title: Interactive influences of peroxisome proliferator-activated receptor alpha activation and glucocorticoids on pancreatic beta cell compensation in insulin resistance induced by dietary saturated fat in the rat.
abstract: OBJECTIVE
  We sought to elucidate whether excess glucocorticoids and increased dietary lipids act synergistically to impair glucose tolerance and, if so, whether activation of peroxisome proliferator-activated receptor alpha (PPARalpha) has an adverse or beneficial effect on glucose tolerance.
  
  
  METHODS
  Dexamethasone (100 microg kg(-1) body weight day(-1); 5 days) was administered to insulin-resistant rats fed a high-saturated-fat (HF) diet for 4 weeks. The PPARalpha agonist WY14643 was administered (50 mg kg(-1) body weight intraperitoneally) 24 h before sampling. Glucose-stimulated insulin secretion (GSIS) was assessed in vivo after an acute glucose bolus injection, and in vitro using step-up and step-down islet perifusions.
  
  
  RESULTS
  Although neither PPARalpha activation nor dexamethasone alone affected fasting glycaemia in the HF group, dexamethasone in combination with PPARalpha activation elicited marked postabsorptive hyperglycaemia. Dexamethasone treatment of HF rats had little effect on GSIS after an acute glucose challenge in vivo, but induced glucose intolerance. PPARalpha activation augmented GSIS in dexamethasone-treated HF rats in vivo, restoring glucose tolerance. Contrasting with data obtained in vivo, greatly enhanced peak rates of GSIS were observed ex vivo in perifusions of islets from dexamethasone-treated HF rats compared with those from untreated HF rats, an effect attenuated by antecedent PPARalpha activation.
  
  
  CONCLUSIONS
  The study demonstrates that glucocorticoid excess precipitates the development of glucose intolerance in rats maintained on a high-saturated-fat diet. It does this by interrupting the negative feedback loop between insulin sensitivity and secretion in vivo, such that further enhancement of compensatory insulin secretion is not possible. PPARalpha activation restores the coupling between insulin secretion and action.
authors.affiliation: Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Holness
authors.forename: N D
authors.initials: ND
authors.lastname: Smith
authors.forename: G K
authors.initials: GK
authors.lastname: Greenwood
authors.forename: M C
authors.initials: MC
authors.lastname: Sugden
mesh_terms: D000818:Animals; D002469:Cell Separation; D003907:Dexamethasone / Q000494:pharmacology; D004032:Diet; D004357:Drug Synergism; D005227:Fatty Acids / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D020738:Leptin / Q000097:blood; D008055:Lipids / Q000097:blood; D047495:PPAR gamma / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D005227:Fatty Acids; D005938:Glucocorticoids; D020738:Leptin; D008055:Lipids; D047495:PPAR gamma; D003907:Dexamethasone