要全面的方法来重新评估通过代谢途径的通量关系 人β细胞。 Kibbey Lab最近开发了这样一个称为Mass Isotopomer Multi的平台 纵向光谱分析（MIMOSA），可以遵循质量同位素标记为底物的逐步转移 通过糖酵解和TCA周期。在这里提出的这项创新的扩展包括附加 代谢通量测量结果将评估正常和糖尿病人类β细胞。含羞草将首先应用 为了表征正常β细胞代谢的基本原理，以响应不同的燃料，代谢 刺激和药物。第二个目标将跟进葡萄糖酶激活剂还原的观察结果 糖尿病人类中的胰岛素分泌，但由于有毒代谢而最终会松散耐用性。这是自上而下的 使用小分子将“推动”代谢与从底部的“拉”代谢进行比较 酶促激活剂。使用Mimosa的初步数据确定了激活同性恋的进口优势 丙酮酸羧化酶代谢在正常，糖毒素和糖尿病人类胰岛中。但是，自上而下 将导致糖酵解代谢产物溢流到有害的代谢途径中 药理学卸载糖酵解。第三个目标将在体内转化这些发现，其中激活 预计构摩力调节的丙酮酸激酶同工型可以改善葡萄糖稳态。 刺激胰岛素分泌，但也通过浪费徒劳的周期来解开糖异生的作用 胰岛素灵敏度。因此，该提案共同利用创新的代谢通量平台来识别 Beta细胞如何工作以及它们如何失败并将这些信息转换为体内的机械基本原理 验证一种潜在的新型治疗方法来治疗糖尿病。