Proposed trial: safety and efficacy of resveratrol for the treatment of non-alcoholic fatty liver disease (NAFLD) and associated insulin resistance in adolescents who are overweight or obese adolescents — rationale and protocol

2015 ◽  
Vol 93 (5) ◽  
pp. 522-530 ◽  
Author(s):  
Brandy Wicklow ◽  
Kristy Wittmeier ◽  
Geert W. t’ Jong ◽  
Jonathon McGavock ◽  
Marni Robert ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Liver ◽  
Outcome Measures ◽  
Side Effect ◽  
Controlled Trial ◽  
Whole Body ◽  
Secondary Outcome ◽  
Side Effect Profile ◽  
Obese Adolescent ◽  
Alcoholic Fatty Liver

Non-alcoholic fatty liver (NAFL) disease (NAFLD) affects 30% of overweight adolescents and increases the risk of type 2 diabetes mellitus (T2D). Resveratrol is a naturally occurring compound with potential to reverse NAFL and its associated insulin resistance in adults. The use of resveratrol to reduce risk for T2D through its effect on NAFL has not been examined to date in youth. This paper provides a literature review and protocol for a 30 day proof of principle trial of resveratrol in a population of adolescents at risk for T2D. This randomized double-blind controlled trial is designed with the primary objective of evaluating a twice daily supplementation of 75 mg of resveratrol for safety and tolerability in overweight and obese adolescent subjects (13 to <18 years of age) with NAFL. Secondary objectives are to determine the effect size of the intervention on hepatic steatosis and whole body insulin sensitivity. Adolescents in the intervention arm (n = 10) will receive oral supplementation of resveratrol 75 mg twice daily (with breakfast and dinner) for a total daily dose of 150 mg for the duration of 30 days. The comparison group (n = 10) will receive a placebo twice daily for 30 days. Both cases and controls will receive a standardized lifestyle intervention program. Subjects in both groups will be followed for an additional 30 days post intervention for total study duration of approximately 60 days. Primary outcome measures include a primary side effect profile determined by participant interview, a side effect profile determined by serum biochemistry and vital signs. Secondary outcome measures include an oral glucose tolerance test, liver and cardiac fat content measured by magnetic resonance spectroscopy, anthropometric measures of overweight/obesity, inflammatory markers, and cardiac function and morphology measured with ultrasonography. Additional outcome measures include serum concentrations of resveratrol, compliance to protocol, physical activity, and nutritional assessment. This study will determine the safety and tolerability of resveratrol in an overweight adolescent population and inform the design of a larger randomized controlled trial.

scholarly journals SUN-LB52 The Protective Effects of Hepatocyte GH Receptor (GHR) Signaling Against Steatosis and Liver Injury Is Sexually Dimorphic and Autonomous of IGF1

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Andre Sarmento-Cabral ◽  
Mercedes del Rio-Moreno ◽  
Mari C Vazquez-Borrego ◽  
Mariyah Mahmood ◽  
Elena Gutierrez-Casado ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Injury ◽  
Fatty Liver ◽  
Negative Feedback ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Whole Body ◽  
Chow Diet ◽  
Alcoholic Fatty Liver ◽  
Systemic Insulin Resistance

Abstract GH dysregulation contributes to the development of non-alcoholic fatty liver disease (NAFLD), however debate remains as to the relative contribution of the direct vs indirect effects of GH, via IGF1. Mouse models with congenital, liver-specific knockout of the GHR, JAK2 or STAT5, as adults exhibit steatosis, glucose intolerance, insulin resistance and white adipose tissue (WAT) lipolysis. It is believed that fatty liver is due to the dramatic reduction in circulating IGF1 altering systemic metabolism, due to loss of the insulin-like effects of IGF1 and the loss of IGF1 negative feedback to the pituitary leading to a rise in GH that promotes systemic insulin resistance and WAT lipolysis shifting the flux of fatty acids to the liver. In addition, low IGF1/high GH alters the development of other metabolically relevant tissues, which could indirectly contribute to the liver phenotype observed with congenital loss of hepatic GH signaling. To directly test the actions of GH on adult hepatocyte function, we developed a mouse model of adult-onset, hepatocyte-specific knockdown of the GHR (aHepGHRkd; 12 week-old, GHRfl/fl mice treated with AAV8-TBGp-Cre). aHepGHRkd enhanced hepatic de novo lipogenesis (DNL), rapidly leading to steatosis in males, but not females. In males, enhanced DNL and steatosis was sustained with age and associated with hepatocyte ballooning, inflammation and mild fibrosis. These changes occurred independent of severe systemic insulin resistance and WAT lipolysis, although the aHepGHRkd mice exhibit low IGF1/high GH similar to that of congenital models. To directly test the role of hepatocyte GHR signaling, independent of changes in IGF1, aHepGHRkd mice were treated with a vector expressing rat IGF1 targeted specifically to hepatocytes (AAV8-TBGp-rIGF1). Mice were fed standard chow diet and tissues collected 8m post-AAV. IGF1 replacement elevated plasma IGF1 in aHepGHRkd mice, resulting in a reduction in plasma GH and pituitary expression of Gh, Ghrhr and Ghsr, indicating negative feedback of IGF1 was restored. In male aHepGHRkd mice, IGF1 replacement reduced insulin and whole body lipid utilization and increased WAT, however it did not reduce steatosis or alter hepatic fatty acid composition indicative of DNL and had minimal effects on liver injury markers. RNAseq analysis of liver extracts showed IGF1 replacement also had no major impact on the differentially expressed genes observed after aHepGHRkd. These results demonstrate that steatosis, DNL and liver injury observed in male aHepGHRkd mice are autonomous of IGF1. Despite the fact that hepatic GHR protein levels were not detectable in both female and male aHepGHRkd mice, females maintained moderate levels of IGF1 and were protected from steatosis. The mechanism by which female mice are protected remains to be elucidated, however is consistent with clinical data indicating pre-menopausal women are resistance to NAFLD.

scholarly journals Ipragliflozin Additively Ameliorates Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Controlled with Metformin and Pioglitazone: A 24-Week Randomized Controlled Trial

2020 ◽  
Vol 9 (1) ◽  
pp. 259 ◽  
Author(s):  
Eugene Han ◽  
Yong-ho Lee ◽  
Byung-Wan Lee ◽  
Eun Seok Kang ◽  
Bong-Soo Cha
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Liver ◽  
Visceral Fat ◽  
Controlled Trial ◽  
Subcutaneous Fat ◽  
Liver Fat ◽  
Whole Body ◽  
Alcoholic Fatty Liver ◽  
Fatty Liver Index

Despite the benefits of pioglitazone in the treatment of non-alcoholic fatty liver disease (NAFLD), many treated patients continue to experience disease progression. We aimed to investigate the additive effect of ipragliflozin on NAFLD in patients with type 2 diabetes treated with metformin and pioglitazone. In this 24-week randomized controlled trial, 44 patients with type 2 diabetes and comorbid NAFLD were either randomized to receive 50 mg/day of ipragliflozin as an add-on treatment (n = 29) or maintained on metformin and pioglitazone (n = 15). The fatty burden was assessed using the fatty liver index, NAFLD liver fat score, and controlled attenuation parameter (CAP). Changes in fat and muscle depots were measured by dual-energy x-ray absorptiometry and abdominal computed tomography scans. The enrolled patients were relatively controlled (mean baseline glycated hemoglobin of 6.6% ± 0.6%) and centrally obese (mean waist circumference of 101.6 ± 10.9 cm). At week 24, patients in the ipragliflozin add-on group exhibited reduced hepatic fat content (fatty liver index: −9.8 ± 1.9, p = 0.002; NAFLD liver fat score: −0.5 ± 0.2, p = 0.049; CAP: −8.2 ± 7.8 dB/m2, p = 0.133). Ipragliflozin add-on therapy also reduced whole-body visceral fat and the ratio of visceral to subcutaneous fat (change in whole-body visceral fat: −69.6 ± 21.5 g; change in abdominal visceral fat: −26.2 ± 3.7 cm2; abdominal visceral to subcutaneous fat ratio: −0.15 ± 0.04; all p < 0.05). In conclusion, ipragliflozin treatment significantly ameliorates liver steatosis and reduces excessive fat in euglycemic patients with type 2 diabetes and NAFLD taking metformin and pioglitazone.

Genistein supplementation improves insulin resistance and inflammatory state in non-alcoholic fatty liver patients: A randomized, controlled trial

2018 ◽  
Vol 37 (4) ◽  
pp. 1210-1215 ◽  
Author(s):  
Sasan Amanat ◽  
Mohammad Hassan Eftekhari ◽  
Mohammad Fararouei ◽  
Kamran Bagheri Lankarani ◽  
Seyed Jalil Massoumi
Keyword(s):  
Insulin Resistance ◽  
Randomized Controlled Trial ◽  
Fatty Liver ◽  
Controlled Trial ◽  
Alcoholic Fatty Liver ◽  
Randomized Controlled ◽  
Inflammatory State

Therapeutic Effect of Metformin and Vitamin E Versus Prescriptive Diet in Obese Adolescents with Fatty Liver

2011 ◽  
Vol 81 (6) ◽  
pp. 398-406 ◽  
Author(s):  
Akcam ◽  
Boyaci ◽  
Pirgon ◽  
Kaya ◽  
Uysal ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Vitamin E ◽  
Fatty Liver ◽  
Liver Steatosis ◽  
Tnf Alpha ◽  
Dietary Advice ◽  
Model Assessment ◽  
Fasting Insulin ◽  
Alcoholic Fatty Liver ◽  
Obese Adolescents

Objective: The aim of the study was to determine whether metformin or vitamin E treatment for six months is effective in reducing body weight, blood pressure, and also ameliorating insulin resistance, adiponectin, and tumor necrosis factor (TNF)-alpha in obese adolescents with non-alcoholic fatty liver disease (NAFLD). Methods: Sixty-seven obese adolescents with liver steatosis (age range, 9 - 17 years) were included in the study. The metformin group received an 850-mg dose of metformin daily and the vitamin E group received 400 U vitamin E /daily, in capsule form for 6 months, plus an individually tailored diet, exercise, and behavioral therapy. Results: After 6 months later, there was a significant decline in body mass index, and fasting insulin and homeostatic model assessment (HOMA) values in all three groups. Moreover, in comparingson of changes in HOMA among the groups, the metformin- treated group showed significantly improved metabolic control and insulin sensitivity (HOMA) at the end of the study. There were no significant differences for changes of adiponectin, TNF-alpha, in all three groups after 6 months study. Conclusion: These data suggest that metformin treatment is more effective than dietary advice and vitamin E treatment in reducing insulin resistance, and also in ameliorating metabolic parameters such as fasting insulin and lipid levels, in obese adolescents having NAFLD.

Non-Alcoholic Fatty Liver Disease in Overweight Children and its Relationship with Retinol Serum Levels

2008 ◽  
Vol 78 (1) ◽  
pp. 27-32 ◽  
Author(s):  
Suano de Souza ◽  
Silverio Amancio ◽  
Saccardo Sarni ◽  
Sacchi Pitta ◽  
Fernandes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Lipid Profile ◽  
Fatty Liver Disease ◽  
Thiobarbituric Acid ◽  
Serum Levels ◽  
Control Group ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Objectives: To evaluate the frequency of non-alcoholic fatty liver disease, the retinol serum levels, lipid profile, and insulin resistance in overweight/obese children. To relate these biochemical variables with the risk of this disease in the population studied. Methods: The study was cross-sectional and prospective, with 46 overweight/obese school children (28 female, 18 male; mean age 8.6 years). The control group consisted of 45 children, paired by age and gender. Hepatic steatosis, evaluated by ultrasound, was classified as normal, mild, moderate, or severe. Also evaluated were serum retinol levels; thiobarbituric acid reactive substances; lipid profile; and fasting glucose and serum insulin levels, used for the calculation of the Homeostasis Model Assessment. Results: Hepatic ultrasound alterations were found in 56.5% and 48,9% of the overweight/obese and control group children, respectively. Presence of obesity was associated with high levels of triglycerides (OR = 4.6; P = 0.002). In the studied children, the risk of steatosis was related to a trend to a higher percentage of retinol inadequacy (OR = 2.8; p = 0.051); there was no association with thiobarbituric acid reactive substances, lipid profile, or insulin resistance. Conclusions: The high frequency of non-alcoholic fatty liver disease in both groups, evaluated by hepatic ultrasound, in low-socioeconomic level children, independent of nutritional condition and without significant association with insulin resistance, emphasizes that especially in developing countries, other risk factors such as micronutrient deficiencies (e.g. vitamin A) are involved.

Non-alcoholic fatty liver disease and its association with insulin resistance in an obese population

2018 ◽  
Author(s):  
Frederique Van de Velde ◽  
Marlies Bekaert ◽  
Anne Hoorens ◽  
Marleen Praet ◽  
Arsene-Helene Batens ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Obese Population ◽  
Alcoholic Fatty Liver Disease

Resveratrol Supplementation in Patients with Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-analysis

2017 ◽  
Vol 26 (1) ◽  
pp. 59-67 ◽  
Author(s):  
Ahmed Elgebaly ◽  
Ibrahim A. I. Radwan ◽  
Mohamed M. AboElnas ◽  
Hamza H. Ibrahim ◽  
Moutaz F. M. Eltoomy ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Randomized Clinical Trials ◽  
Controlled Trial ◽  
Antioxidant Properties ◽  
Density Lipoprotein ◽  
Current Evidence ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Background: Resveratrol is a potential treatment option for management of non-alcoholic fatty liver disease (NAFLD) due to its anti-inflammatory, antioxidant properties, and calorie restriction-like effects. We aimed to synthesise evidence from published randomized clinical trials (RCTs) about the efficacy of resveratrol in the management of NAFLD.Methods: A computer literature search of PubMed, Scopus, Web of Science, and Cochrane Central was conducted using relevant keywords. Records were screened for eligible studies and data were extracted and synthesized using Review Manager Version 5.3 for windows. Subgroup analysis and sensitivity analysis were conducted.Results: Four RCTs (n=158 patients) were included in the final analysis. The overall effect estimates did not favor resveratrol group in terms of: serum ALT (MD -2.89, 95%CI [-15.66, 9.88], p=0.66), serum AST (MD -3.59, 95%CI [-13.82, 6.63], p=0.49), weight (MD -0.18, 95%CI [-0.92, 0.55], p=0.63), BMI (MD -0.10, 95 %CI [-0.43, 0.24], p=0.57), blood glucose level (MD -0.27, 95%CI [-0.55, 0.01], p=0.05), insulin level (MD -0.12, 95%CI [-0.69, 0.46], p=0.69), triglyceride level (MD 0.04, 95%CI [-0.45, 0.53], p=0.87), and LDL level (MD 0.21, 95%CI [-0.41, 0.83], p=0.51). Pooled studies were heterogeneous.Conclusion: Current evidence is insufficient to support the efficacy of resveratrol in the management of NAFLD. Resveratrol does not attenuate the degree of liver fibrosis or show a significant decrease in any of its parameters.Abbreviations: ALT: Alanine aminotransferase; AMPK: AMP-activated protein kinase; AST: Aspartate aminotransferase; BMI: Body mass index; CK-18: Cytokeratin-18; CRP: C-reactive protein; HC: Head circumference; HDL: High density lipoprotein; IL-6: Interleukin-6; LDL: Low density lipoprotein; MD: Mean difference; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; RCT: Randomized Controlled Trial; RR: Relative risk; SIRT1: Silent information regulation 2 homologue 1; TNF-α: Tumor necrosis factor α; WC: Waist circumference; WHR: Waist hip ratio.

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