Effect Of Berberine On Insulin Resistance And Its Mechanisms In Skeletal Muscle

According to the World Health Organization (WHO), and to the American Diabetes Association, the incidence of type 2 diabetes is rising worldwide without indications of abatement. A hallmark feature of type 2 diabetes is skeletal muscle insulin resistance. Skeletal muscle is the largest tissue in the human body by mass and is the primary site of insulin-stimulated glucose disposal. The component of skeletal muscle physiology remains largely unperturbed in type 2 diabetes, suggesting the existence of signaling pathways for glucose uptake that circumvent elements of the insulin signaling pathway defective with type 2 diabetes. Moreover, previous studies have shown that in vivo levels of insulin sensitivity and glycogen synthesis activity are maintained in skeletal muscle cells grown in vitro. Although the molecular mechanisms of insulin-dependent glucose up-take in skeletal muscle have been extensively investigated, there are no reports of the molecular mechanisms underlying glucocorticoid hormone action in this tissue.Altered glucocorticoid hormone action may contribute to the etiology of the metabolic syndrome, but the molecular mechanisms are poorly defined. Tissue sensitivity to glucocorticoid is regulated by expression of the glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase typeⅠ(11β-HSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed GR and 11β-HSD1 expression in skeletal muscle from Wistar rats (n=24) with contrasting levels of insulin sensitivity (FINS), fasting blood glucose (FBG) and impaired glucose tolerance test (IGTT).Natural products have been a rich resource for the development of novel therapeutics used to treat a variety of human diseases. We have recently reported that berberine (BBR) displays insulin-sensitizing properties in rat models of insulin resistance and diabetes. Berberine (BBR) is commonly used as a nonprescription oral drug in China to treat gut infections and diarrhea with few side effects, andits therapeutic potential for the treatment of diabetes and dyslipidemia in humans has been reported. These beneficial effects are related in part to the ability of Berberine to activate AMPK. Therefore, it is essential to investigate deeply the expression and effect to the key enzymes in glycometabolism of 11β-HSD1.Objective:The aims of this investigation were to characterize the regulation of glucocorticoid hormone; 11β-HSD action in skeletal muscle and to investigate thier role in the development of the metabolic syndromeMethods:Male Wistar rats were randomly divided into four groups:Berberine was administrated at50mg/kg for LB and at for HB100 mg/Kg twice a day at 10:00 and 22:00 by gastric gavage for 5 weeks. Control rats were gavaged with an equal volume of vehicle (distilled water). After six months on HFD. the animals were divided into control (n=6), diabetes mellitus (n=6), treated with low Berberine (n=6) groups, and treated with high Berberine(n=6) group. Glucose tolerance test, insulin tolerance test and relevant index calculation were used to evaluate the fasting blood glucose, self-regulating ability of blood glucose and levels of insulin sensitivity and insulin resistance for analysis of analogues.On the successful analogues, the expression levels in skeletal muscle of 11β-HSD1 and GR, which are two rate-limiting enzymes in gluconeogenesis, were assessed in two groups by Western Blot.Results:1. Low-dose berberine group (50mg/kg) rats fasting plasma glucose to decline, but the effect was not significant (P>0.05); while high doses of 100mg/kg of berberine can make the model, fasting blood glucose by the 12.67 mmol/L decreased to 8.41 mmol/L, reducing the blood glucose was significantly (P<0.05).2. Glucose tolerance test results show the model group of the glucose area under the curve were significantly higher and berberine in high and low blood glucose, and area under the curve were compared with model group, and showed significant dose-dependent. Type 2 diabetic rats decreased glucose tolerance, insulin resistance occurs, and berberine treatment significantly increased the amount the body glucose tolerance and improved insulin resistance.3. Berberine reduced body weight in diabetic rats, decreased serum triglyceride levels, suggesting that berberine also good lower blood lipids, improve the role of lipid disorders.11(3-HSD1 and GR protein expression in skeletal muscle were both significantly decreased with high-Berberine intake rats (P<0.05);4. The rats of high-Berberine group showed a decreasing expression of the rate-limiting enzymes,11β-HSD1 and GR (P<0.05).Conclusion:1. Berberine decrease fasting blood glucose, lipids and improve glucose tolerance in rats to improve insulin resistance in a dose-dependent in fat combined with low dose STZ-induced diabetes model.2. Berberine might inhibit 11β-HSD1 and GR expression, to improve the high-fat plus low dose STZ-induced diabetes model skeletal muscle insulin resistance.