Studies on the mechanisms of glucolipotoxicity in human beta cells in the context of type 2 diabetes mellitus

2型糖尿病背景下人β细胞糖脂毒性机制的研究

• 批准号: 448830864
• 负责人: Dr. Thomas Plötz
• 金额: --
• 依托单位: Division Diabetes and Nutritional Sciences
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/448830864?language=en
• 关键词: Studies; mechanisms; glucolipotoxicity; human; beta

Diabetes mellitus is one of the most prevalent diseases worldwide with a rapidly increasing incidence. More than 90% of patients suffer from type 2 diabetes. Obesity is of particular importance in the pathogenesis, a consequence of Western style diet with an excess of carbohydrate and high-fat food constituents. Subsequent insulin resistance results in dysfunction and stepwise loss of insulin-secreting beta cells through gradual deterioration of glucose tolerance, thereby causing hyperglycaemia and increased plasma free fatty acid levels. These phenomena are also known as glucotoxicity and lipotoxicity. Reactive oxygen species (superoxide radicals, hydrogen peroxide, hydroxyl radicals) mediate this toxicity, which arise in the metabolism of fatty acids and glucose. The term glucolipotoxicity combines both phenomena and is in the focus of this project. Despite the great scientific interest, the underlying mechanisms are not fully understood. For this purpose, in the planned project, the analysis of the structure-toxicity relationships of fatty acids in combination with increased glucose concentrations is the main conceptual tool to be used, which has proven to be particularly helpful in the elucidation of the underlying pathomechanisms. The studies will be performed on human EndoC-βH1 beta cells and in primary islets of patients with and without type 2 diabetes. This focus has been chosen to create optimal conditions for translation to the patient. Three main goals have been defined for this project. 1) Comparative genome analyses after fatty acid and glucose exposure are to be carried out. 2) Verification of interesting target genes using RT-qPCR with special attention to the interactions between glucotoxicity and lipotoxicity. 3) In a final step, genetically modified human EndoC-βH1 beta cells are to be generated to gain a deeper insight in the in-depth mechanistic understanding. For this purpose the importance of the various subcellular organelles (mitochondria, peroxisomes, endoplasmic reticulum) for glucolipotoxicity will be elucidated using a broad range of methods with regard to the formation of mediators, in particular toxic reactive oxygen species. The intention of these planned studies is to advance the understanding of the molecular mechanisms underlying glucolipotoxicity to the extent that a complete picture of the mechanisms of toxicity and their signaling pathways can be presented. This should open up perspectives for the establishment of new interventional measures. These may be preventative lifestyle measures, specifically with respect to a healthy diet, but also new pharmaco-therapeutic approaches aiming at an improvement of the impaired glucose tolerance in the type 2 diabetic metabolic state by restoring normal beta cell function.

糖尿病是世界范围内最常见的疾病之一，发病率迅速上升。超过90%的患者患有2型糖尿病。肥胖在发病机制中特别重要，是具有过量碳水化合物和高脂肪食物成分的西式饮食的结果。随后的胰岛素抵抗通过葡萄糖耐量的逐渐恶化导致功能障碍和胰岛素分泌β细胞的逐步损失，从而引起高血糖症和血浆游离脂肪酸水平增加。这些现象也被称为糖毒性和脂毒性。活性氧（超氧自由基，过氧化氢，羟基自由基）介导这种毒性，这在脂肪酸和葡萄糖的代谢中出现。术语“糖脂毒性”结合了这两种现象，是本项目的重点。尽管有很大的科学兴趣，但其基本机制尚未完全理解。为此，在计划的项目中，脂肪酸与葡萄糖浓度增加的结构-毒性关系的分析是要使用的主要概念工具，这已被证明是特别有助于阐明潜在的病理机制。这些研究将在人EndoC-βH1 β细胞和患有和不患有2型糖尿病的患者的原代胰岛中进行。选择这一重点是为了创造最佳条件，以便向患者转移。为这个项目确定了三个主要目标。1)将在脂肪酸和葡萄糖暴露后进行比较基因组分析。2)使用RT-qPCR验证感兴趣的靶基因，特别关注糖毒性和脂毒性之间的相互作用。3)在最后一步中，将产生基因修饰的人EndoC-βH1 β细胞，以获得深入机制理解的更深入见解。为此，将使用多种方法阐明各种亚细胞器（线粒体、过氧化物酶体、内质网）对糖脂毒性的重要性，这些方法涉及介质的形成，特别是毒性活性氧。这些计划研究的目的是促进对糖脂毒性潜在分子机制的理解，以提供毒性机制及其信号传导途径的完整图像。这将为制定新的干预措施开辟前景。这些可能是预防性的生活方式措施，特别是关于健康饮食，但也是新的药物治疗方法，旨在通过恢复正常的β细胞功能来改善2型糖尿病代谢状态中的葡萄糖耐量受损。