Lingguizhugan Decoction, a Chinese herbal formula, improves insulin resistance in overweight/obese subjects with non-alcoholic fatty liver disease: a translational approach

Abstract

Lingguizhugan Decoction (LGZG) has been investigated in basic studies, with satisfactory effects on insulin resistance in non-alcoholic fatty liver disease (NAFLD). This translational approach aimed to explore the effect and underlying mechanism of LGZG in clinical setting. A randomized, double-blinded, placebo-controlled trial was performed. A total of 243 eligible participants with NAFLD were equally allocated to receive LGZG (two groups: standard dose and low dose) or placebo for 12 weeks on the basis of lifestyle modifications. The primary efficacy variable was homeostasis model assessment of insulin resistance (HOMA-IR). Analyses were performed in two populations in accordance with body mass index (BMI; overweight/obese, BMI ≥ 24 kg/m²; lean, BMI < 24 kg/m ²). For overweight/obese participants, low-dose LGZG significantly decreased their HOMA-IR level compared with placebo (−0.19 (1.47) versus 0.08 (1.99),P = 0.038). For lean subjects, neither dose of LGZG showed a superior effect compared with placebo. Methylated DNA immunoprecipitation sequencing and real-time qPCR found that the DNA N6-methyladenine modification levels of protein phosphatase 1 regulatory subunit 3A (PPP1R3A) and autophagy related 3 (ATG3) significantly increased after LGZG intervention in overweight/obese population. Low-dose LGZG effectively improved insulin resistance in overweight/obese subjects with NAFLD. The underlying mechanism may be related to the regulation of DNA N6-methyladenine modification of PPP1R3A and ATG3. Lean subjects may not be a targeted population for LGZG.

Keywords

insulin resistance / non-alcoholic fatty liver disease / Chinese herbal medicine / randomized controlled trial / DNA N6-methyladenine modification

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Acknowledgements

This study is supported by the National Natural Science Foundation of China (No. 816220108030), the Evidence-based Capacity Building Project for Basic Traditional Chinese Medicine-Specialized Diseases (No. 2019XZZX-XH012), and Shanghai Three-year Action Plan for Accelerating the Development of Traditional Chinese Medicine (ZY(2018-2020)-CCCX-2002-01).

Compliance with ethics guidelines

Liang Dai, Jingjuan Xu, Baocheng Liu, Yanqi Dang, Ruirui Wang, Lijie Zhuang, Dong Li, Lulu Jiao, Jianying Wang, Lei Zhang, Linda L.D. Zhong, Wenjun Zhou, and Guang Ji declare that they have no conflict of interest. The study protocol was approved by the Medical Ethics Committee of Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (No. 2017LCSY069) and registered at the Chinese Clinical Trial Registry (No. ChiCTR1800014364) on January 8, 2018. All three health centers acknowledged the ethical approval from the Medical Ethics Committee of Longhua Hospital. This trial was conducted strictly following the Helsinki Declaration. All participants provided a written inform consent before entering the study.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-021-0880-3 and is accessible for authorized users.

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