Diabetes mellitus and islet cell specific autoimmunity as adverse effects of immunsuppressive therapy by FK506/Tacrolimus

The induction of diabetes has been recognised as adverse effect of the immu nsuppressive drug FK506/Tacrolimus. The aim of this study was to clarify wh ether insulinopenia or insulin resistance dominates and whether islet cell autoantibodies are present in patients treated by FK506. We investigated 58 patients 1-3 years after liver transplantation while under therapy with FK 506 or CsA and prednisolone (0-7.5 mg) for basal blood glucose levels and i slet-cell specific autoantibodies. A subgroup of 20 patients on FK506, 10 p atients on cyclosporin and 15 healthy volunteers were metabolically tested by oGTT. Five patients had diabetes pre-transplantation After transplantati on, 9/28 FK506-treated patients developed newly diagnosed diabetes compared to 0/25 cyclosporin-treated patients (p<0.01). Both patient groups showed significantly higher fasting blood glucose, insulin or C-peptide levels com pared to controls. Through the oGTT, FK506-treated patients without diabete s, but not cyclosporin-treated patients, had higher C-peptide levels compar ed to controls (pi 0.05). Five/32 patients on FK506 compared to 0/26 patien ts on cyclosporin (p<0.05) had islet cell specific autoantibodies, mainly I CA without GAD- or IA2-Ab, a feature described for latent autoimmune diabet es in adults. TCA positivity was correlated to the diabetes associated HLA haplotype DR4/DQ*0302 (p<0.05). Although the interpretation of our metaboli c data in patients with concomitant liver disease and prednisolone therapy has limitations, we suggest insulin resistance caused by treatment with FK5 06. However, manifestation of diabetes was associated with relative insulin openia rather than insulin resistance in patients on FK506. Immunsuppressiv e therapy by FK506 was not able to suppress islet cell autoimmunity, and ma y even induce it in genetically predisposed patients.