title: 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.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Bell
authors.forename: Jiangxia
authors.initials: J
authors.lastname: Wang
authors.forename: Sriya
authors.initials: S
authors.lastname: Muralidharan
authors.forename: Sadhana
authors.initials: S
authors.lastname: Chalasani
authors.forename: Allison M
authors.initials: AM
authors.lastname: Fullenkamp
authors.forename: Laura A
authors.initials: LA
authors.lastname: Wilson
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.forename: Brent A
authors.initials: BA
authors.lastname: Neuschwander-Tetri
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Brunt
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: McCullough
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Bass
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
authors.forename: Aynur
authors.initials: A
authors.lastname: Unalp-Arida
authors.forename: Naga
authors.initials: N
authors.lastname: Chalasani
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D000077205:Pioglitazone; D012016:Reference Values; D045162:Thiazolidinediones / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome; D014810:Vitamin E / Q000008:administration & dosage*
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D014810:Vitamin E; D000077205:Pioglitazone