| Summary: | 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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