Tacrolimus and sirolimus have distinct effects on insulin signaling in male and female rats.

Although the contribution of the immunosuppressants tacrolimus (TAC) and sirolimus (SIR) to the development of posttransplant diabetes mellitus (PTDM) are being increasingly recognized, the mechanisms of immunosuppressant-induced hyperglycemia are unclear. SIR induces insulin resistance predominantly, but is associated with ß-cell dysfunction in rodents. TAC affects islet function but is associated with worsening insulin sensitivity in a few, and improvement in some, clinical studies. We sought to clarify the contributions of TAC and SIR to insulin resistance and islet function. Four groups of male and female Sprague-Dawley rats received TAC, SIR, TAC and SIR, or control for 2 weeks. All rats were administered an oral glucose challenge at the end of treatment. Half the groups were sacrificed 10 minutes after administration of regular insulin whereas the other half did not receive insulin before sacrifice. Liver, pancreas, fat, and muscle were harvested subsequently. Quantification of Western blots revealed that SIR and TAC plus SIR suppressed the phospho-Akt (pAkt)-to-Akt ratios in liver, muscle, and fat compared with control, regardless of sex. TAC alone did not impair the pAkt-to-Akt ratios in any of the tissues in male and female rats. ß-Cell mass was reduced significantly after TAC treatment in male rats. SIR did not affect ß-cell mass, regardless of sex. Our study demonstrated very clearly that SIR impairs insulin signaling, without any effect on ß-cell mass, and TAC does not impair insulin signaling but reduces ß-cell mass. Our efforts are key to understanding the mechanisms of immunosuppressant-induced hyperglycemia and to tailoring treatments for PTDM.

Metformin improves immunosuppressant induced hyperglycemia and exocrine apoptosis in rats.

BACKGROUND: Immunosuppressants are an important cause of posttransplantation diabetes mellitus. We have shown that tacrolimus and sirolimus induce hyperglycemia and hyperinsulinemia in normal rats. We hypothesized that metformin, given concurrently with tacrolimus and/or sirolimus, prevents disturbances in glucose and insulin metabolism. METHODS: Eight groups (n=6) of normal Sprague-Dawley rats were studied: four groups received tacrolimus, sirolimus, tacrolimus/sirolimus, or control for 14 days, and four more groups received similar treatments along with metformin. Daily glucoses were measured. All rats were administered an oral glucose challenge before sacrifice. Pancreata were analyzed by terminal deoxynucleotide tranferase-mediated dUTP nick-end labeling staining and immunohistochemistry. RESULTS: Tacrolimus, sirolimus, and tacrolimus/sirolimus impaired glucose tolerance compared to control. Sirolimus and tacrolimus/sirolimus also increased random blood glucose levels. Sirolimus alone resulted in hyperinsulinemia after oral glucose challenge compared to control. In the sirolimus/metformin and tacrolimus/sirolimus/metformin groups, mean daily random glucose was no longer increased, although the response to glucose challenge was still impaired. Metformin decreased pancreatic exocrine and trended to decrease endocrine apoptosis in tacrolimus/sirolimus group and reduced islet insulin content in sirolimus group. CONCLUSIONS: This is the first study to show that metformin can improve immunosuppressant-induced hyperglycemia, when administered concurrently, and reduces exocrine apoptosis (reducing the impact on potential islet progenitor cells).