The Effects of Rosiglitazone on Insulin Sensitivity, Lipolysis, and Hepatic and Skeletal Muscle Triglyceride Content in Patients With Type 2 Diabetes

  1. Adam B. Mayerson1,
  2. Ripudaman S. Hundal1,
  3. Sylvie Dufour13,
  4. Vincent Lebon13,
  5. Douglas Befroy13,
  6. Gary W. Cline1,
  7. Staffan Enocksson1,
  8. Silvio E. Inzucchi1,
  9. Gerald I. Shulman123 and
  10. Kitt F. Petersen1
  1. 1Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
  2. 2Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
  3. 3Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut


    We examined the effect of three months of rosiglitazone treatment (4 mg b.i.d.) on whole-body insulin sensitivity and in vivo peripheral adipocyte insulin sensitivity as assessed by glycerol release in microdialysis from subcutaneous fat during a two-step (20 and 120 mU · m−2 · min−1) hyperinsulinemic-euglycemic clamp in nine type 2 diabetic subjects. In addition, the effects of rosiglitazone on liver and muscle triglyceride content were assessed by 1H-nuclear magnetic resonance spectroscopy. Rosiglitazone treatment resulted in a 68% (P < 0.002) and a 20% (P < 0.016) improvement in insulin-stimulated glucose metabolism during the low- and high- dosage−insulin clamps, respectively, which was associated with ∼40% reductions in plasma fatty acid concentration (P < 0.05) and hepatic triglyceride content (P < 0.05). These changes were associated with a 39% increase in extramyocellular lipid content (P < 0.05) and a 52% increase in the sensitivity of peripheral adipocytes to the inhibitory effects of insulin on lipolysis (P = 0.04). In conclusion, these results support the hypothesis that thiazolidinediones enhance insulin sensitivity in patients with type 2 diabetes by promoting increased insulin sensitivity in peripheral adipocytes, which results in lower plasma fatty acid concentrations and a redistribution of intracellular lipid from insulin responsive organs into peripheral adipocytes.


    • Address correspondence and reprint requests to Kitt F. Petersen, M.D., Department of Internal Medicine, Yale University School of Medicine, 333 Cedar St., Fitkin 1, Box 208020, New Haven, CT 06520-8020. E-mail: kitt.petersen{at}

      Received for publication 3 October 2001 and accepted in revised form 31 October 2001.

      S.E.I. has received honoraria and is on the speakers’ bureau for both Glaxco/SmithKline and Takeda Pharmaceuticals America and has also received research support from Takeda. G.I.S. has served as a research consultant for Glaxo/SmithKline Beecham.

      DEXA, dual-energy X-ray absorptiometry; EMLC, extramyocellular lipid content; GDR, glucose disposal rate; ETOH, ethanol; ETOHin, ethanol concentration measured in the perfusate; ETOHout, ethanol concentration in the dialysate; GCMS, gas chromatography−mass spectrometry; GIR, glucose infusion rate; GP, endogenous glucose production; IMLC, intramyocellular lipid content; NMR, nuclear magnetic resonance; PPAR-γ, peroxisome proliferator−activated receptor-γ; TNF-α, tumor necrosis factor-α; TZD, thiazolidinedione.

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