Berberine Improves Glucose Metabolism in Diabetic Rats by Inhibition of Hepatic Gluconeogenesis

University of Hong Kong, China
PLoS ONE (Impact Factor: 3.23). 02/2011; 6(2):e16556. DOI: 10.1371/journal.pone.0016556
Source: PubMed


Berberine (BBR) is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French). It improves glucose metabolism in type 2 diabetic patients. The mechanisms involve in activation of adenosine monophosphate activated protein kinase (AMPK) and improvement of insulin sensitivity. However, it is not clear if BBR reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to BBR in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that BBR decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase), were decreased in liver by BBR. Hepatic steatosis was also reduced by BBR and expression of fatty acid synthase (FAS) was inhibited in liver. Activities of transcription factors including Forkhead transcription factor O1 (FoxO1), sterol regulatory element-binding protein 1c (SREBP1) and carbohydrate responsive element-binding protein (ChREBP) were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, BBR inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP) level. The data suggest that BBR improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that BBR improves glucose metabolism through an insulin-independent pathway.

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    • "However, the treatment of diabetic patients for diarrhea with these plants (and through them, with their main active compound, BBR) leads to the finding of its hypoglycemic properties. These effects have been extensively explored and investigated in several studies, which demonstrated that BBR is capable of not only improving glycemia in vivo and in vitro (Kim et al., 2007; Leng et al., 2004; Lu et al., 2009; Xia et al., 2011), but also increasing insulin expression, β-cell regeneration, antioxidant enzyme activity, glucose uptake, while decreasing lipid peroxidation (Wang et al., 2009a; Zhang et al., 2008; Zhou et al., 2009) and cholesterol and triglyceride synthesis (Brusq et al., 2006). All these effects appear to be insulin independent, relying instead in an increase in the AMP/ATP ratio, thus increasing AMPK activity (Cheng et al., 2006; Xia et al., 2011; Zhou et al., 2007). "
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    ABSTRACT: Berberine is an isoquinoline alkaloid with anti-diabetic properties. Despite the central role of liver and thus hepatic mitochondria in whole-body metabolism, berberine effects on hepatic mitochondrial function in an obesity model are still unknown. Here, we demonstrate that berberine treatment recovers mitochondrial efficiency when altered by a high-fat feeding. Mitochondria isolated from the liver of high-fat fed rats exhibited decreased capacity to accumulate calcium and impaired oxidative phosphorylation (OXPHOs) capacity, as shown by impaired mitochondrial membrane potential, oxygen consumption and cellular ATP levels. Interestingly, the recovery of mitochondrial function by berberine was associated with an increased activity of the mitochondrial sirtuin 3 (SirT3). In conclusion, berberine potent protective effects against metabolic syndrome may rely on increasing mitochondrial SirT3 activity, normalizing mitochondrial function and preventing a state of energetic deficit caused by impaired OXPHOs.
    Mitochondrion 09/2013; 13(6). DOI:10.1016/j.mito.2013.09.002 · 3.25 Impact Factor
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    • "Additionally, glucose transporter (GLUT4) is a rate-limiting factor for glucose uptake in skeletal muscle, and Akt (protein kinase B) is a central mediator of insulin-induced GLUT4 translocation from cytosol to membrane [6]. These protein expressions have been shown to be associated with the pathogenesis in streptozotocin (STZ)-induced diabetic rats [7-9]. "
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    ABSTRACT: Background It has been suggested that Sorghum, a rich source of phytochemicals, has a hypoglycemic effect, but the mechanism is unknown. We investigated the effects of oral administration of sorghum extract (SE) on hepatic gluconeogenesis and the glucose uptake of muscle in streptozotocin-induced diabetic rats for six weeks. Methods Male Wistar rats were divided in five groups (n=5 per group): normal control (NC), rats with STZ-induced diabetic mellitus (DM), diabetic rats administrated 0.4 g/kg body weight of SE (DM-SE 0.4) and 0.6 g/kg body weight of SE (DM-SE 0.6), and diabetic rats administrated 0.7 mg/kg body weight of glibenclamide (DM-G). Results Administration of SE and G reduced the concentration of triglycerides, total and LDL-cholesterol and glucose, and the area under the curve of glucose during intraperitoneal glucose tolerance tests down to the levels observed in non-diabetic rats. In addition, administration of 0.4 and 0.6 g/kg SE and 0.7 mg/kg glibenclamide (G) significantly reduced the expression of phosphoenolpyruvate carboxykinase and the phosphor-p38/p38 ratio, while increased phosphor adenosine monophosphate activated protein kinase (AMPK)/AMPK ratio, but the glucose transporter 4 translocation and the phosphor-Akt/Akt ratio was significantly increased only by administration of G. Conclusions These results indicate that the hypoglycemic effect of SE was related to hepatic gluconeogenesis but not the glucose uptake of skeletal muscle, and the effect was similar to that of anti-diabetic medication.
    Nutrition & Metabolism 11/2012; 9(1):106. DOI:10.1186/1743-7075-9-106 · 3.26 Impact Factor
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    • "For example, berberine’s immunoregulatory potential has been demonstrated by inhibiting HIV protease inhibitor-induced TNF and IL-6 production in macrophages [2], enhancing progression of type 1 diabetes in mice, and decreasing Th17 and Th1 cell differentiation and cytokine production [3]. Other effects of berberine on diseases include reducing cholesterol levels in humans and hamsters by elevating LDL receptor expression [4], inhibiting hepatic gluconeogenesis to improve glucose metabolism in diabetic rats [5], and reducing the permeability of the blood-brain barrier and attenuating autoimmune encephalomyelitis in mice [6]. "
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    ABSTRACT: Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the mouse immorto-Min colonic epithelial (IMCE) cells carrying the Apc(min) mutation, and of normal colon epithelial cells, namely young adult mouse colonic epithelium (YAMC) cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF) release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth.
    PLoS ONE 05/2012; 7(5):e36418. DOI:10.1371/journal.pone.0036418 · 3.23 Impact Factor
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