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The aberrant changes of fussion/fission-related proteins can trigger mitochondrial dynamics imbalance, which cause mitochondrial dysfunctions and result insulin resistance (IR). However, the relationship between the inner mitochondrial membrane fusion protein optic atrophy 1 (Opa1) and hepatic IR as well as the specific molecular mechanisms of signal transduction has not been fully elucidated. In this study, we explore whether abnormalities in the Opa1 cause hepatic IR and whether berberine (BBR) can prevent hepatic IR through the SIRT1/Opa1 signalling pathway. High-fat diet (HFD)-fed mice and db/db mice are used as animal models to study hepatic IR in vivo. IR, morphological changes, and mitochondrial injury of the liver are examined to explore the effects of BBR. SIRT1/Opa1 protein expression is determined to confirm whether the signalling pathway is damaged in the model animals and is involved in BBR treatment-mediated mitigation of hepatic IR. A palmitate (PA)-induced hepatocyte IR model is established in HepG2 cells in vitro. Opa1 silencing and SIRT1 overexpression are induced to verify whether Opa1 deficiency causes hepatocyte IR and whether SIRT1 improves this dysfunction. BBR treatment and SIRT1 silencing are employed to confirm that BBR can prevent hepatic IR by activating the SIRT1/Opa1 signalling pathway. Western blot analysis and JC-1 fluorescent staining results show that Opa1 deficiency causes an imbalance in mitochondrial fusion/fission and impairs insulin signalling in HepG2 cells. SIRT1 and BBR overexpression ameliorates PA-induced IR, increases Opa1, and improves mitochondrial function. SIRT1 silencing partly reverses the effects of BBR on HepG2 cells. SIRT1 and Opa1 expressions are downregulated in the animal models. BBR attenuates hepatic IR and enhances SIRT1/Opa1 signalling in db/db mice. In summary, Opa1 silencing-mediated mitochondrial fusion/fission imbalance could lead to hepatocyte IR. BBR may improve hepatic IR by regulating the SIRT1/Opa1 signalling pathway, and thus, it may be used to treat type-2 diabetes.