title: Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin.
abstract: OBJECTIVE
  Thiazolidinediones can enhance clearance of whole-body non-esterified fatty acids and protect against the insulin resistance that develops during an acute lipid load. The present study used [(3)H]-R-bromopalmitate to compare the effects of the thiazolidinedione, rosiglitazone, and the biguanide, metformin, on insulin action and the tissue-specific fate of non-esterified fatty acids in rats during lipid infusion.
  
  
  METHODS
  Normal rats were treated with rosiglitazone or metformin for 7 days. Triglyceride/heparin (to elevate non-esterified fatty acids) or glycerol (control) were then infused for 5 h, with a hyperinsulinaemic clamp being performed between the 3rd and 5th hours.
  
  
  RESULTS
  Rosiglitazone and metformin prevented fatty-acid-induced insulin resistance (reduced clamp glucose infusion rate). Both drugs improved insulin-mediated suppression of hepatic glucose output but only rosiglitazone enhanced systemic non-esterified fatty acid clearance (plateau plasma non-esterified fatty acids reduced by 40%). Despite this decrease in plateau plasma non-esterified fatty acids, rosiglitazone increased fatty acid uptake (two-fold) into adipose tissue and reduced fatty acid uptake into liver (by 40%) and muscle (by 30%), as well as reducing liver long-chain fatty acyl CoA accumulation (by 30%). Both rosiglitazone and metformin increased liver AMP-activated protein kinase activity, a possible mediator of the protective effects on insulin action, but in contrast to rosiglitazone, metformin had no significant effect on non-esterified fatty acid kinetics or relative tissue fatty acid uptake.
  
  
  CONCLUSIONS
  These results directly demonstrate the "lipid steal" mechanism, by which thiazolidinediones help prevent fatty-acid-induced insulin resistance. The contrasting mechanisms of action of rosiglitazone and metformin could be beneficial when both drugs are used in combination to treat insulin resistance.
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: J-M
authors.initials: JM
authors.lastname: Ye
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Dzamko
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: M E
authors.initials: ME
authors.lastname: Cleasby
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: B D
authors.initials: BD
authors.lastname: Hegarty
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: S M
authors.initials: SM
authors.lastname: Furler
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: G J
authors.initials: GJ
authors.lastname: Cooney
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia. e.kraegen@garvan.org.au.
authors.forename: E W
authors.initials: EW
authors.lastname: Kraegen
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000187:drug effects / Q000378:metabolism; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism; D005990:Glycerol / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000097:blood*; D008687:Metformin / Q000494:pharmacology*; D051381:Rats; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014280:Triglycerides / Q000494:pharmacology
chemical_list: D001798:Blood Proteins; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D008055:Lipids; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone; D006493:Heparin; D008687:Metformin; D005990:Glycerol