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

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.

Grant Number: 5K23DK131363-03
NIH Institute/Center: NIH
Principal Investigator: Brittany Bruggeman