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Title: Endogenous insulin secretion in long duration type 1 diabetes
Author: Oram, Richard Anthony
ISNI:       0000 0004 5362 2655
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2014
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Type 1 diabetes(T1 D) is defined as a disease of progressive autoimmune destruction of pancreatic beta cells, leading to absolute insulin deficiency. In each individual with the disease there is a critical point when the loss of beta cells is sufficiently great that blood glucose can no longer be controlled, and they develop diabetes. Most people have some remaining endogenous insulin after diagnosis with T1 D but this "honeymoon period" is thought to last for a relatively brief period of time (months to 1-2 years) before all remaining beta cells are destroyed. However, there is mounting evidence from autopsy specimens and from recent studies of endogenous insulin in longstanding T1 D, that some people with T1 0 have persistent functional beta cells for many more years than previously thought. Endogenous insulin production is best measured using C-peptide, as C-peptide is secreted in equimolar amounts to insulin from pancreatic beta cells, C-peptide assays do not cross react with insulin, and C-peptide has a longer half-life. Very low levels of C-peptide are now measurable using highly sensitive electrochemiluminescence assays. A new method of measuring endogenous insulin developed by the Exeter team, urine C-peptide creatinine ratio (UCPCR), correlates very well with blood measures of C-peptide and can be posted from home, allowing the study of large numbers of people and repeated measurements of C-peptide. This thesis aims to assess the prevalence of low-level insulin production in people with longstanding T1 D. using a highly sensitive C-peptide assay in blood and urine, and to assess the use of repeated home UCPCR to monitor islet transplant recipients. 3 In Chapter 1 We review the current methods and recent advances in measurement of endogenous insulin in T1 D, and the natural history of endogenous insulin production in T1D. In Chapter 2 we assess the prevalence of low-level detectable serum and urine Cpeptide in 74 patients with long-duration T1 D. We assess whether very low levels reflect functional beta cells by comparing C-peptide levels before and after a meal stimulus. We demonstrate that most patients continue to secrete very low levels of endogenous insulin, which are detectable in either blood or a spot UCPCR sample, and that the detectable low levels of C-peptide increase after meals. In Chapter 3 we further explore the findings from Chapter 2, using a home stimulated UCPCR to assess endogenous insulin in a large cross-sectional, population-based study of patients with T1 D. Our findings provide confirmation that the majority of long duration patients with T1 D have detectable urine C-peptide and that 8% have much higher levels of endogenous insulin secretion. In Chapter 4 we assess if UCPCR posted from home can be used as a marker of islet transplant function. We find that home UCPCR correlates with clinical and metabolic measures of islet transplant function and provides a valid measure of Cpeptide production in islet transplant recipients. In Chapter 5 we test whether UCPCR could be a surrogate measure of insulin resistance by examining the correlation of UCPCR with serum insulin, C-peptide and HOMA2 (Homeostasis Model Assessment 2)-insulin resistance in people without diabetes and a subgroup with chronic kidney disease (CKD). We find in participants with normal renal function, UCPCR may be a simple, practical method for the 4 assessment of insulin resistance, but that in patients with CKD, UCPCR does not correlate with serum C-peptide, insulin or HOMA2-IR. An overview of the major findings of each chapter, their implications and possible future research are discussed in Chapter 6. 5
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available