EFFECTS OF IMMUNOSUPPRESSIVE AGENTS ON GLUCOSE-METABOLISM - IMPLICATIONS FOR THE DEVELOPMENT OF POSTTRANSPLANT DIABETES-MELLITUS

Diabetogenic effects have been ascribed to several drugs currently use d for immunosuppression following organ transplantations, including co rticosteroids, cyclosporin and tacrolimus (FK-506). Azathioprine appea rs to be devoid of adverse effects on carbohydrate metabolism. The pat hogenesis of immunosuppression-associated diabetes mellitus has not be en clearly defined, and may be multifactorial in organ transplant reci pients. Metabolic similarities between post-transplant diabetes and no n-insulin-dependent diabetes mellitus include defective insulin secret ion and impaired insulin action in target tissues. The predominant eff ect of corticosteroids is induction of a state of insulin resistance. Cyclosporin and tacrolimus have been shown to inhibit endogenous insul in secretion and may also have adverse effects on tissue sensitivity t o insulin. Postoperative diabetes mellitus developing de novo is a fre quent complication of organ transplantation. Treatment with diet, oral antidiabetic agents or insulin may be necessary. Postoperative diabet es may be a transient phenomenon in some patients, whereas others may require long term. insulin treatment. Although clinically overt diabet es is readily diagnosed, the prevalence of subclinical degrees of gluc ose intolerance may be higher than is currently recognised.The long te rm clinical implications of immunosuppression-associated glucose intol erance and diabetes are uncertain and rely on extrapolations from stud ies in non-transplant populations. Patients with impaired glucose tole rance may have an increased probability of progression to diabetes mel litus, whereas long term diabetes carries the risk of tissue damage fr om specific microvascular complications, i.e. diabetic retinopathy, ne uropathy and nephropathy. Epidemiological and experimental studies hav e implicated glucose intolerance and hyperinsulinaemia as risk factors for atherosclerosis. Hypertension and atherogenic plasma lipid profil es are also frequently encountered in transplant recipients treated wi th cyclosporin, tacrolimus and corticosteroids. Thus, patients treated with these drugs, particularly in combination, may possess a multipli city of risk factors for macrovascular disease. These factors may be r elevant to the development of accelerated atherosclerosis that occurs in renal and cardiac transplant recipients. However, their contributio n to post-transplant macrovascular disease is uncertain at present. Ca refully designed prospective studies will be necessary to determine th e natural history of postoperative diabetes in organ transplant recipi ents. We recommend that future clinical studies of immunosuppressive a gents should avoid arbitrary diagnostic criteria for diabetes and shou ld incorporate rigorous methods for the assessment of glucose toleranc e, insulin secretion and insulin action. Modifications of existing imm unosuppressive drug regimens may reduce the incidence or severity of p ostoperative diabetes. Elucidation of the molecular mechanisms respons ible for this metabolic complication should provide a more logical bas is for prevention and treatment.