Role of fatty acid oxidation in islet beta-cell function

项目总结： 1型糖尿病(T1D)是由于胰岛素分泌总量减少或功能减弱所致 朗格汉斯人胰岛内的β细胞。脂类代谢如何影响胰岛功能 分泌胰岛素、调节葡萄糖代谢和增殖的β细胞几乎已被大量研究。 仅在隔离的胰岛中使用急性体外方法。然而，在体外进行的研究已经导致 结果不同，而且往往是相互冲突的。在这里，我们提出了两个新的鼠标模型，使我们能够解决 来自两个关键细胞器的脂代谢在研究体内靶向性和特异性结果中的作用。 这种方法将使我们能够回答基本的问题：抑制脂肪酸氧化在 胰腺组织，包括胰岛β细胞，有助于在衰老过程中观察到的β细胞功能的变化， 胰岛素抵抗和糖尿病？为了解决这个问题，我们将使用缺乏肉碱或肉碱的小鼠 棕榈酰转移酶-1a(CPT-1a；Aim 1)是一种线粒体基因，或Pex5(Peroxisomal gene；Aim 2)。 胰腺和胰岛组织。在特定的目标1中，我们将使用胰腺特异性的CPT1A基因缺失在 结合低脂和高脂饮食确定限制脂肪酸氧化是否提高血糖 支持胰岛素分泌的新陈代谢。在这个实验中，我们还将评估脂肪酸氧化是否 对于体内观察到的胰岛素抵抗状态下的β细胞的扩张至关重要。在具体目标2中，我们 会限制脂质体内的脂肪酸氧化，这会调节很长时间的新陈代谢 链脂肪酸，以确定这是增强β细胞功能还是促进脂肪储存以产生 代谢应激和脂毒性的主要特征。这些新的遗传方法将提供关键的见解 脂肪氧化在衰老和肥胖过程中的作用。理解原则和机制 体内胰岛生物学中潜在的脂肪酸氧化对抑制、治疗和 治疗肥胖和衰老相关的代谢性疾病。

Project Summary: Type 1 diabetes mellitus (T1D) results from reduced total number or diminished function of insulin-producing beta-cells within the pancreatic islets of Langerhans. How lipid metabolism influences the ability of the islet beta-cells to secrete insulin, regulate glucose metabolism, and proliferate has been largely studied almost exclusively in isolated islets using acute in vitro approaches. However, studies conducted in vitro have led to differential and often conflicting results. Herein, we propose two novel mouse models that allow us to address the role of lipid metabolism from two critical organelles to investigate targeted and specific outcomes in vivo. This approach will allow us to answer the fundamental question: does inhibition of fatty acid oxidation in pancreatic tissue, including islet beta-cells, contribute to alterations in beta-cell function observed during aging, insulin resistance, and diabetes? To address this question, we will use mice lacking either carnitine palmitoyltransferase-1a (CPT-1a; Aim 1), a mitochondrial gene, or Pex5 (peroxisomal gene; Aim 2) in pancreatic and islet tissue. In Specific Aim 1, we will use the pancreas-specific deletion of the Cpt1a gene in combination with low-fat and high-fat diets to determine whether limiting fatty acid oxidation enhances glucose metabolism to support insulin secretion. In this experiment, we will also assess whether fatty acid oxidation is critical for the expansion of beta-cells observed during states of insulin resistance in vivo. In Specific Aim 2, we will limit fatty acid oxidation in the peroxisomal compartment, which regulates the metabolism of very long chain fatty acids, to determine whether this enhances beta-cell function or promotes lipid storage to generate metabolic stress and key features of lipotoxicity. These novel genetic approaches will provide critical insights into the role of lipid oxidation during aging and obesity. Understanding the principles and mechanisms underlying fatty acid oxidation on islet biology in vivo have important implications for suppressing, treating, and curing obesity- and aging-associated metabolic diseases.