title: Tacrolimus and sirolimus have distinct effects on insulin signaling in male and female rats.
abstract: 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 β-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. β-Cell mass was reduced significantly after TAC treatment in male rats. SIR did not affect β-cell mass, regardless of sex. Our study demonstrated very clearly that SIR impairs insulin signaling, without any effect on β-cell mass, and TAC does not impair insulin signaling but reduces β-cell mass. Our efforts are key to understanding the mechanisms of immunosuppressant-induced hyperglycemia and to tailoring treatments for PTDM.
authors.affiliation: VA Nebraska-Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, Neb; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Neb. Electronic address: vijay.shivaswamy@va.gov.
authors.forename: Vijay
authors.initials: V
authors.lastname: Shivaswamy
authors.affiliation: VA Nebraska-Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, Neb; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Neb; Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Neb.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bennett
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Neb.
authors.forename: Cara C
authors.initials: CC
authors.lastname: Clure
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Neb.
authors.forename: Brendan
authors.initials: B
authors.lastname: Ottemann
authors.affiliation: VA Nebraska-Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, Neb; Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Neb; Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Neb.
authors.forename: John S
authors.initials: JS
authors.lastname: Davis
authors.affiliation: VA Nebraska-Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, Neb; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Neb.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Larsen
authors.affiliation: VA Nebraska-Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, Neb; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Neb.
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Hamel
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D005260:Female; D006943:Hyperglycemia / Q000139:chemically induced / Q000209:etiology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood*; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*; D019737:Transplants
chemical_list: D007166:Immunosuppressive Agents; D007328:Insulin; D020123:Sirolimus; D016559:Tacrolimus