When a person is diagnosed with Type 1 diabetes (T1D), the amount of beta–cell mass each individual loses is highly variable despite their clinical need for insulin therapy. Attempts to detect robust markers in the blood that precisely describe disease activity in the islets are ongoing, but without a full understanding of the disease course in the pancreas, when attempting to target therapy to the organ, we are still operating partially blindfolded. We have previously reported that two forms, or endotypes, of T1D are evident in the pancreas[1–4]. These differ according to the degree of beta–cell loss, the composition of the islet–specific immune infiltrate, and how beta cells process insulin. Additionally, we now have preliminary data that suggests the beta–cells themselves may vary between the two forms), even hinting that successful beta–cell regeneration may be more likely in one form than the other. Our proposed study will expand on these investigations, and we will compare pancreatic protein expression profiles between people diagnosed with T1D at different ages, with different durations of disease and compare this to those without diabetes and with Type 2 diabetes (as a proxy for metabolic dysregulation). We will leverage advanced histological and imaging techniques to analyse the presence of multiple critical proteins in granular detail in whole sections of pancreas. We will then (based on several features of pancreatic T1D and beta–cell loss), construct a nuanced ‘pseudo’ timeline of disease progression in T1D to illustrate the life and loss of beta–cells in T1D and explore if this is the same in all people, randomly different between people– or stratifiably different between groups of people living with T1D. With this information we will better understand if we should be looking for distinct forms of T1D, and this may help scientists and trialists understand why some people respond brilliantly in clinical trials, whilst other do not.
