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

摘要： 胰岛β细胞是维持血糖稳态和预防糖尿病的最后一道防线。 过去一些增强了它们功能的疗法与耐久性的丧失有关，部分原因是 β细胞的损伤和去分化。对联系在一起的代谢特征的清楚理解得到了改善 功能以及那些有害的可能有助于开发新的治疗方法。世界上大部分的 对葡萄糖如何代谢以产生释放胰岛素的信号的了解已经在 零碎的时尚。因此，在以下问题上出现了令人惊讶的分歧，而不是趋同 代谢-分泌-偶联以及代谢毒性等基本原理。新的量化和 需要综合的方法来重新评估通过代谢途径的通量关系。 人类的β细胞。Kibbey实验室最近开发了这样一个平台，称为质量异构体多 跟踪质量同位素标记底物逐步转移的纵谱分析(MIMOSA) 通过糖酵解和三氯乙酸循环。以下是这项创新的扩展建议，以包括其他 新陈代谢流量测量将评估正常和糖尿病人的β细胞。将首先使用含羞草 为了表征正常的β细胞代谢对不同燃料、代谢的反应的基本原理 刺激物和药物。第二个目标是在观察到葡糖激活剂恢复 糖尿病人的胰岛素分泌，但最终由于有毒代谢而失去持久性。这里是自上而下的 “推动”新陈代谢将被比作使用小分子从底部“拉”新陈代谢。 酶激活剂。使用Mimosa的初步数据确定了激活抗蚀作用的重要好处 正常、糖毒性和糖尿病人胰岛中丙酮酸羧基酶的代谢。但是，自上而下 推进会导致糖酵解代谢产物溢出进入有害的代谢途径，这种代谢途径可通过以下方式缓解 药物作用下的糖酵解作用。第三个目标是在体内翻译这些发现，在那里激活 变构调节的丙酮酸激酶亚型有望通过以下两种途径改善血糖稳态 刺激胰岛素分泌，但也通过浪费能量来解偶联糖异生，从而改善无效循环 胰岛素敏感性。综上所述，这项提议利用一个创新的代谢流量平台来确定 β细胞如何工作以及它们如何失败的机械基础，并在体内将这些信息转化为 验证一种潜在的治疗糖尿病的新方法。

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.