title: Clinical determinants of glucose homeostasis after pancreas transplantation.
abstract: Although successful simultaneous pancreas and kidney transplantation (SPK) achieves normoglycemia in the majority of diabetic recipients with end-stage renal disease, little is known about the factors that influence long-term endocrine function. In this prospective study of 48 bladder-drained SPK patients, 209 oral glucose tolerance tests were performed between 3 months and 6 years after transplantation. Normal fasting glucose levels and systemic hyperinsulinemia were stable for up to 6 years after SPK. Multivariate analysis revealed that increased area-under-curve (AUC) levels of C-peptide 3 months after transplantation were predicted by short surgical pancreas anastomosis time, greater recipient body weight, and total HLA mismatch score. Episodes of acute pancreas rejection were not associated with reduced allograft insulin output in the long term. Insulin output, stimulated by oral glucose tolerance tests and assessed by the ratio of AUC insulin to AUC glucose, fell gradually after transplantation and was decreased by an elevated serum calcium level and high cyclosporine dose. The ratio of fasting insulin to glucose, which acts as a marker of peripheral insulin resistance, fell with time after transplantation and was increased by greater body weight, higher prednisolone dose, and lower cyclosporine dose. The inhibitory effect of cyclosporine on both fasting and postprandial insulin output was, however, minor when quantified by multivariate analysis. Endocrine function of the transplanted pancreas was not correlated with its exocrine function measured by urinary amylase excretion, nor was there a correlation with change in renal function measured by isotopic glomerular filtration rate. In summary, simultaneous pancreas and kidney transplantation leads to excellent long-term glucose homeostasis maintained at the expense of systemic hyperinsulinemia. The key factors adversely affecting peripheral resistance in SPK were corticosteroid therapy, body weight, and time after transplantation. The susceptibility of islets to ischemia-reperfusion injury, as quantitated by surgical anastomosis time, may have implications for islet transplantation programs, as may the relative resistance of islets to allograft rejection. Glucose homeostasis after SPK, while remaining abnormal, may be used as the standard against which islet transplantation must be measured.
authors.affiliation: National Pancreas Transplant Unit, Westmead Hospital, Sydney, Australia.
authors.forename: B J
authors.initials: BJ
authors.lastname: Nankivell
authors.forename: J R
authors.initials: JR
authors.lastname: Chapman
authors.forename: K J
authors.initials: KJ
authors.lastname: Bovington
authors.forename: S T
authors.initials: ST
authors.lastname: Spicer
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Connell
authors.forename: R D
authors.initials: RD
authors.lastname: Allen
mesh_terms: D000328:Adult; D002096:C-Peptide / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology*; D007676:Kidney Failure, Chronic / Q000601:surgery; D016030:Kidney Transplantation; D008099:Liver / Q000378:metabolism; D008112:Liver Glycogen / Q000096:biosynthesis; D008137:Longitudinal Studies; D008875:Middle Aged; D015999:Multivariate Analysis; D016035:Pancreas Transplantation; D011446:Prospective Studies; D013997:Time Factors
chemical_list: D002096:C-Peptide; D007328:Insulin; D008112:Liver Glycogen; D005947:Glucose