Natural History and Mechanisms of Exocrine Pancreatic Dysfunction in Pre-Type 1 Diabetes

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PROJECT SUMMARY. Type 1 diabetes (T1D) is historically described as an endocrine (β-cell) specific autoimmune disease. However, reduced pancreatic size and subclinical exocrine insufficiency are also present at T1D diagnosis. The mechanisms, natural history, and role of these findings in T1D pathogenesis remains unclear. Exocrine atrophy may even precede the onset of multiple islet autoantibodies (Stage 1 T1D) in some subjects, signifying that clinical measures of exocrine mass and function could be helpful early T1D biomarkers. The primary objective of this proposal is to establish the natural history of exocrine loss in pre-T1D and to identify exocrine T1D- predictive biomarkers. We will measure fecal elastase (FE-1), a clinical marker of exocrine function, throughout the course of pre-T1D within TEDDY (The Environmental Determinants of Diabetes in the Young) subject banked samples (Aim 1A). An enrolling R01-funded study of TrialNet (TN) subjects (Campbell-Thompson and Haller, mPIs) will prospectively examine pancreas volume by MRI in single islet autoantibody positive (AAb+), multiple AAb+, and AAb- T1D first degree relatives (FDRs) to evaluate its prognostic utility. Herein we propose to add evaluation of serum and stool exocrine functional markers in this complementary population to evaluate their prognostic utility and determine timing of exocrine loss (Aim 1B). We hypothesize that exocrine markers will be reduced prior to Stage 1 T1D in those destined for progression and that their rate of decline can be used to predict disease onset. Lastly, the mechanisms underlying reduced exocrine pancreatic mass and function in T1D remain unclear; leading hypotheses include a lack of insulin secretion or autoimmunity to exocrine tissue leading to pancreas atrophy. The secondary objective of this study will use samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) cohort to investigate these potential mechanisms and evaluate exocrine pancreatic autoantibodies as biomarkers of risk (Aim 2). We hypothesize that exocrine autoimmunity is present in subjects with multiple islet AAb+ and those with clinical T1D and leads to diminished exocrine mass and function. We hypothesize that insulinopenia is present in those with clinical T1D and leads to further exocrine atrophy. If our hypothesis is proven, this will represent a paradigm shift in our traditional understanding of the pathogenesis of T1D as an endocrine-specific autoimmune disease. This proposal will advance my early career goal to better understanding the timing and role of T1D exocrine pancreas changes and apply this knowledge in prevention and intervention trials. The skills set forth within this research proposal and career development plan will promote independence as a clinical investigator and include collaborations in several large T1D research consortia and training in 1) human subjects research trial design, implementation, and analysis 2) biomarker evaluation and 3) translational science design and technique. The collaborative rapport, excellent mentorship, and mission of training the next generation of investigators across University of Florida institutes and departments provides an ideal environment for career success.