Abstract
The combination of plant-derived compounds with anti-diabetic agents to manage hepatic steatosis closely associated with diabetes mellitus may be a new therapeutic approach. Silymarin, a complex of bioactive substances extracted from Silybum marianum, evinces an antioxidative, anti-inflammatory, and hepatoprotective activity. In this study, we investigated whether metformin (300 mg/kg/day for four weeks) supplemented with micronized silymarin (600 mg/kg/day) would be effective in mitigating fatty liver disturbances in a pre-diabetic model with dyslipidemia. Compared with metformin monotherapy, the metformin–silymarin combination reduced the content of neutral lipids (TAGs) and lipotoxic intermediates (DAGs). Hepatic gene expression of enzymes and transcription factors involved in lipogenesis (Scd-1, Srebp1, Pparγ, and Nr1h) and fatty acid oxidation (Pparα) were positively affected, with hepatic lipid accumulation reducing as a result. Combination therapy also positively influenced arachidonic acid metabolism, including its metabolites (14,15-EET and 20-HETE), mitigating inflammation and oxidative stress. Changes in the gene expression of cytochrome P450 enzymes, particularly Cyp4A, can improve hepatic lipid metabolism and moderate inflammation. All these effects play a significant role in ameliorating insulin resistance, a principal background of liver steatosis closely linked to T2DM. The additive effect of silymarin in metformin therapy can mitigate fatty liver development in the pre-diabetic state and before the onset of diabetes.
Highlights
Type 2 diabetes (T2DM) and liver steatosis are closely related diseases
The control group (HHTg/C, n = 8) was fed a standard diet (Altromin, Maintenance diet for rats and mice, Lage, Germany), the metformin-treated group (HHTg/MET) was fed a standard diet supplemented with metformin (Teva Pharmaceuticals, Brno, Czech Republic) at a dose of 300 mg/kg of body weight per day, and the combination therapy-treated group (HHTg/MET+SM) was fed a standard diet supplemented with a mix of MET and micronized SM with a declared purity of 80%
While most studies of inflammatory markers focus on circulation in the bloodstream or cell cultures, our study examines the concentrations of pro-inflammatory markers in hepatic tissue
Summary
Type 2 diabetes (T2DM) and liver steatosis are closely related diseases. T2DM, a complex disorder primarily affecting glycaemic status, is characterised by insulin resistance and insulin secretory deficiency. The condition develops during pre-diabetes, which is characterised by impaired fasting glucose and glucose tolerance [1]. Pre-diabetes is connected with overweight and impaired insulin resistance and liver lipid storage, and it is considered a high-risk state for progression to T2DM. There is a strong connection between T2DM and non-alcoholic fatty liver disease (NAFLD). Liver steatosis may precede the development of T2DM and even hyperglycaemia. NAFLD is not a consequence and a causal factor in the pathophysiology of these complications [2] and, as such, a strong independent risk factor for pre-diabetes [3]. Because of difficulties with NAFLD quantification, these figures are most likely underestimated
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