Celebrating Scholarship and Creativity Day (2018-)

Document Type

Thesis

Publication Date

4-30-2026

Disciplines

Biochemistry, Biophysics, and Structural Biology

Advisor

Claire Otteson

Abstract

This research aims to determine how the formation of hybrid insulin peptides (HIPs) contributes to the two-phase decline of C-peptide production in type 1 diabetes (T1D). C-peptide is used to determine the level of insulin production within human pancreatic beta-cells because it is secreted in equimolar amounts with mature insulin peptide. The two-phase decline is characterized by an initial rapid and exponential loss of beta-cell function, followed by a prolonged plateau phase of residual insulin secretion. During this plateau phase, residual beta-cells continue to generate HIPs through both enzymatic transpeptidation and spontaneous formation via anhydride intermediates. These processes are problematic because their HIP products elicit a chronic autoimmune attack on the pancreas. This immune response contributes to the continued destruction of beta-cells, leading to a further increase in HIP production, causing T1D development. This project proposes that the biochemical pathways responsible for HIP formation are key drivers of the transition between the rapid decline phase and the plateau phase of C-peptide loss. Targeting HIP formation or antigen presentation through prescription inhibitors could preserve residual beta-cell function. This would reduce the risk of hypoglycemia and diabetic ketoacidosis, while  improving long-term metabolic outcomes. These targeted strategies shift the focus from general immunosuppression therapies, toward precise treatments that directly interrupt neoantigen-driven immune responses. Future research should combine T-cell avatar assays with long term C-peptide monitoring to better understand the relationship between HIP-specific immune activity and the rate of beta-cell decline.

Additional Files
Capstone Presentation.pptx (4998 kB)
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