Use of immunosuppressive agents is mandatory after organ transplantations but may be complicated by the development of hyperglycemia or diabetes. The prevalence of diabetes after liver transplantation in adulthood ranges from 13.6 to 33% (1,2) with a progressive increase in risk that parallels the time after transplant (3). Tacrolimus, a calcineurin inhibitor, is a recent immunosuppressive agent largely used to prevent and treat transplant rejections often following other immunosuppressive failures (4–5). The incidence of post-transplant diabetes mellitus (PTDM) in tacrolimus-treated patients was significantly higher than in those treated with cyclosporine (6,7) and in pediatric-age patients (8). Usually PTDM refers to renal recipients, and only one pediatric case has been reported after liver transplantation (9). PTDM in tacrolimus-treated patients has been related to reduced pancreatic β-cell function and is generally reversed by dose reduction (10–11).
Here we describe the β-cell function in a 15-year-old male liver transplant recipient treated with tacrolimus at the onset of PTDM and 1 year after remission. He underwent liver transplantation at age 7 years for Alagille Syndrome and was subsequently treated with steroids and cyclosporine. Because of acute rejection at age 15, treatment with cyclosporine was switched to tacrolimus and mycophenolate mofetil. One month later, he presented symptomatic hyperglycemia (42 mmol/l) without ketoacidosis; his BMI was 21.3 kg/m2, and his HbA1c was 9.4% (normal values 3.3–6.0). Initially, the patient required 1.8 units · kg−1 · day−1 of insulin. β-Cell function was investigated by glucagon stimulation—basal C-peptide levels were 0.90 nmol/l (normal values 0.165–0.993) and 1.67 nmol/l after 6 min (relative increase 186%, normal values 130–377%). Tacrolimus was substituted by cyclosporine while continuing other immunosuppressive agents. This allowed a gradual decrease of insulin and its withdrawal within 5 weeks. One year later, an oral glucose tolerance test showed normal glucose tolerance (basal levels 4.5 mmol/l, peak 7.7). In addition, stimulated C-peptide response was normal (relative increase 231%), fasting insulin level was 54.6 pmol/l, and HbA1c was 5.6%.
The absence of ketoacidosis and the presence of normal C-peptide levels during tacrolimus treatment indicate that β-cell function was normal in our patient, not confirming the β-cell impairment ascribed to tacrolimus (9,10). The high insulin dose required suggests that insulin resistance, which was not due to steroids since they were never withdrawn from therapy, may have played a role. Furthermore, because proneness to diabetes depends on several genetic mechanisms, it is possible that immunosuppressive agents play only a triggering role in PTDM. In addition, since most PTDM cases were described after renal transplantations, we cannot exclude a putative role of the transplanted liver itself on the abnormal peripheral insulin action. With the spreading use of tacrolimus in liver transplantation, pediatric diabetes practitioners will probably face many new cases of PTDM.
