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; Sanyal, Arun J.; Kowdley, Kris V.; Neuschwander‐Tetri, Brent A.; Brunt, Elizabeth M.; McCullough, Arthur J.; Bass, Nathan M.; Diehl, Anna Mae; Ünalp–Arida, Aynur; Chalasani, Naga

doi:10.1002/hep.25805

Cited by 92 publications

(47 citation statements)

References 16 publications

(24 reference statements)

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“…Participants in the upper two tertiles who responded to treatment with a reduction in FPG and HbA 1c levels were at a reduced risk of developing lower leg oedema, a major AE associated with glitazone treatment. These efficacy and safety data are highly relevant for predicting benefit-to-risk ratios for patients treated with glitazones; this should also apply when the medications are considered for other indications, such as liver disease [32][33][34].…”

Section: Discussionmentioning

confidence: 99%

“…The ECM and its products, especially procollagen type VI and endotrophin, may be of particular relevance in fatty liver, including in the severe form of the disease, non-alcoholic steatohepatitis (NASH). NASH is a metabolic-fibrotic disorder of the liver that shows at least a partial overlap with type 2 diabetes [32][33][34]. Accordingly, we expect that this novel biomarker should assist in the diagnosis and management of NASH patients where insulin sensitisers may be beneficial for subpopulations, both for the treatment of insulin resistance and liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes

et al. 2016

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Aims/hypothesis The treatment of type 2 diabetes with full peroxisome proliferator-activated receptor gamma (PPARγ) agonists improves insulin sensitivity, but is associated with weight gain, heart failure, peripheral oedema and bone loss. Endotrophin, the C-terminal fragment of the α3 chain of procollagen type VI (also called Pro-C6), is involved in both adipose tissue matrix remodelling and metabolic control. We established a serum assay for endotrophin to assess if this novel adipokine could identify type 2 diabetic patients who respond optimally to PPARγ agonists, improving the risk-to-benefit ratio. Methods The BALLET trial (NCT00515632) compared the glucose-lowering effects and safety of the partial PPARγ agonist balaglitazone with those of pioglitazone in individuals with type 2 diabetes on stable insulin therapy. The per protocol population (n = 297) was stratified into tertiles based on baseline endotrophin levels. Participants were followed-up after 26 weeks, after which correlational analysis was carried out between endotrophin levels and measures of glucose control. This is a secondary post hoc analysis. Results Endotrophin was significantly associated with therapeutic response to balaglitazone and pioglitazone. At week 26, only individuals in the upper two tertiles showed significant reductions in HbA 1c and fasting serum glucose compared with baseline. The OR for a 1% and a 0.5% reduction in HbA 1c for individuals in the upper two tertiles were 3.83 (95% CI 1.62, 9.04) p < 0.01, and 3.85 (95% CI 1.94, 7.61) p < 0.001, respectively. Endotrophin levels correlated with adipose tissue mass, insulin resistance and fatty liver index. Notably, PPARγ-associated adverse effects, such as moderate-to-severe lower extremity oedema, only occurred in the lower tertile. Conclusions/interpretation Elevated endotrophin serum levels predict response to two insulin sensitisers and reduce the risk of associated adverse effects, thereby, identifying patients with type 2 diabetes who may profit from PPARγ agonist treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes

et al. 2016

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“…Activation of PPARγ improves insulin sensitivity by promoting fatty acid storage in adipocytes, inhibiting the production of inflammatory mediators and cytokines, and lowering blood glucose levels [10,11]. Several studies have clearly shown that serum level of adipokine RBP4 is significantly down-regulated by TZDs treatment in obese mice and type 2 diabetic patients [12,13,14].…”

Section: Introductionmentioning

confidence: 99%

Pioglitazone Lowers Serum Retinol Binding Protein 4 by Suppressing its Expression in Adipose Tissue of Obese Rats

Zhu

Xiao²,

Liu³

et al. 2015

Cell Physiol Biochem

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Background/Aims: Pioglitazone, a peroxisome proliferator-activated receptor γ activator, is clinically used to treat insulin resistance. However, the underlying mechanism of pioglitazone's action remains unclear. We investigated whether, and how, pioglitazone modulates serum level of retinol binding protein 4 (RBP4), an adipocytokine associated with obesity and insulin resistance. Methods: Insulin sensitivity was determined by oral glucose tolerance test, and RBP4 expression was detected by RT-PCR and Western blotting. Results: Pioglitazone treatment significantly decreased serum RBP4 levels in obese rats, which was correlated with reduced body weight and increased insulin sensitivity. Moreover, pioglitazone greatly decreased RBP4 mRNA and protein levels in adipose tissue but not in the liver. Consistently, pioglitazone treatment significantly reduced RBP4 protein expression in 3T3-L1 adipocytes but not in HepG2 cells. Conclusion: These results demonstrate that pioglitazone inhibits the level of serum RPB4 by suppressing RBP4 expression in adipose tissue of obese rats, suggesting that inhibiting RBP4 expression in adipocytes may provide a mechanism by which pioglitazone improves insulin sensitivity in insulin-resistant subjects.

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“…Whole-body insulin resistance was determined using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), a well-validated estimation of insulin resistance as determined by euglycemic-hyperinsulinemic clamp experiments (Hermans et al, 1999, Wallace et al, 2004): HOMA-IR = Glucose (mg/dl) × Insulin (mU/L)/405. Adipose-tissue specific insulin resistance was calculated using the ADIPO-IR index, which was first introduced in therapeutic studies of nonalcoholic fatty liver disease (Gastaldelli et al, 2009, Bell et al, 2012): ADIPO-IR = Free fatty acids (μM) × Insulin (mU/L).…”

Section: Methodsmentioning

confidence: 99%

Stratification of Risk of Death in Severe Acute Alcoholic Hepatitis Using a Panel of Adipokines and Cytokines

Rachakonda

Gabbert

Raina

et al. 2014

Alcoholism Clin & Exp Res

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Background: Dysregulated adipose tissue metabolism has been implicated in the pathogenesis of alcoholic liver disease in murine models. We aimed to characterize serum markers of adipose tissue metabolism and inflammation in patients with severe acute alcoholic hepatitis (AAH) and determine their utility to predict survival in severe AAH. Methods: A prospective, case control study design was used. Seventy-six patients hospitalized with severe AAH and twenty-five ambulatory patients with alcoholic cirrhosis as controls were included. Serum samples were collected for biochemical analyses. Patients were followed for 180 days after enrollment to determine survival. Results: AAH patients exhibited higher serum glycerol and free fatty acid levels, suggesting enhanced adipose tissue triglyceride hydrolysis. Patients with AAH demonstrated a distinct serum lipidomic profile compared with alcoholic cirrhosis but not in systemic and adipose-specific insulin resistance. AAH patients had higher serum resistin and plasmin activation inhibitor-1 levels, while serum leptin was decreased. Serum levels of the prolipolytic cytokines tumor necrosis factor α (TNF- α), interleukin (IL)-6, IL-8 and IL-15 were significantly higher in AAH patients. Only 53% of AAH patients survived 180 days after admission, while all cirrhotic patients were alive at the end of the study period. Among patients with severe AAH, white blood cell count, hemoglobin, resistin, IL-6, and TNF-α were associated with 180-day survival, and all five markers demonstrated accuracy by area under receiver-operator curve (AUC) analysis. Serum IL-6 levels ≥ 38.66 pg/ml most precisely identified deaths in severe AAH. Patients with IL-6 ≥ 38.66 pg/ml had significantly decreased mean survival compared to those with lower levels. Conclusions: AAH patients demonstrate evidence of increased adipose tissue lipolysis and altered serum lipidomic profile compared with alcoholic cirrhosis patients. IL-6 may be a useful biomarker to risk-stratify severe AAH patients at the highest risk of mortality.

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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

Cited by 92 publications

References 16 publications

Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes

Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes

Pioglitazone Lowers Serum Retinol Binding Protein 4 by Suppressing its Expression in Adipose Tissue of Obese Rats

Stratification of Risk of Death in Severe Acute Alcoholic Hepatitis Using a Panel of Adipokines and Cytokines

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