A role and regulation of glucose responsive lipolysis in pancreatic beta cells

胰腺β细胞中葡萄糖反应性脂肪分解的作用和调节

• 批准号: 10341103
• 负责人: Yumi Imai
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341103
• 关键词: Affect; Beta Cell; Cell physiology; Cells; Data; Defect; Development; Emotional; Event; Exhibits; Exocytosis; Failure; Fatty Acids; Functional disorder; Glucose; Goals; Health; High Prevalence; Human; Impairment; Inflammation; Lead; Lipase; Lipid Mobilization; Lipids; Lipolysis; Mental Depression; Modeling; Molecular; Nature; Non-Insulin-Dependent Diabetes Mellitus; Overnutrition; Oxidative Stress; Pathogenesis; Pathway interactions; Pharmacology; Phenotype; Physiological; Population; Post-Traumatic Stress Disorders; Prevalence; Process; Protein S; Regulation; Reporting; Role; SNAP receptor; Shiga-Like Toxin I; Signal Transduction; Stress; Structure of beta Cell of islet; Testing; Triglycerides; Type 2 diabetic; Veterans; base; blood glucose regulation; endocrine pancreas development; endoplasmic reticulum stress; functional decline; functional loss; improved; insulin granule; insulin secretion; insulin sensitivity; islet; knock-down; mitochondrial dysfunction; non-diabetic; novel; palmitoylation; perilipin; preservation; prevent; protein complex; response; syntaxin 1A

T2D is a major health problem for US veterans that imposes significant physical, financial, and emotional tolls. Thus, there is a strong and urgent need for an effective and widely applicable therapy. Excessive accumulation of lipids in beta cells is considered to contribute to the development of T2D. Experimental data supports that lipid overload activates multiple stress pathways including inflammation, ER stress, oxidative stress, and mitochondrial dysfunction ultimately leading to the loss of functional beta cell mass. We have found evidence that the accumulation of triglycerides (TG) in human islets from T2D donors is associated with dysregulation of lipolysis, a previously unrecognized defect in T2D islets that accelerates TG accumulation in T2D islets. Glucose activates lipolysis in non-diabetic human islets but not in T2D islets. Furthermore, our preliminary data indicates that the dysregulation of lipolysis impairs insulin secretion by reducing the stability of syntaxin1a (Stx1a), one of the SNARE complex proteins important for exocytosis. When we tested the impact of dysregulation of lipolysis using human pseudoislets in which the expression of the principal TG lipase (ATGL) is down-regulated, ATGL deficient human pseudoislets showed excessive lipid droplet (LD) accumulation and impaired insulin secretion along with proteasomal degradation of Stx1a. Importantly, the reduction of Stx1a is a defect reported in human T2D islets. Thus, we hypothesize that the dysregulation of lipolysis in response to glucose reduces the stability of Stx1a and impairs insulin secretion in T2D islets. To understand molecular mechanism behind the defects in T2D islets, it will be imperative to determine how glucose upregulates lipolysis in beta cells, why glucose fails to upregulate lipolysis in T2D islets, and how the impairment in lipolysis reduces Stx1a. We will approach our questions using human pseudoislets and INS1 cells as models since they exhibit similarity with human islets in LD formation, the regulation of lipolysis, and phenotypes of ATGL deficiency. We expect to obtain novel information regarding how dysregulation of lipid mobilization causes beta cell dysfunction in T2D through the following aims. Specific aim 1: Determine a mechanism by which ATGL increases lipolysis in response to glucose in non-diabetic beta cells We will systematically test potential targets by which glucose increases lipolysis in INS1 cells and non-diabetic human beta cells. Aim 1a will test which glucose generated signals regulates lipolysis in beta cells. Aim 1b-d will test whether glucose increases lipolysis by modifying ATGL, co-lipases, or perilipins. Specific aim 2: Determine a mechanism by which lipolysis is dysregulated in type 2 diabetic beta cells Aim 1 dissects a mechanism by which glucose regulates lipolysis in beta cells. Leveraging on the information from Aim 1, we will determine why T2D islets are unable to increase lipolysis in response to glucose and how we can restore lipolysis in T2D islets. Specific Aim 3: Test the hypothesis that defective lipolysis destabilizes stx1a in T2D islets Stx1a is proposed to contribute to the impairment of insulin secretion in T2D as Stx1a is reduced in islets of T2D models and human islets affected by T2D. However, it has been unknown why Stx1a is reduced in T2D islets. Our preliminary data implicates that the impairment of lipolysis may cause the reduction of Stx1a in T2D islets. Thus, we will test the hypothesis that reduced lipolysis contributes to the reduction of Stx1a in T2D islets through accelerating degradation of Stx1a due to reduced palmitoylation. Our study combines pharmacological and molecular approaches to increase our understanding of the pathogenesis of beta cell dysfunction in T2D. The information obtained will potentially lead us to a novel target that improves beta cell function in T2D by restoring LD mobilization in beta cells.

对于美国退伍军人来说，T2D是一个主要的健康问题，造成了重大的身体，财务和情感上的伤害。 因此，迫切需要有效且广泛适用的治疗。 脂质在β细胞中的过度积累被认为有助于T2D的发展。 实验数据支持脂质超负荷激活多种应力途径，包括炎症，ER 应力，氧化应激和线粒体功能障碍最终导致功能性β细胞的丧失 大量的。我们发现证据表明，T2D供体在人类胰岛中甘油三酸酯（TG）的积累是 与脂解的失调相关，这是T2D胰岛中先前未识别的缺陷，可加速TG 在T2D胰岛中积累。葡萄糖激活非糖尿病人类胰岛中的脂解，但在T2D胰岛中不激活脂解。 此外，我们的初步数据表明脂解的失调会损害胰岛素的分泌 降低了Syntaxin1a（STX1A）的稳定性，这是对胞吐作用很重要的SNARE复合物蛋白之一。 当我们使用人类伪群检测脂解的影响时，其中表达的表达 主TG脂肪酶（ATGL）被下调，ATGL缺乏人类假脂质显示出过多的脂质 液滴（LD）积累和胰岛素分泌受损以及STX1A的蛋白酶体降解。 重要的是，STX1A的还原是人类T2D胰岛中报道的缺陷。因此，我们假设 脂解的失调对葡萄糖的反应降低了STX1A的稳定性并损害胰岛素的分泌 T2D小岛。要了解T2D小岛缺陷背后的分子机制，必须 确定葡萄糖如何上调β细胞中的脂解，为什么葡萄糖无法上调T2D中的脂解 胰岛，以及脂解的损害如何减少STX1A。我们将使用人类处理问题 伪符和INS1细胞作为模型，因为它们在LD形成中与人类胰岛表现出相似性， 调节脂解和ATGL缺乏的表型。我们希望获得有关有关的新信息 脂质动员的失调如何通过以下目标引起T2D中的β细胞功能障碍。 特定目标1：确定ATGL增加脂肪分解的机制，以响应葡萄糖 非糖尿病β细胞 我们将系统地测试潜在的靶标，葡萄糖会增加INS1细胞和非糖尿病的脂肪分解 人β细胞。 AIM 1A将测试哪些葡萄糖产生的信号调节β细胞中的脂解。 AIM 1B-D 将通过修饰ATGL，共脂酶或丘疹蛋白来测试葡萄糖是否增加脂解会增加脂解。 特定目标2：确定在2型糖尿病β细胞中脂解的机制 AIM 1解剖葡萄糖调节β细胞中脂解的机制。利用信息 从AIM 1中，我们将确定为什么T2D胰岛因葡萄糖而无法增加脂肪分解以及如何增加。 我们可以恢复T2D胰岛中的脂解。 特定目的3：检验以下假设：有缺陷的脂解会破坏T2D胰岛中STX1A的稳定 提议STX1A有助于T2D中胰岛素分泌的损害，因为STX1A在胰岛中减少了 T2D模型和受T2D影响的人类胰岛。但是，尚不清楚为什么在T2D中降低STX1A 胰岛。我们的初步数据暗示脂解的损害可能导致T2D中STX1A的减少 胰岛。因此，我们将检验以下假设：减少脂解会导致T2D胰岛中STX1A的降低 通过加速由于棕榈酰化减少而导致STX1A的降解。 我们的研究结合了药理和分子方法，以提高我们对 T2D中β细胞功能障碍的发病机理。获得的信息可能会导致我们进入新的目标 通过恢复β细胞中的LD动员，可以改善T2D中的β细胞功能。