Objective
Our goal is to study certain proteins called chromogranins and secretogranins in the cells of the pancreas that produce insulin, called beta cells and in those that produce glucagon, called alpha cells. We think that during the development of type 1 diabetes (T1D), the levels of these proteins change, which might help trigger the immune system to attack the insulin-producing cells. We also believe that these changes can be detected in the pancreas and in the blood, which could help identify early signs of the disease. In the first part of our study, we will look at the levels of these proteins in the pancreas of people with and without T1D. In the second part, we will use isolated human pancreatic cells and lab-grown cells to understand how these proteins respond to stress and how they affect the development and function of insulin-producing cells. In the third part, we will measure these proteins in the blood of people with and without T1D to see if they can be used as markers to track the progression of the disease.
Background Rationale
Type 1 diabetes (T1D) is a disease where the immune system attacks the cells in the pancreas that produce insulin. This attack might be linked to stress in these cells, causing them to process proteins incorrectly, which can trigger an immune response. While most research has focused on errors in processing a protein called proinsulin, other proteins in the insulin granules, like chromogranins and secretogranins (collectively known as granins) might also be processed incorrectly and targeted by the immune system. Granins are important for the proper function of insulin granules in beta cells. Different types of granins have specific roles: some help assemble the granules, others regulate insulin sorting, and some influence energy storage and metabolism. This study aims to understand how these proteins are expressed, where they are in the cells, and how they interact with each other. Changes in the levels of these proteins might indicate problems with the insulin-producing cells, potentially signaling the onset of T1D.
Description of Project
Type 1 diabetes (T1D) is a disease where the body's immune system attacks the cells in the pancreas that produce insulin. This attack is influenced by both genetic and environmental factors. Recent research suggests that the insulin-producing cells themselves might also play a role in triggering the disease. When these cells are stressed, they can process proteins incorrectly, which might provoke an immune response. We are currently studying errors in the processing of a protein called proinsulin in these cells. However, other proteins, known as granins, have not been studied as much. In this project, we plan to look at the levels of granins in pancreatic tissue obtained from deceased organ donors from different groups of people: those without diabetes, those with early signs of diabetes, and those with T1D. Our preliminary studies suggest that in people with early signs of diabetes, the levels of granins are lower in insulin-producing cells. This suggests that changes in these proteins might happen before the disease fully develops. Interestingly, in people with T1D, the remaining insulin-producing cells had normal levels of granins, which might mean that the immune system targets and destroys the cells with defective granins first. Overall, in this project we aim to investigate if changes in granin levels could be early indicators of T1D and might help in preventing the disease.
Anticipated Outcome
We will understand how granin levels change at different stages of type 1 diabetes (T1D). We will also see how these changes relate to other important proteins like proinsulin in the insulin-producing cells. Using human pancreatic cells (isolated human islets) and lab-grown cells (stem-cell islets) we expect to observe changes in the amount of granins and their ability to function properly in response to stress. Last, we expect that several granins will be higher in the blood of people in both advanced and early stages of T1D, which will establish certain granin proteins as good markers for disease progression.
Relevance to T1D
If we find that the levels of granins change in the pancreas at different stages of type 1 diabetes (T1D), and confirm this in stressed human pancreatic cells, it could lead to the development of drugs that would help increase insulin production and improve the formation and function of insulin granules. Additionally, our research could help identify new markers of mature insulin-producing cells, leading to better methods for creating these cells in the lab. Granins could also serve as markers to monitor the function of lab-grown cells implanted in people with T1D, which is important, as these cells are currently being tested in clinical trials. Furthermore, granins might help track the success of transplanted human pancreatic cells and provide insights into immune attacks on these cells. Overall, detecting changes in granin levels in the blood could be valuable for diagnosing, predicting, and monitoring T1D.