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Title: Identification of monogenic diabetes utilising biomarkers clinical criteria, and molecular genetics
Author: McDonald, Timothy James
ISNI:       0000 0004 2721 595X
Awarding Body: Exeter and Plymouth Peninsula Medical School
Current Institution: Exeter and Plymouth Peninsula Medical School
Date of Award: 2011
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Maturity-onset diabetes of the young (MODY) is caused by highly penetrant, mutations in a single gene that result in non-insulin dependent diabetes typically presenting in lean young adults. MODY accounts for approximately 1 % of diabetes and is often misdiagnosed as Type 1 diabetes or Type 2 diabetes. Over 80% of MODY patients in the UK remain unidentified. The aim of this thesis was to develop, characterise and determine the diagnostic accuracy of existing and novel biomarkers that could be used to identify patients with a monogenic form of diabetes. Blood C-peptide can aid in the diagnosis of MODY, but practical reasons limit its widespread use. In chapters 1 and 2 the measurement of C-peptide in urine is explored. We find Urinary C-peptide creatinine ratio is a stable and reproducible measure of endogenous insulin secretion, which correlates strongly with 24 hour urine C-peptide and, both fasting and stimulated, blood C-peptide in non- diabetic controls and patients with Type 2 diabetes. In chapter 3 we assess assay specific stability of C-peptide and insulin in blood on a number of analytical platforms and storage conditions. In contrast to many published reports we find C-peptide is stable in K +-EDTA whole blood for at least 24 hours at ambient room temperature. The aim of chapter 4 was to determine the prevalence of GADA and IA-2 autoantibodies in a large cohort (n=508) of patients with a confirmed genetic diagnosis of MODY. Less than 1 % of MODY patients had islet autoantibodies and a combination of GADA and IA-2A testing gave the best discrimination between Type 1 diabetes and MODY (sensitivity of 99% and specificity of 82%). A pilot study previously showed hsCRP is lower in HNF1A-MODY than in other forms of diabetes. In chapter 5 we confirm that plasma hsCRP levels are lower in HNF1A-MODY than Type 2 diabetes, Type 1 diabetes, GCK-, HNF4A- and HNF1 B-MODY. In addition, an hsCRP level of <0.75 mg/L discriminates HNF1A-MODY from Type 2 diabetes with a sensitivity of 79% and specificity of 70%. In chapter 6 we investigate the lipid profiles in HNF1A-MODY. The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non- diabetic controls. HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY (sensitivity of 75% and specificity of 63%). In the final chapter we determine the diagnostic accuracy of the biomarkers studied in this thesis (C-peptide, islet antibodies, HDL-cholesterol and hsCRP) within a single test set of patients. We determine that all the biomarkers with the exception of hsCRP add discriminative value to a clinical prediction model for MODY compared to using clinical criteria alone. An overview of the major findings of each chapter, the clinical implications and areas of future research are discussed in chapter 8.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available