Mechanisms mediating reversible lipotoxicity of the pancreas in obesity-induced type 2 diabetes

肥胖引起的 2 型糖尿病中胰腺可逆性脂毒性的介导机制

• 批准号: MR/X007669/1
• 负责人: Ahmad Al-Mrabeh
• 金额: $ 166.07万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX007669%2F1
• 关键词: Mechanisms; mediating; reversible; lipotoxicity; pancreas

"Why did I develop type 2 diabetes (T2D) even though I'm not overweight?" This is a common question asked by patients in diabetes clinics and one that has been hard to understand. My research will focus on the mechanisms that might explain this conundrum by focusing on the impact of fat on the pancreas and failure of the insulin producing beta cells of this organ that is a leading cause of T2D. Currently we do not know precisely how changes in fat (lipid) metabolism lead to a failure of pancreatic cells to secrete adequate amounts of insulin (the key factor in regulating blood sugar levels).My previous work has shown that although pancreas fat level is elevated, pancreas volume is 30-40% smaller and has irregular shape. I have shown that fall in pancreas fat after weight loss was associated with remission of T2D and recovery of normal pancreas volume. Now, I want to understand exactly how weight loss leads to remission and restoring the function of the insulin-producing cells within the pancreas. Can we mimic this by designing new drugs in future as a new and effective diabetes treatment?To investigate this, I am going to use exciting, advanced techniques to study what happens to the pancreas in people as they become diabetic and when they lose weight to recover from diabetes. I will use specially programmed MRI scanner to study four groups of people at different stages of diabetes development. In parallel, participants will be asked to swallow a small quantity of safe, specially labelled form of water to measure the rate at which the liver makes fat from glucose, and to assess whether this is related to T2D remission. MRI scans will evaluate how tissue inflammation of pancreas and insulin secretory function of the pancreatic beta cells are affected by change in fat profile during weight loss and remission of diabetes.I also aim to study what happens to the cells and genes in the pancreas during T2D development and remission. To do so, (i) I will mimic the process of T2D development/remission in specific type of mice that has similar T2D susceptibility factors as in human. (ii) I will study donated human pancreas tissues from people with and without T2D. The particular kind of fat that can cause damage to pancreatic tissues will be determined using sophisticated imaging, genomics, and analytical approaches.Collectively, this will identify the precise sequence of events leading to diabetes development and remission. It will lead to more targeted strategies for remission of diabetes apart from the challenging weight loss approach, improving the quality of life of people with diabetes, and decreasing the burden to the NHS budget.

“为什么我没有超重，却患上了2型糖尿病？”这是糖尿病诊所患者经常问的一个问题，也是一个很难理解的问题。我的研究将集中在脂肪对胰腺的影响以及这个器官中产生胰岛素的β细胞的衰竭，这是T2D的主要原因，从而集中在可能解释这个难题的机制上。目前，我们还不清楚脂肪(脂)代谢的变化如何导致胰腺细胞无法分泌足够数量的胰岛素(调节血糖水平的关键因素)。我以前的工作表明，虽然胰腺脂肪水平升高，但胰腺体积小30%-40%，形状不规则。我已经证明，体重减轻后胰腺脂肪的减少与T2D的缓解和正常胰腺体积的恢复有关。现在，我想确切地了解减肥是如何导致缓解和恢复胰腺内产生胰岛素的细胞的功能的。未来我们能否通过设计新的药物来模仿这一点，作为一种新的有效的糖尿病治疗方法？为了研究这一点，我将使用令人兴奋的先进技术来研究当人们患上糖尿病以及当他们为了从糖尿病中恢复而减肥时，胰腺会发生什么。我将使用专门编程的核磁共振扫描仪对四组处于不同糖尿病发展阶段的人进行研究。同时，参与者将被要求吞下少量安全的、特别标记的水，以测量肝脏从葡萄糖产生脂肪的速率，并评估这是否与T2D缓解有关。MRI扫描将评估在糖尿病减轻和缓解期间脂肪分布的变化如何影响胰腺组织炎症和胰岛β细胞的胰岛素分泌功能。我还旨在研究T2D发育和缓解期间胰腺细胞和基因的变化。为此，(I)我将在具有与人类相似的T2D易感因素的特定类型的小鼠中模拟T2D的发展/缓解过程。(Ii)我将研究患有和不患有T2D的人捐赠的胰腺组织。可以对胰腺组织造成损害的特定类型的脂肪将使用复杂的成像、基因组学和分析方法来确定。总体而言，这将确定导致糖尿病发展和缓解的准确事件序列。除了具有挑战性的减肥方法外，它还将导致更有针对性的糖尿病缓解战略，改善糖尿病患者的生活质量，并减轻NHS预算的负担。

项目成果

Metabolic phenotyping of the polygenic mouse model (NONcNZO10/LtJ) of type 2 diabetes to mimic the process of diabetes development and remission in human

2 型糖尿病多基因小鼠模型 (NONcNZO10/LtJ) 的代谢表型分析，模拟人类糖尿病的发展和缓解过程

• DOI: 10.1530/endoabs.94.p352
• 发表时间: 2023
• 期刊: Endocrine Abstracts
• 作者: Ojeda L