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; 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.

“即使我没有超重，我为什么还会患上2型糖尿病（T2D）？”这是患者在糖尿病诊所中提出的一个常见问题，也很难理解。我的研究将重点放在可能解释这一难题的机制上，通过关注脂肪对胰腺的影响和胰岛素产生该器官的β细胞的失败，这是T2D的主要原因。目前，我们还不知道脂肪（脂质）代谢的变化如何导致胰腺细胞失败，无法分泌足够的胰岛素（调节血糖水平的关键因素）。我以前的工作表明，尽管胰腺脂肪水平升高，但胰腺体积升高，占30-40％的体积较小，并且具有不规则的形状。我已经表明，体重减轻后胰腺脂肪降低与T2D的缓解和正常胰腺体积的恢复有关。现在，我想准确地了解减肥是如何导致胰腺内产生胰岛素细胞的功能的缓解和恢复的功能。我们可以通过将来设计新药作为一种新的有效的糖尿病治疗来模仿这一点吗？为了调查这一点，我将使用令人兴奋的，先进的技术来研究胰腺中胰腺的糖尿病患者会发生什么，而当他们减肥以从糖尿病中恢复过来。我将使用专门编程的MRI扫描仪研究糖尿病发育不同阶段的四组人。同时，将要求参与者吞下少量的安全，特殊标记的水，以测量肝脏从葡萄糖中产生脂肪的速率，并评估这是否与T2D缓解有关。 MRI扫描将评估胰腺β细胞的胰腺炎症和胰岛素分泌功能如何受到体重减轻和糖尿病减轻脂肪的变化的影响。我还旨在研究T2D发育和缓解期间胰腺细胞和基因的情况。为此，（i）我将模仿具有与人类相似的T2D易感因素的特定类型的T2D开发/缓解过程。 （ii）我将研究有或没有T2D的人的捐赠人类胰腺组织。可能会使用复杂的成像，基因组学和分析方法来确定可能损害胰腺组织的特殊脂肪。进行策略，这将确定导致糖尿病发育和缓解的确切事件序列。除了具有挑战性的减肥方法，改善糖尿病患者的生活质量，并减轻了NHS预算的负担，这将导致更具针对性的糖尿病策略。