title: Effect of cyclosporine A on hepatic carbohydrate metabolism and hepatic gene expression in rat.
abstract: OBJECTIVE
  Cyclosporine A (CsA)-based therapy has been implicated in the development of diabetes. Hence, its effects on hepatic carbohydrate metabolism and gene expression will be investigated.
  
  
  METHODS
  Sprague-Dawley rats given 15 mg/kg body weight/day of CsA for 20 days, as well as healthy untreated animals, received a glucose load enriched with [U-(13)C]glucose and deuterated water to resolve load and endogenous contributions to plasma glucose. Blood glucose and plasma insulin levels were assayed and at 60-min post-load, plasma glucose (13)C and (2)H-enrichments were analyzed by nuclear magnetic resonance spectroscopy and liver tissue analyzed for hepatic gene expression.
  
  
  RESULTS
  CsA-treated rats were glucose intolerant relative to controls (AUC(glucose) = 21,297 ± 857 versus 14,183 ± 1094, p < 0.01). Contributions from endogenous glucose production (EGP) were significantly elevated in CsA-treated rats (179 ± 16 versus 123 ± 13 mg/dl, p < 0.05). The increased endogenous contributions were attributable to glycogenolysis or glucose-G6P cycling and not to gluconeogenesis. Significantly higher expressions of fatty acid synthase and acetyl-CoA carboxylase 1 and 2 genes were observed in CsA-treated rats.
  
  
  CONCLUSIONS
  CsA-altered glucose metabolism and gene expression could reflect increased hepatic insulin resistance. In the liver of CsA-treated animals, EGP suppression is impaired whereas hepatic de novo lipogenesis is enhanced contributing to dysregulated glucose and lipid metabolism.
authors.affiliation: Biophysics and Biomedical NMR, Center for Neurosciences and Cell Biology of Coimbra, Coimbra, Portugal.
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Delgado
authors.forename: Cristina
authors.initials: C
authors.lastname: Barosa
authors.forename: Patrícia M
authors.initials: PM
authors.lastname: Nunes
authors.forename: Donald K
authors.initials: DK
authors.lastname: Scott
authors.forename: Robert M
authors.initials: RM
authors.lastname: O'Doherty
authors.forename: Sebastián
authors.initials: S
authors.lastname: Cerdán
authors.forename: Carlos F G C
authors.initials: CF
authors.lastname: Geraldes
authors.forename: John G
authors.initials: JG
authors.lastname: Jones
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000187:drug effects*; D050261:Glycogenolysis / Q000187:drug effects*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D007328:Insulin; D016572:Cyclosporine