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

> **NIH NIH R03** · UNIVERSITY OF FLORIDA · 2022 · $106,750

## Abstract

PROJECT SUMMARY.
Type 1 diabetes (T1D) is historically described as an endocrine (β-cell) specific autoimmune disease.
However, a substantial reduction in pancreatic exocrine cell mass is also present at T1D diagnosis resulting in
a 20-50% reduction in pancreas organ size and subclinical exocrine pancreatic insufficiency. The mechanisms,
natural history, and role of reduced exocrine pancreatic mass in T1D pathogenesis remains unclear.
Evaluation of pancreatic volume and function by magnetic resonance imaging (MRI) and fecal elastase (FE-1)
has shown that exocrine atrophy may even precede the onset of multiple islet autoantibodies (Stage 1 T1D) in
some subjects, signifying that these measures could be helpful early T1D biomarkers. The primary objective of
this proposal is to investigate the natural history of exocrine loss in T1D by measuring FE-1 throughout the
course of pre-T1D within TEDDY (The Environmental Determinants of Diabetes in the Young) subject banked
samples (Aim 1A). We hypothesize that FE-1 levels will be reduced even prior to Stage 1 T1D in those
destined to develop T1D and that the rate of decline in FE-1 can be used as a disease-predictive biomarker.
FE-1 will be the first studied marker of exocrine pancreatic function to inform the large body of data already
collected within TEDDY. This will allow for future collaborative studies of potential mechanisms and
downstream effects of a decline in pancreatic function within pre-T1D, including associations with nutritional
changes such as fat-soluble vitamin deficiencies or lipid abnormalities and with other changes in the lipidome,
proteome or microbiome of at-risk TEDDY subjects. An upcoming R01-funded study of TrialNet (TN) subjects
(Campbell-Thompson and Haller, mPIs) will prospectively examine pancreas volume by MRI and serum
markers of pancreatic exocrine function in single islet autoantibody positive (AAb+), multiple AAb+, and AAb-
first degree relatives (FDRs) of T1D patients to evaluate the prognostic utility of these measures. Herein we
propose to add evaluation of FE-1 to this trial in order to examine its efficacy as a disease predictive biomarker
(Aim 1B). Lastly, the mechanisms underlying reduced exocrine pancreatic mass and function in T1D remain
unclear. Previous studies have found exocrine pancreas Aabs and immune infiltrates to be present in subjects
with T1D, making autoimmune destruction of both exocrine and endocrine tissue a plausible mechanism worth
further investigation. The secondary objective of this study is to use samples from the Network for Pancreatic
Organ donors with Diabetes (nPOD) cohort to investigate exocrine autoimmunity as a potential mechanism for
the changes in pancreatic size and function seen in T1D (Aim 2). We hypothesize that exocrine autoimmunity
is present in subjects with multiple islet AAb+ without dysglycemia as well as those with clinical T1D and that it
is associated with exocrine histopathologic changes. If we find that autoimmunity ...

## Key facts

- **NIH application ID:** 10483133
- **Project number:** 5R03DK129971-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Brittany Bruggeman
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $106,750
- **Award type:** 5
- **Project period:** 2021-09-07 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10483133

## Citation

> US National Institutes of Health, RePORTER application 10483133, Natural History and Mechanisms of Exocrine Pancreatic Dysfunction in Pre-Type 1 Diabetes (5R03DK129971-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10483133. Licensed CC0.

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