Objective
To work out whether straightforward and cheap tests to measure how the whole pancreas functions can help us predict which individuals at risk of type 1 diabetes will develop diabetes quickly and who will develop the condition slowly.
Background Rationale
In this application we describe some recent data showing that measuring levels of trypsinogen differentiates identical twins who have type 1 diabetes compared with those who do not. We are also able to validate this in a large cohort of cases and controls. Particularly important is the observation that decreases in trypsinogen, and pancreatic mass can be detected before the clinical symptoms of diabetes occur. In this project we have designed several approached to examine how levels of exocrine enzymes are affected over time in people who are at risk of developing diabetes in the future. In addition we will work out whether autoantibodies exist to the exocrine compartment in autoimmune diabetes.
Description of Project
In many ways studies in identical twins are perfect; they allow us to control for both age and genetics. This is almost impossible to do in any other study design in human studies. In our preliminary studies, comparing protein levels in the serum of identical twins who do and do not develop autoimmune diabetes, we were taken aback by the results. All the biggest effects were for proteins which are turned on in the pancreas but not in the cells that make insulin. They are expressed in the exocrine pancreas. We knew that the pancreas gets smaller before and after the onset of type 1 diabetes. Suddenly it became clear that we had overlooked the importance of our own observations. We had been focused on markers that measure the the 2-3% of the pancreatic cells which express insulin, beta cells in the endocrine compartment, in order to measure beta cell loss. However the scarcity of beta cells can make these tests difficult. In light of these findings, we need to focus on exocrine cell markers and this application describes these studies. Firstly we will test exocrine enzyme levels in some very well characterised people "at risk" of type 1 diabetes. We have multiple samples taken from each individual sometimes over very long periods of time. This will allow us to examine what is happening to pancreatic function over time before the development of clinical symptoms of diabetes. We already have lots of data on these individuals adding value to this study. In addition we are going to look for antibodies to the exocrine proteins. If identified these would be important additional type 1 diabetes biomarkers. By the end of this project will will know a lot more about the exocrine pancreas in people who are at risk of type 1 diabetes and whether these biomarkers will be useful in clinical trials.
Anticipated Outcome
Given the preliminary data we have, we feel confident that systematically measuring pancreas function using relatively simple tests will help to predict those who develop type 1 diabetes quickly compared with those who do not. This is really important, firstly to inform study participants accurately about their risk but also to make clinical trials more effective as including slow progressors in clinical trials is not helpful and currently there is no robust way to measure progression rate.
Relevance to T1D
This research is important for people living with diabetes on many different levels. Although it has been known by researchers for decades that the pancreas gets smaller over the natural history of type 1 diabetes this observation has not been investigated to translate research from the "bench to the bedside". Our data show the importance of straightforward measures to proxy pancreas size and function. We think that these tests will help us to predict type 1 diabetes progression rate and potentially to measure positive effects in clinical trials.