title: Insulin downregulates SIRT1 and AMPK activation and is associated with changes in liver fat, but not in inflammation and mitochondrial oxidative capacity, in streptozotocin-diabetic rat.
abstract: OBJECTIVE
  Involvement of insulin in diabetes-associated liver triglyceride deposition and its potential pathways remain incompletely defined. SIRT1 may negatively modulate lipogenesis and liver triglyceride accumulation, involving AMP-activated protein kinase (AMPK) activation. In streptozotocin-diabetic rats, we hypothesized that insulin negatively modulates liver SIRT1 and activates AMPK-inhibited lipogenic mediators leading to triglyceride accumulation. The impact of insulin deprivation (INS-) and replacement (INS+) on liver inflammation and mitochondrial oxidative capacity (also potentially regulating triglyceride deposition) was also measured.
  
  
  METHODS
  Streptozotocin-diabetic rats under chronic (8-week) INS- and INS+.
  
  
  RESULTS
  Compared to INS- (P < 0.05), INS+ had low liver SIRT1 with low AMPK activating phosphorylation, low inactivating phosphorylation of its lipogenic target acetyl-CoA carboxylase and high tissue triglycerides. INS- (P < 0.05 vs Control) had liver inflammation and high mitochondrial oxidative capacity, but neither was modulated by INS+. Pair-feeding showed no influence of spontaneous overeating on insulin-induced changes.
  
  
  CONCLUSIONS
  Insulin replacement downregulates SIRT1 and AMPK activation in vivo in streptozotocin-diabetic rat liver, likely contributing to insulin-induced liver triglyceride accumulation. Under the current experimental conditions, insulin-deprived diabetes is associated with liver inflammation and high mitochondrial oxidative capacity, that are not affected by insulin replacement and are therefore unlikely to contribute to tissue triglyceride changes in this model.
authors.affiliation: Clinica Medica, Department of Medical Technological and Translational Sciences, University of Trieste, Trieste, Italy. barazzon@units.it
authors.forename: Rocco
authors.initials: R
authors.lastname: Barazzoni
authors.forename: Michela
authors.initials: M
authors.lastname: Zanetti
authors.forename: Mauro
authors.initials: M
authors.lastname: Sturnega
authors.forename: Marco
authors.initials: M
authors.lastname: Stebel
authors.forename: Annamaria
authors.initials: A
authors.lastname: Semolic
authors.forename: Alessia
authors.initials: A
authors.lastname: Pirulli
authors.forename: Pierandrea
authors.initials: P
authors.lastname: Vinci
authors.forename: Lorena
authors.initials: L
authors.lastname: Zentilin
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.forename: Luigi
authors.initials: L
authors.lastname: Cattin
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Guarnieri
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D056564:Sirtuin 1 / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D007328:Insulin; D012333:RNA, Messenger; D014280:Triglycerides; D055372:AMP-Activated Protein Kinases; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000103:Acetyl-CoA Carboxylase