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Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis

Authors

  • Amalia Gastaldelli,

    1. Diabetes Division, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX
    2. Fondazione G. Monasterio and Institute of Clinical Physiology, National Research Council, Pisa, Italy
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  • Stephen A. Harrison,

    1. Gastroenterology Division, Brooke Army Medical Center, San Antonio, TX
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  • Renata Belfort-Aguilar,

    1. Diabetes Division, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX
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  • Lou Jean Hardies,

    1. Radiology Department, Research Imaging Center, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX
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  • Bogdan Balas,

    1. Diabetes Division, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX
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  • Steven Schenker,

    1. Gastroenterology Division, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX
    2. Audie L. Murphy Veterans Administration Medical Center, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX
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  • Kenneth Cusi

    Corresponding author
    1. Diabetes Division, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX
    2. Audie L. Murphy Veterans Administration Medical Center, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX
    • Diabetes Division, Department of Medicine, The University of Texas Health Science Center at San Antonio, Audie L. Murphy Veterans Administration Medical Center, San Antonio, TX 78248
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    • fax: 210-567-6554.


  • Potential conflict of interest: Dr. Balas is an employee of F. Hoffmann-La Roche. Dr. Schenker is a consultant for and advises Sanofi-Aventis, Lilly, Roche, Schering-Plough, Novartis, and Pfizer.

Abstract

Pioglitazone treatment improves insulin resistance (IR), glucose metabolism, hepatic steatosis, and necroinflammation in patients with nonalcoholic steatohepatitis (NASH). Because abnormal lipid metabolism/elevated plasma free fatty acids (FFAs) are important to the pathophysiology of NASH, we examined the impact of pioglitazone therapy on adipose tissue insulin resistance (Adipo-IR) during the treatment of patients with NASH. To this end, we assessed glucose/lipid metabolism in 47 patients with impaired glucose tolerance/type 2 diabetes mellitus and NASH and 20 nondiabetic controls. All individuals underwent a 75-g oral glucose tolerance test (OGTT) in which we measured glucose tolerance, IR, and suppression of plasma FFAs. We also measured Adipo-IR index (fasting, FFAs × insulin), hepatic fat by magnetic resonance spectroscopy, and liver histology (liver biopsy). Patients were randomized (double-blind) to diet plus pioglitazone (45 mg/day) or placebo for 6 months, and all measurements were repeated. We found that patients with NASH had severe Adipo-IR and low adiponectin levels. Fasting FFAs were increased and their suppression during the OGTT was impaired. Adipo-IR was strongly associated with hepatic fat (r= 0.54) and reduced glucose clearance both fasting (r=0.34) and during the OGTT (r=0.40, all P <0.002). Pioglitazone significantly improved glucose tolerance and glucose clearance, steatosis and necroinflammation (all P<0.01-0.001 versus placebo). Fasting/postprandial plasma FFAs decreased to levels of controls with pioglitazone (P<0.02 versus placebo). Adipo-IR decreased by 47% and correlated with the reduction of hepatic fat (r=0.46, P=0.009) and with the reduction in hepatic necroinflammation (r=0.47, P=0.0007). Conclusion: Patients with NASH have severe Adipo-IR independent of the degree of obesity. Amelioration of Adipo-IR by pioglitazone is closely related to histological improvement and plays an important role during treatment of patients with NASH. (HEPATOLOGY 2009)

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