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The mixed meal tolerance test (MMTT) is the gold standard measure of endogenous insulin secretion in Type 1 diabetes (T1 D), but practical issues limit its use in clinical practice. Urine C-peptide creatinine ratio (UCPCR) had recently been demonstrated to be stable for 3 days at room temperature using boric acid as a preservative. In this thesis I present work on the validation and utility of urinary C- peptide measurement in children and young adults with diabetes. Chapter 1 assesses the ability of UCPCR to be used instead of a MMTT stimulated serum C-peptide in 72 patients with T1 D. Ninety minute MMTT stimulated serum C-peptide (90CP) was highly correlated to 120 minute UCPCR taken during a MMTT (rs=0.97, p<0.0001) or after a home evening meal (rs=0.91, p<0.0001). Postprandial UCPCR testing was a sensitive and specific method for detecting endogenous insulin secretion (84% sensitivity/97% specificity). Chapter 2 assesses the impact of exogenous insulin administration on serum C- peptide during the MMTT in 91 adults with insulin-treated diabetes, and the ability of fasting C-peptide (FCP) to be used as an alternative to 90CP. 90CP was highly correlated in the MMTT with and without exogenous insulin (rs=0.98, p<0.0001). Although there was a 20% reduction in the peak C-peptide value when insulin was given, the original C-peptide cut-off for significant endogenous insulin secretion (90CP ~0.2nmol/l) still correctly classified 90/91 patients (98% sensitivity/1 00% specificity). FCP was also highly correlated to 90CP during the MMTT (rs=0.97, p<0.0001). FCP~0.07nmol/l was the optimal cut off (100% sensitivity/97% specificity) for 90CP ~0.2nmol/l. Insulin omission may not always be necessary during a MMTT and FCP may offer a practical alternative in insulin treated patients. Chapter 3 assesses whether 90CP and FCP are reliable measures of peak insulin secretion. In a collaboration with Professor Johnny Ludvigsson in Sweden, 1334 MMTTs in 421 children and adolescents (aged <18 years) with T1 D were analysed. Area Under the Curve C-peptide (AUC CP) was highly correlated to 90CP (rs=O.99, p<0.0001) and strongly correlated to FCP (rs=0.88, p<0.0001). AUC CP ~23nmol/l/150minutes was the equivalent cut-off for peak C-peptide ~0.2nmol/1 (98% sensitivity/97% specificity). 90CP ~0.2nmol/l correctly classified 96% patients using AUC or peak CP, whereas FCP ~0.1 nmol/l correctly classified 83 and 85% patients, respectively. The C-peptide peak occurred earlier in patients with longer diabetes duration (6.1 minutes earlier for every 1 year increase in duration) and diagnosed at a younger age (2.5 minutes later for every year increase in age at diagnosis). 90CP is a highly sensitive and specific measure of AUC and peak CP in children and adolescents with T1 D and offers a practical alternative to full MMTT. Chapter 4 assesses the ability of postprandial UCPCR to discriminate diabetes subtypes in 220 adults with diabetes ~5 years. UCPCR ~0.2nmol/mmol discriminates hepatic nuclear factor 1 alpha and hepatic nuclear factor 4 alpha Maturity Onset Diabetes of the Young (HNF1 A/4A MODY) from T1 D (97% sensitivity/ 96% specificity). UCPCR was not able to discriminate HNF1 A/4A MODY from Type 2 diabetes (T2D). Chapter 5 extends the ability of UCPCR to discriminate diabetes subtypes in 262 patients aged <20 years. UCPCR ~O. 7nmol/mmol can be used in children and adolescents with diabetes duration >2 years to discriminate non-T1D (MODY and T2D) from T1 0 (100% sensitivity/ 97% specificity). An overview of the major findings of each chapter, the clinical implications and areas of future research are discussed in Chapter 6.

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Type I diabetes effects over 16,500 children in the UK. For these young people, care is needed to maintain 'near normal' blood glucose levels in order to relieve the unpleasant symptoms of high and low blood glucose. Although good metabolic control may decrease the risk of severe long term complications, adolescents often have difficulty juggling all the aspects of a complex and demanding treatment regimen, and poor adherence is commonplace. The literature review proposes a theoretical framework for understanding the role of responsibility in the management of type 1 diabetes during adolescence. The pattern of responsibility is explored in relation to the individual and their interpersonal context. In terms of health outcome, the effects of individual and shared responsibility are considered, necessitating a balance between the adolescent's assumption of responsibility and their level of parental involvement. Suggestions for clinical practice are discussed, methodological limitations raised, and future research opportunities identified. The role of dietary self efficacy in predicting self care during adolescence is established. Using data for two distinct phases of adolescence, paper 1 examines whether social support from family and friends makes any additional contribution to the prediction of dietary self care, over and above that of self efficacy. For the younger group (aged 12-13), the prediction of self care is improved by better perceived support from friends. An interactive effect of shared family responsibility is also reported, confirming the importance of shared responsibility, between parent and child, to facilitate good self management as highlighted in the literature review. None of the variables are significant predictors of self care in the older group (14-18 year olds).

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