Analysing the genetic, immunological and pancreatic characteristics of type 1 diabetes to gain new insights into the aetiology of the disease

Abstract

Type 1 diabetes (T1D) is caused by T-cell mediated destruction of insulin-producing pancreatic islet beta cells and for a long time the disease was considered to be beta cell specific. Therefore, over the years, most studies on T1D focused on beta cells. Studies have also shown evidence that T1D patients have exocrine dysfunction, exocrine pancreatic insufficiency and pancreas atrophy. It is known that islets account for only 2% of the pancreas so the reduced pancreas size cannot be from beta cell loss alone.
The present study has investigated autoimmunity against the exocrine antigens pancreatic lipase (PNLIP) and carboxyl ester lipase (CEL) by radioimmunoassay. The study also examined immunoreactive trypsinogen (IRT) and faecal elastase-1 (FET) as biomarkers of loss of exocrine mass and function in T1D patients and first-degree relatives (FDRs) participating in the Bart’s Oxford (BOX) family study. IRT levels were also explored in well characterised populations such as PATSI, ENDIT and ADDRESS-2. IRT was determined by a modified DELFIA protocol whilst FET levels were determined by sandwich ELISA.
This study found no evidence of autoantibodies against exocrine antigens CEL and PNLIP. IRT levels were reduced in new-onset and established T1D patients compared with age and gender-matched islet autoantibody negative relatives. The median IRT in T1D patients 2 years from diagnosis was 13 (6-30) compared with 24 (10-47) ng/ml in matched relatives (p<0.0001). FET levels decreased with age and showed a decrease in patients compared with relatives.
The exocrine pancreas function is decreased in type 1 diabetes. The proteomics analysis identified proteins that are different between type 1 diabetes cases and controls. This analysis was hypothesis generating and will be explored further in future.

Date of Award	29 Sept 2020
Original language	English
Awarding Institution	University of Bristol
Supervisor	Alistair J K Williams (Supervisor), Kathleen M Gillespie (Supervisor) & Anna E Long (Supervisor)