Novel biomarkers of beta-cell preservation in trials of immunotherapy in patients with type 1 diabetes

Mahmood, Zainab 2025. Novel biomarkers of beta-cell preservation in trials of immunotherapy in patients with type 1 diabetes. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Emerging evidence suggests that pancreatic beta cells in individuals with long-standing type 1 diabetes (T1D) may continue to secrete proinsulin despite minimal or absent C-peptide production, indicating a persistent defect in prohormone processing rather than absolute beta cell loss. This thesis evaluated a comprehensive panel of pancreatic peptides and their precursors, including C-peptide proinsulin (total and intact), islet amyloid polypeptide (IAPP), proIAPP, glucagon, proglucagon, and exocrine enzymes, to characterise beta, alpha, and exocrine cell function in T1D. Particular emphasis was placed on proinsulin-to-C-peptide ratios as potential biomarkers for disease progression. To further assess prohormone processing, a novel total-to-intact proinsulin (TPI:IPI) ratio was introduced. This measure reflects the burden of misfolded or incompletely processed proinsulin. A stepwise increase in the TPI:IPI ratio was observed across disease stages, from healthy donors to newly diagnosed and long-standing T1D, suggesting progressive endoplasmic reticulum dysfunction. Longitudinal data further showed a rise in the TPI:IPI ratio over two years, supporting its utility as an indicator of declining beta cell function. IAPP levels declined initially and then plateaued, remaining detectable even in participants with long-standing T1D. This pattern suggests that insulin production may be more profoundly impaired than the secretion of other beta cell peptides. Alternative explanations include potential extra-pancreatic sources of IAPP or assay cross reactivity with pro IAPP. Beyond the endocrine pancreas, this thesis also examined exocrine dysfunction in T1D. Cross-sectional analyses showed significantly reduced levels of amylase, lipase, and trypsinogen in newly diagnosed and long-standing T1D. Longitudinally, lipase and trypsinogen remained stable in the first year, while amylase declined slightly, suggesting differing temporal dynamics. Together, these findings underscore the value of peptide-based ratios, such as TPI:IPI, in monitoring T1D. The integrated characterisation of endocrine and exocrine dysfunction enhances understanding of disease progression and informs future biomarker development and early intervention strategies.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	8 December 2025
Last Modified:	08 Dec 2025 15:54
URI:	https://orca.cardiff.ac.uk/id/eprint/182979

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