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

“为什么我没有超重，却患上了2型糖尿病（T2D） ？”这是糖尿病患者在诊所经常问的一个问题，也是一个很难理解的问题。我的研究将集中在可能解释这个难题的机制上，通过关注脂肪对胰腺的影响，以及胰腺中产生胰岛素的细胞的衰竭，这是导致糖尿病的主要原因。目前我们还不能确切地知道脂肪代谢的变化是如何导致胰腺细胞分泌足够数量的胰岛素（调节血糖水平的关键因素）的失败的。我之前的研究表明，虽然胰腺脂肪水平升高，但胰腺体积缩小30-40%，形状不规则。我已经证明，减肥后胰腺脂肪的下降与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病情缓解并恢复胰腺中产生胰岛素的细胞的功能的。我们能否在未来通过设计新的药物来模仿这一过程，作为一种新的有效的糖尿病治疗方法？为了调查这个问题，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减肥从糖尿病中恢复过来时，胰腺会发生什么变化。我将使用专门编程的核磁共振扫描仪来研究四组处于糖尿病发展不同阶段的人。与此同时，参与者将被要求吞下少量安全的、特殊标记的水，以测量肝脏从葡萄糖中生成脂肪的速度，并评估这是否与T2D缓解有关。MRI扫描将评估胰腺组织炎症和胰腺β细胞的胰岛素分泌功能如何受到体重减轻和糖尿病缓解期间脂肪谱变化的影响。我还致力于研究在T2D发展和缓解期间胰腺细胞和基因发生了什么变化。为此，(i)我将模拟具有与人类相似的T2D易感性因素的特定类型小鼠的T2D发展/缓解过程。（ii）研究t2dm患者和非t2dm患者捐献的胰腺组织。可以对胰腺组织造成损害的特定类型的脂肪将通过复杂的成像、基因组学和分析方法来确定。总的来说，这将确定导致糖尿病发展和缓解的事件的精确顺序。除了具有挑战性的减肥方法之外，它将导致更有针对性的糖尿病缓解策略，提高糖尿病患者的生活质量，并减少NHS预算的负担。

"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.