EFFECT OF THE IMMUNOSUPPRESSANT FK506 ON GLUCOSE-INDUCED INSULIN SECRETION FROM ADULT RAT ISLETS OF LANGERHANS

Abstract

The clinical use of cyclosporine has been a key advance in organ transplantation in the past decade (1). This agent is currently used in patients who receive all types of allografts. Also, CsA has been useful in preventing the onset of insulin-dependent diabetes in animal models (2) and inducing remissions in new-onset type I diabetes in humans (3). Despite the impressive achievements with cyclosporine, nephrotoxicity and graft rejection are still significant problems. Additionally, CsA decreases insulin synthesis and secretion in several species (4–7) and decreases glucose induced insulin secretion from human islets in vitro (8). It has been reported to decrease intravenous glucose tolerance when compared with azathioprine used in the same patient (9). The long-term consequences of these findings continue to be of concern. FK506 is a new immunosuppressive agent that is more potent on a weight basis than CsA (10). These drugs share many similar effects although the binding proteins for these two agents appear to be different. The binding sites share a novel isomerase enzyme system: peptidyl proline isomerase, which may represent an important common site of action (11). FK506 has recently been used successfully in trials in humans undergoing organ transplantation (12). In baboons, others have raised the issue of its potential adverse effect on glucose tolerance (13). Preliminary studies in human recipients of liver allografts showed that 6/12 patients had oral glucose tolerance tests that deviated from normal at at least one time point; 2 patients had impaired glucose tolerance, but only one patient had overt diabetes (14). These findings do not appear to differ from historical controls undergoing liver transplantation who did not receive FK506—however, the question of the effect of this agent on glucose metabolism remains an important unanswered question. FK506 apparently does not alter morphology or interfere with insulin secretion from fetal islets of Langerhans (15). Glucose-induced insulin secretion in neonatal and fetal islets is not comparable to the adult response (16, 17). Since adult tissues are often used in transplant studies, we looked at the effect of FK506 on glucose-induced insulin secretion from adult rat islets of Langerhans. We used freshly isolated islets obtained by collagenase digestion of the pancreas, from adult male Wistar rats (18). Insulin was measured by standard radioimmunoassay using a charcoal and dextran separation method (19). After isolation, islets were washed 5 times in basal (2.8 or 5.6 mM) glucose containing buffer.