World J. Surg. 25, 487–496, 2001 DOI: 10.1007/s002680020342 WORLD Journal of SURGERY © 2001 by the Socie ´te ´ Internationale de Chirurgie Pancreas Transplantation for Treatment of Diabetes Mellitus David E.R. Sutherland, M.D., Rainer W.G. Gruessner, M.D., Angelika C. Gruessner, Ph.D. Department of Surgery, University of Minnesota, Mayo Mail Code 280, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA Published Online: April 11, 2001 Abstract. Pancreas transplantation is the only treatment for type I dia- betes mellitus that can induce an insulin-independent normoglycemic state. Because of the need for immunosuppression, it has been most widely applied in uremic diabetic recipients of kidney transplant with a high success rate, particularly when done as a simultaneous (SPK) pro- cedure (insulin independence > 80% at 1 year) with patient and kidney graft survival rates equivalent to or higher than in those who receive a kidney transplant alone. The results of solitary pancreas transplants (PAK in nephropathic diabetic recipients or PTA in nonuremic recipi- ents) have also dramatically improved; 1-year graft survival rates are more than 80% and 70%, respectively, with the new immunosuppressants tacrolimus and mycophenolate mofetil. Multiple factors are important for successful application of pancreas transplantation, as summarized in this review. During the last decade of the twentieth century the role of pan- creas transplantation in the treatment of diabetes dramatically expanded [1]. It is the only treatment for type I diabetes (an autoimmune disease) that consistently establishes an insulin-in- dependent, normoglycemic state [2]. Advances in transplantation in general (particularly in immu- nosuppression) have made pancreas grafting increasingly benign as a treatment for diabetes. If strategies to prevent or treat the pathogenesis of type I diabetes materialize (e.g., thwarting auto- immunity before onset or, if after onset, coupling thwarting with stimulation of beta cell regeneration) [3], pancreas (and islet) transplantation could become obsolete. However, as the second millennium ended, pancreas transplantation had advanced to the therapeutic realm, whereas preventive or regenerative strategies not. Rationale The main objective of pancreas (or islet) transplantation is to estab- lish euglycemia and free the diabetic patient of the daily burden of multiple insulin injections or dose or diet adjustments based on multiple fingerstick blood glucose determinations. This burden must be assumed not only to keep them alive (for type I diabetes) but also to lower the risk of secondary diabetic complications. The Diabetes Control and Complication Trial (DCCT) conclu- sively proved that tight diabetic control reduces the incidence of secondary complications [4]. The price is the rigorous self-disci- pline required to lower glycohemoglobin as much toward normal as possible plus an increased frequency of insulin reactions and hypoglycemic episodes [5]. Even in the DCCT group given intense insulin treatment, mean glycosolated hemoglobin levels averaged 1% above normal. Some individuals developed secondary compli- cations even when glycosolated hemoglobin levels were only mod- erately elevated. The incidence of secondary complications de- creases progressively with decreasing mean glycosolated hemoglobin levels, but the threshold for zero risk is a constantly normal value, something that currently can be achieved only with pancreas transplantation. A closed-loop insulin pump coupled to a glucose sensor should theoretically do the same, but a minia- turized, implantable, practical device awaits during this new mil- lennium. At the moment, perfect diabetic control is provided only by beta cell replacement. The main current drawback of both pancreas and islet transplantation is the need to immunosuppress the re- cipient, but this can be done with oral drugs without the need for constant dose adjustments. A pancreas transplant requires major surgery; but a successful graft makes the recipient euglycemic, and glycosolated hemoglobin levels are normal for as long as the graft functions [6]. The need for immunosuppression is only a relative drawback, as it is used for other organ transplants even when alternative treatments are available, such as dialysis for renal failure. Pancreas transplants are ideally applied before complications occur. Because of uncertainty in an individual patient as to whether he or she is complication-prone (even with poor control not all patients develop complications) and the uncertainty over what the individual side effects of immunosuppression will be, only a few institutions perform pancreas transplants soon after the onset of disease [7]. This will change, however, as antirejection strategies become more specific, decreasing the side effects of immunosuppression [8, 9]. During the past decade pancreas transplants alone were largely employed in patients with highly labile diabetes and hypoglycemic unawareness, a syndrome that may emerge many years after the onset of diabetes, particularly in those with neuropathy [10]. In this situation pancreas transplantation is the most effective treat- ment because it completely obviates insulin reactions. However, Correspondence to: D.E.R. Sutherland, M.D.