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

Diabetogenic effects have been ascribed to several drugs currently used for immunosuppression following organ transplantations, including corticosteroids, cyclosporin and tacrolimus (FK-506). Azathioprine appears to be devoid of adverse effects on carbohydrate metabolism. The pathogenesis of immunosuppression-associated diabetes mellitus has not been clearly defined, and may be multifactorial in organ transplant recipients. Metabolic similarities between post-transplant diabetes and non-insulin-dependent diabetes mellitus include defective insulin secretion and impaired insulin action in target tissues. The predominant effect of corticosteroids is induction of a state of insulin resistance. Cyclosporin and tacrolimus have been shown to inhibit endogenous insulin secretion and may also have adverse effects on tissue sensitivity to insulin. Postoperative diabetes mellitus developing de novo is a frequent complication of organ transplantation. Treatment with diet, oral antidiabetic agents or insulin may be necessary. Postoperative diabetes may be a transient phenomenon in some patients, whereas others may require long term. insulin treatment. Although clinically overt diabetes is readily diagnosed, the prevalence of subclinical degrees of glucose intolerance may be higher than is currently recognised. The long term clinical implications of immunosuppression-associated glucose intolerance and diabetes are uncertain and rely on extrapolations from studies in non-transplant populations. Patients with impaired glucose tolerance may have an increased probability of progression to diabetes mellitus, whereas long term diabetes carries the risk of tissue damage from specific microvascular complications, i.e. diabetic retinopathy, neuropathy and nephropathy. Epidemiological and experimental studies have implicated glucose intolerance and hyperinsulinaemia as risk factors for atherosclerosis. Hypertension and atherogenic plasma lipid profiles are also frequently encountered in transplant recipients treated with cyclosporin, tacrolimus and corticosteroids. Thus, patients treated with these drugs, particularly in combination, may possess a multiplicity of risk factors for macrovascular disease. These factors may be relevant to the development of accelerated atherosclerosis that occurs in renal and cardiac transplant recipients. However, their contribution to post-transplant macrovascular disease is uncertain at present. Carefully designed prospective studies will be necessary to determine the natural history of postoperative diabetes in organ transplant recipients. We recommend that future clinical studies of immunosuppressive agents should avoid arbitrary diagnostic criteria for diabetes and should incorporate rigorous methods for the assessment of glucose tolerance, insulin secretion and insulin action. Modifications of existing immunosuppressive drug regimens may reduce the incidence or severity of postoperative diabetes. Elucidation of the molecular mechanisms responsible for this metabolic complication should provide a more logical basis for prevention and treatment.