Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin

Diabetologia. 2004 Jul;47(7):1306-1313. doi: 10.1007/s00125-004-1436-1. Epub 2004 Jul 1.


Aims/hypothesis: 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/interpretation: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Proteins / drug effects
  • Blood Proteins / metabolism
  • Fatty Acids / blood
  • Fatty Acids / metabolism*
  • Fatty Acids, Nonesterified / blood
  • Fatty Acids, Nonesterified / metabolism
  • Glycerol / pharmacology
  • Heparin / pharmacology
  • Hypoglycemic Agents / pharmacology
  • Insulin Resistance / physiology*
  • Lipids / blood*
  • Metformin / pharmacology*
  • Rats
  • Rosiglitazone
  • Thiazolidinediones / pharmacology*
  • Triglycerides / pharmacology


  • Blood Proteins
  • Fatty Acids
  • Fatty Acids, Nonesterified
  • Hypoglycemic Agents
  • Lipids
  • Thiazolidinediones
  • Triglycerides
  • Rosiglitazone
  • Heparin
  • Metformin
  • Glycerol