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

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"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.