Relationship between adipose tissue insulin resistance and... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: A pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study

Bell, Lauren N.1; Wang, Jiangxia2; Muralidharan, Sriya1; Chalasani, Sadhana1; Fullenkamp, Allison M.1; Wilson, Laura A.2; Sanyal, Arun J.3; Kowdley, Kris V.4; Neuschwander-Tetri, Brent A.5; Brunt, Elizabeth M.6; McCullough, Arthur J.7; Bass, Nathan M.8; Diehl, Anna Mae9; Unalp-Arida, Aynur2; Chalasani, Naga1*# for the Nonalcoholic Steatohepatitis Clinical Research Network

1_Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN_

2_The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD_

3_Virginia Commonwealth University, Richmond, VA_

4_Virginia Mason Medical Center, Seattle, WA_

5_Saint Louis University School of Medicine, St. Louis, MO_

6_Washington University School of Medicine, St. Louis, MO_

7_Cleveland Clinic Foundation, Cleveland, OH_

8_University of California San Francisco, San Francisco, CA_

9_Duke University School of Medicine, Durham, NC_

10_National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD_

*M.D., Division of Gastroenterology/Hepatology, Indiana University School of Medicine, 1050 Wishard Boulevard, RG 4100, Indianapolis, IN 46202

Email:[email protected]

Received 3 August 2011; Accepted 17 April 2012

Grant sponsor: PIVENS; Grant Number: K24 DK072101; Grant sponsor: National Institutes of Health (NIH) to the Nonalcoholic Steatohepatitis Clinical Research Network; Grant Numbers: U01DK61718 U01DK61728 U01DK61731 U01DK61732 U01DK61734 U01DK61737 U01DK61738 U01DK61730 U01DK61713; Grant sponsor: NIH intramural program, National Cancer Institute; Grant sponsor: National Institutes of Health General Clinical Research Centers or Clinical and Translational Science Awards; Grant Numbers: UL1RR024989 UL1RR024128 M01RR000750 UL1RR024131 M01RR000827 UL1RR025014 M01RR000065.

Potential conflict of interest: Nothing to report.

#fax: 317-278-1949

Abstract

The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the mechanisms are unknown. We conducted a study to examine the changes in adipose tissue insulin resistance (Adipo-IR) during the PIVENS trial and its relationship to histological endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] × fasting insulin) was calculated at baseline and after 16 and 96 weeks of therapy. Compared to placebo, the baseline Adipo-IR was not different in either the vitamin E group ( P = 0.34) or the pioglitazone group ( P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score ( P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (−15.7 versus −1.91; P = 0.02), but this effect did not persist at 96 weeks (−3.25 versus −4.28; P = 0.31). Compared to placebo, Adipo-IR in the vitamin E group did not change significantly either after 16 weeks ( P = 0.70) or after 96 weeks ( P = 0.85). Change in Adipo-IR at week 16 was not associated with changes in any histological parameters at week 96, but improvement in Adipo-IR at week 96 was significantly associated with improvement in ballooning ( P = 0.03), fibrosis ( P = 0.004), and NAS ( P = 0.01). Conclusion : Vitamin E improved liver histology independent of changes in Adipo-IR, and pioglitazone treatment acutely improved Adipo-IR, but this was not sustained. Changes in Adipo-IR were associated with changes in liver histology, including fibrosis. (Hepatology 2012)