For decades, type 1 diabetes (T1D) has been considered a disorder resulting from the autoimmune destruction of insulin producing pancreatic beta cells. What is often less appreciated, but is in fact equally well established, is the generalized atrophy of the pancreas in new onset T1D as well as in those with established disease. Recent studies by the applicants demonstrated that pancreas weight from organ donors with T1D was significantly reduced. However, and more profound, reductions in pancreas weight were also observed in organ donors with only single diabetes-related autoantibodies. These findings underscore that changes in pancreas weight may represent an early event in the pathogenesis of T1D and raise the intriguing idea that pancreatic volume may serve as a long desired "biomarker" for understanding both disease prediction as well as progression. This application seeks funding for a pilot study to determine whether noninvasive estimations of pancreas volume can be used as a prognostic tool in monitoring autoantibody positive, first-degree relatives of patients with T1D. We hypothesize that T1D is associated with progressive pancreatic atrophy that correlates with functional beta cell mass. We propose to examine pancreas volume in four study groups: controls (age and gender matched to autoantibody positive participants), single autoantibody positive participants, multiple autoantibody positive participants, and recent onset T1D patients. Subjects will be recruited through the NIH TrialNet "Pathway to Prevention" studies and the Pediatric and Adult Endocrinology units at the University of Florida Diabetes Center.
Specific aims i nclude: 1) Utilize noninvasive radiological imaging to determine pancreas volume in control subjects, subjects at increased risk for T1D (single and multiple autoantibody positive groups), and subjects with new onset T1D. Pancreas volume will be assessed by two noninvasive radiological methods, ultrasound (US) and magnetic resonance imaging (MRI). 2) Correlate pancreas volume with beta cell function and autoimmunity.
This aim seeks to determine if biomarkers of beta cell function (fasting glucose, C-peptide and HbA1c) and T1D risk (autoantibodies) correlate with pancreas volume. 3) Correlate pancreas volume with T cell function subsets and HLA.
This final aim seeks to determine whether T cell subset functional studies and HLA types can be utilized to explain variance in pancreatic volume amongst controls, at risk subjects, and subjects with new onset T1D. Innovative aspects of this proposal include application of a highly accessible, noninvasive, and relatively low cost imaging method to assess T1D pathogenesis and the combination of faculty in immunology, pathology, clinical endocrinology (pediatric and adult endocrinology), biostatistics, and radiology to form a highly interactive and complementary research team. If pancreatic volume could be monitored over time and one is able to identify a specific loss of functional beta cell mass which coincides with a certain threshold of pancreas volume, pancreas volume could represent a major complement to other biomarkers used for clinical prevention and intervention trials for patients at risk for T1D. As well, monitoring pancreatic volume over time could function as an accurate, noninvasive, and simple surrogate marker for disease progression, allowing timely and guided clinical care.
At the time of type 1 diabetes diagnosis, pancreas size has decreased to nearly half of the expected size. We have recently studied the weight of pancreases from organ donors with type 1 diabetes-related autoantibodies and found that their pancreas weights were significantly decreased as well. This application proposes a pilot clinical trial to measure pancreas size by radiology in control subjects and those at risk or at onset for type 1 diabetes and study if pancreas size reflects the number of insulin-producing beta cells.
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