leky-latky/berberine/vlivy-ucinky
BBR affects IR by increasing insulin secretion and insulin receptor (InsR) expression via protein kinase C (PKC) activation, inducing glucose transporter (GLUT4) translocation to the cell membrane and lowering ER stress. The alleviation of IR by increasing message ribonucleic acid (mRNA) expression is one of the solutions in treating NAFLD with BBR [8]. BBR can improve patients’ insulin sensitivity through the PPAR-? pathway and enhance tyrosine phosphorylation [9]. Adiponectin—adipokine secreted by adipocytes—increases insulin sensitivity through AMP-activated protein kinase (AMPK) [60]. BBR may improve IR by increasing the expression of adiponectin receptors. BBR increases insulin sensitivity due to its ability to upregulate InsR expression in a dose- and time-dependent manner, which promotes cellular glucose uptake in the presence of insulin [19]. BBR was reported to decrease fasting blood glucose (FBG), hemoglobin A1c (HbA1C), and insulin levels in T2D individuals at levels similar to metformin and rosiglitazone BBR, thanks to its properties, might be proposed as an anti-diabetes agent. BBR may exert a beneficial effect on NAFLD by remodeling glucose metabolism. BBR increases the amount of GLUT4, which can accelerate glucose ingestion and, consequently, reduce glucose concentration in the blood. Additionally, BBR inhibits intestinal glucose absorption, which is linked to the BBR glucose-lowering property. BBR substantially decreased FBG, HbA1C, TG, and insulin levels in individuals with T2D in the clinical study [24]. In the liver, IR manifests itself by excessive glucose production (gluconeogenesis) in the fasting state and impaired glucose uptake after a meal, despite the presence of insulin. IR exhibits lowered glucose uptake in muscles, leading to postprandial hyperglycemia [37]. Some evidence suggests that BBR combined with metformin effectively treats patients with NAFLD and T2D [50,52,60]. For instance, BBR could accelerate insulin secretion, ameliorate IR, inhibit gluconeogenesis, and promote glucose uptake [60]. Furthermore, through AMPK activation, BBR can stimulate glucose uptake in muscles, liver, and adipose and inhibit gluconeogenesis in the liver by downregulation of gluconeogenic enzymes [37]. The hypoglycemic effect of BBR encompasses the regulation of GM, activating the AMPK pathway, inducing intestinal glucagon-like protein-1 secretion, promoting glycolysis in peripheral tissue cells, and enhancing hepatic low-density lipoprotein receptor (LDLR) mRNA expression [38]. 2.5. Berberine vs. MetforminMetformin and BBR have many similar features, regardless of different structures. Both might be excellent drugs for the treatment of T2D, obesity, cardiac diseases, tumor, and inflammation [37]. Metformin lowers macrovascular complications in T2D patients [37]. It inhibits liver glucose production and promotes glucose uptake in muscle and adipose, improving hyperglycemia and hyperlipidemia and alleviating NAFLD. The primary target of metformin is the 5'-AMP-activated protein kinase (AMPK), but some effects seem to be mediated through mechanisms independent from AMPK [37]. In cases of intolerance or refractory to metformin, BBR appears to be a suitable alternative or additive agent to ensure tolerance and lower the risk of adverse effects [37]. Some studies underlie that metformin combined with BBR might be a beneficial therapeutic option [50,52,61]. Studies have reported that the synergistic action of BBR and metformin is due to similar anti-diabetic mechanisms, despite different transporters and metabolism. Combining these two drugs might reduce the dosage of the particular drug to overcome problems such as the oral bioavailability of BBR and adverse effects. BBR presents a high hypoglycemic potential; it has been proven to activate AMPK with subsequent glycolysis induction [23]. BBR is an effective insulin sensitizer with properties comparable to metformin [38]. 2.6. Lipid Lowering Effects of BBRIndividuals with NAFLD present a proatherogenic lipid profile with elevated levels of TG and LDL, accompanied by low HDL concentration. The positive effect of BBR on NAFLD encompasses a direct regulation of lipid metabolism in the liver [58]. Recent studies have demonstrated the impact of BBR on lipid level. BBR exerted an antihyperlipidemic effect by lowering patients’ total cholesterol (TC), TG, and LDL levels. BBR has been reported to reduce oxLDL. The cholesterol-lowering mechanism of BBR was different from that of statins. BBR heightened the LDLR and blocking proprotein convertase subtilisin/kexin type 9 (PCSK9) transcription. PCSK9 modulates lipid homeostasis via degradation of LDLR and lowering LDL [9,23,24,37]. BBR metabolite also promotes the reduction of TG levels. It can aid the excretion of cholesterol from the liver to bile and, as a result, blood lipid can be decreased. Moreover, BBR lowers blood cholesterol levels by minimizing intestinal absorption, cholesterol uptake, and secretion in enterocytes [37]. It regulates the hepatic lipid metabolism by reducing lipid synthesis and induction of fatty acid ß-oxidation, which probably occurs through AMPK activation. BBR played a pivotal role in decreasing liver fat content [24]. According to a meta-analysis including 2569 participants, BBR reduced TG, TC, and LDL concentrations and increased HDL levels [39]. The lipid-lowering effects of BBR seem to be more favorable than the conventional lipid-lowering medicines due to their low toxicity [38,61]. Additionally, their pairing with drugs, such as statins, could improve hyperlipidemic individuals’ therapeutic efficacy and life quality. Numerous randomized clinical trials have demonstrated its lipid-lowering and IR-alleviating actions [23]. The BBR safety profile and the beneficial outcomes from combined therapy confirm its application in individuals with hyperlipidemia and those who do not meet therapeutic goals or do not tolerate statins [8,19]. 2.7. Cardiovascular Complications in NAFLD Preventive Role of BBRBBR is a hypotensive and cardioprotective compound that reduces blood pressure and restores endothelial homeostasis [19]. Clinical research has reported the beneficial effects of BBR in endothelial dysfunction via regulating reactive oxygen species (ROS)/NO balance [8]. BBR promoted endothelium-dependent relaxation mediated by increasing endothelial NO release [19]. BBR application also exhibited protective effects against oxLDL-caused endothelial damage [8]. Clinical evidence suggests that BBR’s capability to reduce endothelial inflammation improves vascular health in individuals affected by CVD. The available evidence indicates a possible use of BBR in managing chronic cardiometabolic disorders [23]. Meta-analysis proved that lifestyle intervention combined with BBR lowers blood pressure more effectively than lifestyle intervention or placebo alone [39]. BBR combined with the oral antihypertensive drug also reduced blood pressure to a greater extent than the same antihypertensive drug [39]. BBR may also function as a calcium channel blocker to lower high blood pressure and increase vascular elasticity [19]. The CV effects of BBR seem to be mediated through the AMPK [19]. BBR inhibits the intracellular accumulation of ROS, cellular apoptosis, and inflammation that contribute to vascular damage, which confirms the vasoprotective actions of BBR [19]. 2.8. BBR Affects Gut MicrobiotaThe regulation of GM is another relevant target of BBR. The rise of gut Akkermansia may be associated with the cardiometabolic protective effects of BBR [60]. BBR affects GM, decreases fat absorption, and reduces inflammation by reducing exogenous antigens and enhancing SCFAs in the gut. It regulates gut barrier integrity. BBR reverts damaged tight junctions in the intestinal epithelium, thereby repairing permeability. There is a need to uncover an exact immunological mechanism for better understanding. BBR modulates hepatic lipid metabolism by direct GM modulation. BBR could trigger the secretion of GM-derived active metabolites such as butyrate. Promoting butyrate production in GM appears to be an essential mechanism of BBR in the regulatory process of energy metabolism. BBR clinically lowers glucose concentration via complex mechanisms. One of the possible paths is its effect on the SCFAs of the GM [62,63]. BBR modulated serum levels of the gut hormones associated with glucose regulation and energy homeostasis, likely interfering with the GM’s composition [64]. BBR exerts its lipid-lowering effect through modulation of the gut microbiome and attenuation of hepatic steatosis [6,8]. 2.9. Hepatic Markers ImprovementAbnormalities in laboratory tests often might be a sign of NAFLD. The most common test results are elevated alanine transaminase (ALT) and aspartate transaminase (AST). The ratio of AST/ALT is usually less than one but may increase as the severity of the liver damage increases. BBR exerts positive effects on NAFLD-associated parameters [12]. BBR has been reported to suppress NAFLD as it lowers ALT and AST levels in T2D patients [37]. Clinical findings have shown that the effects of BBR are associated with the improvement of levels of indirect markers of hepatosteatosis (Hepatic steatosis Index, Lipid Accumulation Product) [12].
