title: Metformin improves immunosuppressant induced hyperglycemia and exocrine apoptosis in rats.
abstract: 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).
authors.affiliation: Department of Medicine, VA Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA. vshivaswamy@unmc.edu
authors.forename: Vijay
authors.initials: V
authors.lastname: Shivaswamy
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bennett
authors.forename: Cara C
authors.initials: CC
authors.lastname: Clure
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Larsen
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Hamel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D006946:Hyperinsulinism / Q000097:blood / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000097:blood; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D046790:Pancreas, Exocrine / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus; D016559:Tacrolimus; D013997:Time Factors
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; D007328:Insulin; D008687:Metformin; D020123:Sirolimus; D016559:Tacrolimus