Metformin Improves Immunosuppressant Induced Hyperglycemia and Exocrine Apoptosis in Rats

Abstract

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. 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. 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. 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).