Berberine On Islet β Cell Research Function And The Derivatives Antidiabetic Activity

Diabetes mellitus is a kind of metabolic disease characterized by the elevation of blood glucose and has impact on the whole body. However, hyperglycemia occurs only when the function of pancreatic β cells declines or forfeits. The study of β cell function has become a pivotal part of the diabetic study in recent years, which have two sections:insulin secretion and insulin synthesis. With the development of the diabetic theories and the discovery of the novel mechanisms in the diabetes field, the anti-diabetic drugs also evolves from solely promoting insulin secretion to rival the elevated blood glucose as a main purpose to a comprehensive goal comprising of lowering blood glucose, modulating blood lipid, ameliorating insulin resistant state and improving the diabetic complications. Among those measures, protection of the β cell function has become a focus of the anti-diabetic drug study. Berberine is the main alkaloid purified from Cortidis rhizoma, whose anti-diabetic action was reported two decades ago. Recently, it was found to have the ability of lowering blood triglyceride as well as cholesterol, and may promote the secretion of GLP-1from intestine cells. Such actions make it a promising candidate to further development and utilization. Despite many conclusions about the action of berberine in the insulin sensitive tissues, the study of berberine on the function of pancreatic β cells are rare. The present study investigated the impact of berberine on insulin expression as a main purpose and also evaluated the anti-diabetic actions of about50derivatives of berberine.In the first part of the study, metabolic syndrome animal model MSG mice and T2DM animal model C57/BL mice were used to investigate the anti-diabetic action as well as the influence on β cells of berberine in the full-scale level. Berberine could improve the insulin resistant state and ameliorate the oral glucose intolerance state remarkably in the two animal models. It could also decrease fasting serum insulin and triglyceride levels in the pancreatic tissues, which reflected its anti-lipotoxicity action in such models. The pathological sections revealed that berberine could restrain the exacerbation of the pathological morphology in the islets of the pancreatic tissues. The insulin immunohistochemistry staining discovered the declining of the insulin content in the islets of pancreases, which reflected a direct regulation of β cells function by berberine. The purpose of the second part of this study was to evaluate if berberine had a direct effect on the insulin expression of the pancreatic β cells and to investigate the underlining mechanism. Using real time PCR method, berberine was found to inhibit the expression of insulin mRNA in NIT-1cell line as well as in the primary pancreatic islets. Furthermore, this inhibition was also confirmed in the protein level. In order to discuss the mechanism of berberine on the insulin gene expression, we constructed two reporter plasmids containing insulin gene promoters and examined the recombinant vectors under different conditions. The results showed that the vectors were sensitive to glucose, palmitatic acid and GLP-1analogue exendin-4and could be used in the further study. Using the constructed plasmids, we found that berberine inhibited the activities of insulin gene promoter in the manner depended on time and dose. Its action is quite different from metformin that mechanism seems to be similar. The further studies revealed that AMPK inhibitor, compound C, could absolutely abolish the inhibition effect of berberine on the activities of insulin gene promoters. Such findings indicated that the effect of berberine on the expression of insulin was through this signal pathway. In the final of this part study, CHOP gene expression was found to decrease significantly and suggested that inhibition of insulin expression by berberine may restrain ER stress in β cells and could have beneficial effect on pancreatic β cells.Using berberine as a precursor compound, some research group had revealed some derivatives of berberine which have better cholesterol lowering effects. This reflected the significance of such research. In the third part of the study, glucose consumption test was conducted to evaluate the glucose consumption promoting ability of the derivates of berberine. Among48chemical compounds,6were found to have satisfactory glucose consumption promotion effect. The subsequent in vivo test discovered WS0704002has blood glucose lowering effect both in normal ICR mice and in high fat fed C57/BL mice, and it also improved insulin resistant state of C57/BL mice. The effect of WS0704002was similar to berberine as the positive refference, and it deserves further research to have better anti-diabetic action.