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

Lauren N Bell, Jiangxia Wang, Sriya Muralidharan, Sadhana Chalasani, Allison M Fullenkamp, Laura A Wilson, Arun J Sanyal, Kris V Kowdley, Brent A Neuschwander-Tetri, Elizabeth M Brunt, Arthur J McCullough, Nathan M Bass, Anna Mae Diehl, Aynur Unalp-Arida, Naga Chalasani, Bradley Aouizerat, Nonalcoholic Steatohepatitis Clinical Research Network

Research output: Contribution to journalArticle

Abstract

UNLABELLED: 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.

Original languageEnglish (US)
Pages (from-to)1311-8
Number of pages8
JournalHepatology
Volume56
Issue number4
DOIs
StatePublished - Oct 2012

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pioglitazone
Vitamin E
Insulin Resistance
Adipose Tissue
Histology
Placebos
Liver
Therapeutics
Fibrosis
Fasting
Non-alcoholic Fatty Liver Disease

Keywords

  • Adipose Tissue
  • Adult
  • Cross-Sectional Studies
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Fatty Liver
  • Female
  • Follow-Up Studies
  • Humans
  • Hypoglycemic Agents
  • Insulin Resistance
  • Male
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease
  • Reference Values
  • Thiazolidinediones
  • Time Factors
  • Treatment Outcome
  • Vitamin E

Cite this

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; Wang, Jiangxia; Muralidharan, Sriya; Chalasani, Sadhana; Fullenkamp, Allison M; Wilson, Laura A; Sanyal, Arun J; Kowdley, Kris V; Neuschwander-Tetri, Brent A; Brunt, Elizabeth M; McCullough, Arthur J; Bass, Nathan M; Diehl, Anna Mae; Unalp-Arida, Aynur; Chalasani, Naga; Aouizerat, Bradley; Nonalcoholic Steatohepatitis Clinical Research Network.

In: Hepatology, Vol. 56, No. 4, 10.2012, p. 1311-8.

Research output: Contribution to journalArticle

Bell, LN, Wang, J, Muralidharan, S, Chalasani, S, Fullenkamp, AM, Wilson, LA, Sanyal, AJ, Kowdley, KV, Neuschwander-Tetri, BA, Brunt, EM, McCullough, AJ, Bass, NM, Diehl, AM, Unalp-Arida, A, Chalasani, N, Aouizerat, B & Nonalcoholic Steatohepatitis Clinical Research Network 2012, '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', Hepatology, vol. 56, no. 4, pp. 1311-8. https://doi.org/10.1002/hep.25805
Bell, Lauren N ; Wang, Jiangxia ; Muralidharan, Sriya ; Chalasani, Sadhana ; Fullenkamp, Allison M ; Wilson, Laura A ; Sanyal, Arun J ; Kowdley, Kris V ; Neuschwander-Tetri, Brent A ; Brunt, Elizabeth M ; McCullough, Arthur J ; Bass, Nathan M ; Diehl, Anna Mae ; Unalp-Arida, Aynur ; Chalasani, Naga ; Aouizerat, Bradley ; Nonalcoholic Steatohepatitis Clinical Research Network. / 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. In: Hepatology. 2012 ; Vol. 56, No. 4. pp. 1311-8.
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abstract = "UNLABELLED: 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.",
keywords = "Adipose Tissue, Adult, Cross-Sectional Studies, Dose-Response Relationship, Drug, Drug Administration Schedule, Fatty Liver, Female, Follow-Up Studies, Humans, Hypoglycemic Agents, Insulin Resistance, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Reference Values, Thiazolidinediones, Time Factors, Treatment Outcome, Vitamin E",
author = "Bell, {Lauren N} and Jiangxia Wang and Sriya Muralidharan and Sadhana Chalasani and Fullenkamp, {Allison M} and Wilson, {Laura A} and Sanyal, {Arun J} and Kowdley, {Kris V} and Neuschwander-Tetri, {Brent A} and Brunt, {Elizabeth M} and McCullough, {Arthur J} and Bass, {Nathan M} and Diehl, {Anna Mae} and Aynur Unalp-Arida and Naga Chalasani and Bradley Aouizerat and {Nonalcoholic Steatohepatitis Clinical Research Network}",
note = "Copyright {\circledC} 2012 American Association for the Study of Liver Diseases.",
year = "2012",
month = "10",
doi = "10.1002/hep.25805",
language = "English (US)",
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pages = "1311--8",
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TY - JOUR

T1 - Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis

T2 - a pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study

AU - Bell, Lauren N

AU - Wang, Jiangxia

AU - Muralidharan, Sriya

AU - Chalasani, Sadhana

AU - Fullenkamp, Allison M

AU - Wilson, Laura A

AU - Sanyal, Arun J

AU - Kowdley, Kris V

AU - Neuschwander-Tetri, Brent A

AU - Brunt, Elizabeth M

AU - McCullough, Arthur J

AU - Bass, Nathan M

AU - Diehl, Anna Mae

AU - Unalp-Arida, Aynur

AU - Chalasani, Naga

AU - Aouizerat, Bradley

AU - Nonalcoholic Steatohepatitis Clinical Research Network

N1 - Copyright © 2012 American Association for the Study of Liver Diseases.

PY - 2012/10

Y1 - 2012/10

N2 - UNLABELLED: 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.

AB - UNLABELLED: 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.

KW - Adipose Tissue

KW - Adult

KW - Cross-Sectional Studies

KW - Dose-Response Relationship, Drug

KW - Drug Administration Schedule

KW - Fatty Liver

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Hypoglycemic Agents

KW - Insulin Resistance

KW - Male

KW - Middle Aged

KW - Non-alcoholic Fatty Liver Disease

KW - Reference Values

KW - Thiazolidinediones

KW - Time Factors

KW - Treatment Outcome

KW - Vitamin E

U2 - 10.1002/hep.25805

DO - 10.1002/hep.25805

M3 - Article

VL - 56

SP - 1311

EP - 1318

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 4

ER -