Role of fatty acid oxidation in islet beta-cell function

项目摘要： 1型糖尿病（T1 D）是由胰岛素产生细胞总数减少或功能减弱引起的。 胰岛内的β细胞。脂质代谢如何影响胰岛功能 β-细胞分泌胰岛素、调节葡萄糖代谢和增殖的作用已被大量研究， 仅在分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 不同的和经常相互矛盾的结果。在此，我们提出了两种新的小鼠模型，使我们能够解决 从两个关键细胞器的脂质代谢的作用，以调查有针对性的和具体的结果在体内。 这种方法将使我们能够回答一个基本问题： 包括胰岛β细胞的胰腺组织，有助于在衰老过程中观察到的β细胞功能的改变， 胰岛素抵抗和糖尿病为了解决这个问题，我们将使用缺乏肉毒碱的小鼠， 棕榈酰转移酶-1a（CPT-1a; Aim 1），线粒体基因，或Pex 5（过氧化物酶体基因; Aim 2）， 胰腺和胰岛组织。在特定目标1中，我们将使用胰腺特异性Cpt 1a基因缺失， 与低脂肪和高脂肪饮食组合以确定限制脂肪酸氧化是否增强葡萄糖 代谢以支持胰岛素分泌。在这个实验中，我们还将评估脂肪酸氧化是否是 对于在体内胰岛素抵抗状态期间观察到的β-细胞的扩增至关重要。在具体目标2中， 将限制过氧化物酶体区室中的脂肪酸氧化，过氧化物酶体区室调节非常长时间的代谢。 链脂肪酸，以确定这是否增强β细胞功能或促进脂质储存，以产生 代谢应激和脂毒性的关键特征。这些新的遗传学方法将提供关键的见解 脂质氧化在衰老和肥胖中的作用。理解原则和机制 潜在的脂肪酸氧化对体内胰岛生物学的影响对于抑制、治疗和 治疗肥胖和衰老相关的代谢疾病。

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.