title: Cyclosporine A enhances gluconeogenesis while sirolimus impairs insulin signaling in peripheral tissues after 3 weeks of treatment.
abstract: Cyclosporine A (CsA) and sirolimus (SRL) are immunosuppressive agents (IA) associated with new-onset diabetes after transplantation (NODAT). This study aims to evaluate the effects of 3-weeks of treatment with either CsA (5 mg/kg BW/day) or SRL (1 mg/kg BW/day) on insulin signaling and expression of markers involved in glucose metabolism in insulin-sensitive tissues, in Wistar rats. Although no differences were observed in fasting glucose, insulin or C-peptide levels, both treated groups displayed an impaired glucose excursion during both glucose and insulin tolerance tests. These results suggest glucose intolerance and insulin resistance. An increase in glucose-6-phosphatase protein levels (68%, p < 0.05) and in protein-tyrosine phosphatase 1B (163%, p < 0.05), a negative regulator of insulin was observed in the CsA-treated group in the liver, indicating enhanced gluconeogenesis and increased insulin resistance. On the other hand, glucokinase protein levels were decreased in the SRL group (35%, p < 0.05) compared to vehicle, suggesting a decrease in glucose disposal. SRL treatment also reduced peroxisome proliferator-activated receptor γ coactivator 1 alpha protein expression in muscle (~50%, p < 0.05), while no further protein alterations were observed in muscle and perirenal adipose tissue nor with the CsA treatment. Moreover, the phosphorylation of key proteins of the insulin signaling cascade was suppressed in the SRL group, but was unchanged by the CsA treatment. Taken together, these data suggest that CsA treatment enhances gluconeogenic factors in liver, while SRL treatment impairs insulin signaling in peripheral tissues, which can contribute to the development of insulin resistance and NODAT associated with immunosuppressive therapy.
authors: Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal. Electronic address: patriciacmmlopes@gmail.com.
authors: P C
authors: PC
authors: Lopes
authors: Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal. Electronic address: lia2211@hotmail.it.
authors: A
authors: A
authors: Fuhrmann
authors: Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal. Electronic address: fabcarvalho27@gmail.com.
authors: F
authors: F
authors: Carvalho
authors: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, 3000-548 Coimbra, Portugal; Institute for Nuclear Sciences Applied to Heath-ICNAS, University of Coimbra, Coimbra, Portugal. Electronic address: jose6sereno@hotmail.com.
authors: J
authors: J
authors: Sereno
authors: Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal. Electronic address: martarebelosantos@gmail.com.
authors: M R
authors: MR
authors: Santos
authors: Department of Medical Sciences, Uppsala University, 75185 Uppsala, Sweden. Electronic address: maria.pereira@medsci.uu.se.
authors: M J
authors: MJ
authors: Pereira
authors: Department of Medical Sciences, Uppsala University, 75185 Uppsala, Sweden. Electronic address: jan.eriksson@medsci.uu.se.
authors: J W
authors: JW
authors: Eriksson
authors: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, 3000-548 Coimbra, Portugal. Electronic address: freis@fmed.uc.pt.
authors: F
authors: F
authors: Reis
authors: Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal; The Portuguese Diabetes Association (APDP), 1250 203 Lisbon, Portugal. Electronic address: ecarvalh@cnc.uc.pt.
authors: E
authors: E
authors: Carvalho
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002096:C-Peptide / Q000097:blood; D016572:Cyclosporine / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects*; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000378:metabolism; D006029:Glycosuria / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071161:Forkhead Box Protein O1
chemical_list: D002096:C-Peptide; D016572:Cyclosporine; D051858:Forkhead Transcription Factors; D006003:Glycogen; D007166:Immunosuppressive Agents; D007328:Insulin; D009419:Nerve Tissue Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D020123:Sirolimus; D014157:Transcription Factors; C501429:Ppargc1a protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C516610:Ptpn1 protein, rat
keywords: Adipocyte; Gluconeogenesis; Immunosuppressive agents; Insulin signaling; Liver; Muscle