Impairment of insulin production is induced by a toxic tacrolimus dosage

Abstract

Introduction: New Onset Diabetes Mellitus is a well known and frequent complication after solid organ transplantation. Due to the complex clinical situation after transplantation it is difficult to distinct between the different influences of various factors. However the application of calcineurin inhibitors especially tacrolimus is considered to be an important diabetogenic factor. An experimental study analyzing the impact of different tacrolimus — dosages on the pancreatic beta-cell function was designed. Methods: Male Wistar rats received different doses of tacrolimus (0.1, 0.5, 1, 10 mg/kg for 14 day) or tap water (control group). After two weeks animals were anesthetized, serum and organs harvested. Serum glucose, insulin and creatinine level were measured. Afterwards pancreas samples were fixed in formaldehyde and stained with anti-insulin antibody. Staining intensity was assessed in a semi quantitative manner within the groups. Results: There was no difference in the serum glucose and insulin levels between experimental and control groups. The insulin amount in pancreas beta cells was decreased after the application of a single toxic tacrolimus dosage (10 mg/kg). At the same time the serum creatinine concentration was significantly increased and weight gain decreased in this group. All other measured parameters did not differ significantly. Conclusions: Therapeutic dosages of tacrolimus have no influence on the pancreas insulin production by the rat. In contrast a single toxic tacrolimus dosage has a deleterious effect on the insulin production. However this effect is not associated with hypoinsulinemia. Additional experiments to prove and expand those observations are necessary.