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.

In Vivo Imaging of Human Pancreatic Microcirculation and Pancreatic Tissue Injury in Clinical Pancreas Transplantation

“…An alternative interpretation is that the concurrence of decreased initial microvascular dysfunction and increased post-transplant C-peptide concentrations at day 2 post-transplant may indeed be due to relatively increased cleavage of C-peptide from pro-insulin, thereby indicating less pronounced islet injury. In this context, Nankivell and co-workers have identified short intraoperative surgical pancreas anastomosis time as a predictive parameter for increased post-transplant C-peptide levels, suggesting a noteworthy susceptibility of b-cells to ischemia/reperfusion injury (45). Therefore, systematic studies are required in order to fully elucidate the prognostic significance and relationship between early pancreatic microvascular dysfunction and post-transplant endocrine organ function in humans.…”

Effect of Venous Drainage Site on Insulin Action After Simultaneous Pancreas-Kidney Transplantation

“…The discrepancy between these results and the severe hyperinsulinemia with insulin resistance reported by other authors (6,7,15,21) can be explained by the low-dose steroid and cyclosporine treatment and by the absence of severe basal hyperinsulinemia in the SPK-S group. Moreover, several authors (22)(23)(24) remarked that insulin resistance after pancreas transplantation is not only related to systemic venous drainage but also depends on body weight, prednisone dose, and time after transplantation. However, minor changes could be observed between the groups: in the SPK-S group, glycemia was mildly decreased, whereas insulin and lipid oxidation values were increased when compared with the SPK-P group.…”

The Long-term Management of Pancreas Transplantation

“…Hyperinsulinemia complicates pancreas transplant with systemic drainage and most of these studies have average follow-up of one year or less (46,48,49,57,58). Nankivell et al (49) show an association of insulin resistance to corticosteroid therapy, body weight, and time posttransplant.…”

“…Nankivell et al (49) show an association of insulin resistance to corticosteroid therapy, body weight, and time posttransplant. In contrast, Petruzzo et al (59) found little difference in insulin metabolism between portal and systemic drainage recipients with both groups falling in the normal range.…”