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

摘要： 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。 过去的一些增强其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。清楚地了解代谢特征， 功能以及那些有害的可能有助于开发新的治疗方法。大部分 已经在一项研究中获得了对葡萄糖如何代谢以产生释放胰岛素的信号的理解， 零碎的方式。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-偶联和代谢毒性等基本原理。新的定量和 需要综合的方法来重新评估通过代谢途径的通量的关系， 人类β细胞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。在此，建议将该创新扩展到包括额外的 代谢通量测量将评估正常和糖尿病人β细胞。MIMOSA将首先应用于 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。第二个目标将跟踪观察葡萄糖激酶激活剂恢复 糖尿病患者的胰岛素分泌，但最终由于毒性代谢而失去耐久性。在这里，自上而下 “推”代谢将被比作“拉”代谢从底部使用小分子 酶促活化剂。使用MIMOSA的初步数据确定了激活回补的进口利益 正常、糖脂毒性和糖尿病人胰岛中的丙酮酸羧化酶代谢。然而，自上而下 推动导致糖酵解代谢物溢出进入有害的代谢途径， 去糖酵解。第三个目标将在体内转化这些发现，其中激活的 预期变构调节的丙酮酸激酶同工型通过以下两种途径改善葡萄糖稳态： 刺激胰岛素分泌，但也通过能量浪费的无效循环使胰岛素生成脱钩， 胰岛素敏感性综上所述，该提案利用创新的代谢通量平台来识别 β细胞如何工作以及它们如何失败的机械原理，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。

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.