Metabolic Functions of Pyruvate Kinase M2 in Pancreatic Beta Cells

摘要 超过3.75亿人患有2型糖尿病(T2D)，这种疾病的定义是胰腺β细胞衰竭。 胰岛素分泌和维持内质网(ER)钙离子水平是β细胞的两项基本功能 已知在T2D模式下失败。因此，发现对这些过程至关重要的代谢调节途径将 允许开发治疗T2D的新疗法。我们认为糖酵解酶丙酮酸的调节 激酶(PK)具有很强的保护和治疗价值。我们发现在这三个人中， 在β细胞中，激活PKM2既能促进胰岛素分泌，又能提高内质网钙离子水平。这个 本申请中描述的研究的目标是使用新的代谢成像方法来识别 β-由PKM2控制的细胞代谢和分泌途径中的特定步骤，并确定 在糖尿病进展过程中，PKM2激活可以保护/恢复胰岛素分泌和内质网钙离子的程度。 为此，我们将：1)确定PKM2如何调节胰岛素的触发和代谢放大途径 分泌，2)确定PKM2在内质网钙稳态和胰岛素神经激素放大中的作用 以及3)评估PKM2活性受损对糖尿病的病理生理和 PKM2活化的治疗潜力。这些目标的完成将提高我们对营养的理解 在胰腺β细胞中的信号转导，并评估T2D预防和治疗的新靶点。

Abstract Over 375 million people suffer from type 2 diabetes (T2D), a disease defined by the failure of pancreatic β-cells. Insulin secretion and maintenance of endoplasmic reticulum (ER) Ca²+ levels are two essential β-cell functions known to fail in T2D. Therefore, uncovering the metabolic regulatory pathways critical to these processes will allow the development of new therapies for T2D. We propose that modulation of the glycolytic enzyme pyruvate kinase (PK) has strong potential to be of protective and therapeutic value. We have discovered that of the three PK isoforms in the β-cell, activation of PKM2 both potentiates insulin secretion and raises ER Ca²+ levels. The objective of the research described in this application is to use novel metabolic imaging methods to identify the specific steps in the β-cell metabolic and secretory pathways that are controlled by PKM2, and to determine the extent to which PKM2 activation can protect/restore insulin secretion and ER Ca²+ during diabetes progression. To do so, we will: 1) Determine how PKM2 regulates the triggering and metabolic amplifying pathways of insulin secretion, 2) Determine the role of PKM2 in ER Ca²+ homeostasis and the neurohormonal amplification of insulin secretion, and 3) Assess the contribution of impaired PKM2 activity to diabetes pathophysiology and the therapeutic potential of PKM2 activation. Completion of these aims will heighten our understanding of nutrient signaling in the pancreatic β-cell, and evaluate promising new targets for the prevention and therapy of T2D.