Bicyclol Regulates Hepatic Gluconeogenesis in Rats with Type 2 Diabetes and Non-alcoholic Fatty Liver Disease by Inhibiting Inflammation

Abstract

Hepatic gluconeogenesis plays an important role in maintaining the body’s glucose metabolism homeostasis. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases, when combined with type 2 diabetes mellitus (T2DM), it can cause severe glucose metabolism disorders. Studies have confirmed that chronic liver inflammatory lesions are the basis of T2DM combined with NAFLD (T2DM–NAFLD), inhibiting liver inflammation can improve glucose metabolism disorders. It is essential to explore safe and effective drugs to inhibit liver inflammation to improve the body’s glucose metabolism disorders. Bicyclol is a biphenyl derivative that has anti-oxidative and anti-inflammatory properties. In the present study, the hepatoprotective effects and underlying mechanisms of bicyclol in T2DM–NAFLD were investigated, and T2DM–NAFLD with/without bicyclol treatment models were established. The results revealed that bicyclol alleviated fasting blood glucose, serum transaminase levels, insulin resistance, hepatic adipogenesis, lipid accumulation and markedly reduced T2DM–NAFLD rat histological alterations of livers. Not only that, bicyclol markedly attenuated T2DM–NAFLD induced production of inflammation factors (IL-1β and TNF-α). Moreover, bicyclol suppressed the expression of insulin/gluconeogenesis signaling pathway (Akt, PGC-1α and PEPCK). These findings suggested that bicyclol might be a potentially effective drug for the treatment of T2DM–NAFLD and other metabolic disorders.

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

“…The beneficial effects of bicyclol on inflammatory and metabolic diseases have been well documented (Li H et al, 2021). The preclinical reports and clinical studies have demonstrated that bicyclol is a potential agent for NAFLD/NASH treatment (Li et al, 2020;.…”

“…A systematic meta-analysis presented the evidence of bicyclol treatment for improving liver function and serum lipid biomarkers in patients with NAFLD, predicting that bicyclol might be an alternative agent for NAFLD (Li et al, 2020). The quality of evidence suggested that bicyclol administration significantly attenuated high-fat diet (HFD)-induced activation of inflammatory-mediated signaling pathway (MAPKs/NF-κB) and gluconeogenesis/insulin signaling pathway (Akt, PGC-1α and PEPCK) (Li H et al, 2021;Zhao W et al, 2021). Pharmacological studies displayed that bicyclol had obvious protective effects against hepatocyte injury caused by tetracycline, alcoholic and non-alcoholic fatty liver associated with cell apoptosis, endoplasmic reticulum (ER), and oxidative stress (Yao et al, 2016;Jia et al, 2022).…”

Experimental model and novel therapeutic targets for non-alcoholic fatty liver disease development

“…Activation of pyruvate to phosphoenolpyruvate is the first step for phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphate (G6Pase)-mediated gluconeogenesis [ 85 ]. Excessive release of glucose via gluconeogenesis enhances IR-mediated inflammation, steatosis, and de novo lipogenesis in patients with NAFLD [ 86 ]. PGC-1α-activated PEPCK expression induced by HFD-mediated inflammation is suppressed by bicyclol, an approved drug for targeting hepatitis, liver fibrosis, and liver injury [ 86 ].…”

“…Excessive release of glucose via gluconeogenesis enhances IR-mediated inflammation, steatosis, and de novo lipogenesis in patients with NAFLD [ 86 ]. PGC-1α-activated PEPCK expression induced by HFD-mediated inflammation is suppressed by bicyclol, an approved drug for targeting hepatitis, liver fibrosis, and liver injury [ 86 ]. Inactivation of the AMPK-mediated SIRT–PGC1 axis is involved in HFD-fed NASH progression [ 83 ].…”

Expression of TNF-α and IL-1β in Peripheral Blood of Patients with T2DM Retinopathy

“…This shows that the two factors play complementary roles in the inflammatory loop of T2DM homoeopathy and together promote the formation of ocular surface inflammation [ 8 ]. TNF- α and IL-1 β are two factors with inflammatory significance in the P38MAPK and PI3K/Akt signaling pathway in T2DM patients with induced T2DM homoeopathy, which can reflect the inflammatory state of the ocular surface [ 9 ]. Our study analyzed the expression of TNF- α and IL-1 β in the peripheral blood of patients with T2DM homoeopathy, aiming to provide more references for the clinical treatment of patients.…”