title: Effects of insulin on pharmacodynamics of immunosuppressive drugs against mitogen-activated human peripheral blood mononuclear cells.
abstract: BACKGROUND
  Diabetes mellitus is one of the most common causes of chronic renal failure. Immunosuppressive efficacies of glucocorticoids, calcineurin inhibitors, and mycophenolic acid are possibly affected by insulin after renal transplantation in these patients.
  
  
  OBJECTIVE
  We investigated the effects of insulin on responses of mitogen-activated human peripheral blood mononuclear cells (PBMCs) to several immunosuppressive drugs.
  
  
  METHODS
  Antiproliferative efficacies of prednisolone, hydrocortisone, cyclosporine, tacrolimus, and mycophenolic acid against concanavalin A-stimulated PBMCs were evaluated in the presence of physiological (5 μunits/mL) and super physiological (50 μunits/mL) concentrations of insulin. Insulin-receptor expressions on PBMCs were evaluated by flow cytometry.
  
  
  RESULTS
  Insulin itself had no effects on the mitogen-induced proliferation of PBMCs. The IC50 values of cyclosporine against the mitogen-activated PBMCs in the presence of 5 or 50 μunits/mL insulin were significantly higher than those of cyclosporine without insulin (p < 0.05). The IC50 values of mycophenolic acid significantly increased by 50 μunits/mL insulin (p < 0.01). Insulin receptors were detected on the mitogen-activated CD4(+)/CD14(+ )cells in PBMCs.
  
  
  CONCLUSIONS
  These results indicate that insulin at even physiological concentration attenuates suppressive efficacies of several immunosuppressive drugs against mitogen-activated proliferation of human PBMCs, possibly via insulin receptors. Insulin used in dialysis patients accompanying diabetes mellitus is suggested to attenuate efficacies of immunosuppressive drugs after renal transplantation.
authors.affiliation: a Department of Clinical Pharmacology, School of Pharmacy , Tokyo University of Pharmacy and Life Sciences , Tokyo , Japan ;|b Cardiovascular Department , Xiyuan Hospital, China Academy of Chinese Medical Sciences , Beijing , P.R. China.
authors.forename: Shuiling
authors.initials: S
authors.lastname: Chen
authors.affiliation: a Department of Clinical Pharmacology, School of Pharmacy , Tokyo University of Pharmacy and Life Sciences , Tokyo , Japan ;
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sugiyama
authors.affiliation: a Department of Clinical Pharmacology, School of Pharmacy , Tokyo University of Pharmacy and Life Sciences , Tokyo , Japan ;
authors.forename: Mariko
authors.initials: M
authors.lastname: Inamura
authors.affiliation: a Department of Clinical Pharmacology, School of Pharmacy , Tokyo University of Pharmacy and Life Sciences , Tokyo , Japan ;
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: a Department of Clinical Pharmacology, School of Pharmacy , Tokyo University of Pharmacy and Life Sciences , Tokyo , Japan ;
authors.forename: Kenji
authors.initials: K
authors.lastname: Onda
authors.affiliation: b Cardiovascular Department , Xiyuan Hospital, China Academy of Chinese Medical Sciences , Beijing , P.R. China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Yin
authors.affiliation: a Department of Clinical Pharmacology, School of Pharmacy , Tokyo University of Pharmacy and Life Sciences , Tokyo , Japan ;
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hirano
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000473:pathology; D008297:Male; D008934:Mitogens / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D007328:Insulin; D008934:Mitogens
keywords: Insulin; T-cell mitogen; peripheral blood mononuclear cells; pharmacodynamics of immunosuppressive drugs; renal transplantation