Pathogenic Mechanisms Associated with Abnormalities in Post Transplant Glucose Metabolism

1. The full 13 time-point Area Under Curve 0-12 (fAUC) for free and total prednisolone will be calculated for each pharmacokinetic profile using the linear trapezoidal rule. Using 15 previously derived limited sampling strategies, predicted AUCs (pAUC) for free prednisolone will be calculated using the appropriate time-points required. 2. After completion of experiment 1, the relationship between blood glucose, free prednisolone exposure and two alternative oral prednisolone dosing strategies will be investigated using continuous glucose monitoring (CGM) in a crossover study of subjects 3-4 weeks post­transplant. Subjects will be randomized from the time of transplantation to daily (QD) (8:00hrs) or divided twice daily (BD) (8:00hrs and 20:00hrs) prednisolone dosing regimens. The prednisolone doses will then adjusted according to the patient’s transplant physician until week three when the total daily prednisolone dose will be fixed for the 5-day study period. Subjects will remain on their randomized dosing regimen for days 1 and 2 before crossover on day 3 to the alternate dosing regimen, i.e. BD to QD, or QD to BD. Day 3 results will be disregarded as a washout period. The iPro2 (registered trade mark) CGM system will be placed on day 1 prior to the morning prednisolone dose at 8:00hrs and removed after 8:00hrs on day 6. Therefore two days of CGM on each dosing regimen will be available for comparison (days 1-2 versus days 4-5). Two Medtronic iPro2 (registered trade mark) CGM systems will be used with Medtronic Enlite (registered trade mark) glucose sensors (Medtronic, California, USA). This system records an average blood sugar measurement every 5 minutes, for up to 6 days at a time. The results are blinded-to-patient and were downloaded using Medtronic CareLink (registered trade mark) iPro (registered trade mark) software. The CGM will be calibrated using the Abbott Optium Xceed (registered trade mark) blood glucose monitoring system with four fingerstick capillary glucose tests per day occurring prior to meals and at bedtime (Abbott Laboratories, Illinois, USA). The study period of 3 to 4 weeks post transplant was chosen as subjects will generally have stabilised after transplant surgery and will remain on moderately high prednisolone doses at that time. 3. Simultaneous with experiment 1 and 2, we will compare the sensitivity and specificity of available diagnostic investigations for post transplant diabetes mellitus (PTDM) at 6 weeks, 12 weeks and 12 months post­transplant fasting plasma glucose (FPG) greater than or equal to 7mmol/L, 2h­post oral glucose tolerance test greater than or equal to 11.1mmol/L, glycated haemoglobin (HbA1c) greater than or equal to 6.5%; pre­dinner home glucometer testing greater than or equal to 11.1mmol/L).