Identification and characterization of anti-diabetic activity of banaba extract, tannic acid and penta-O-galloyl-D-glucose (PGG)

Type II diabetes (T2D) has become a disease of epidemic proportion in this country and in the other parts of the developed world. Its major symptoms include hyperglycemia and insulin resistance. Although genetic factors are involved, T2D is primarily triggered by unhealthy life styles such as excessive food intake and insufficient exercise. Diabesity is a new word coined to describe the close association between T2D and obesity. Unfortunately, most current T2D drugs reduce hyperglycemia but increase weight gain, alleviating one problem for T2D but aggravating the other. There is an urgent need to develop new drugs that are anti-diabetic without promoting weight gain.; In this study, using 3T3-L1 adipocytes and a glucose uptake assay, water extracts of banaba were tested for their glucose transport stimulatory activity. HPLC fractionation, subtraction and biofunction studies led to identification of tannic acid (TA) as the effective component of banaba extract. Further HPLC fractionation followed by MS and NMR analyses led to the final identification of 1,2,3,4,6-Penta-Galloyl-D-Glucose (PGG) as one of the most effective TA that is responsible for the glucose transport stimulatory activity in 3T3-L1 adipocytes. After the bioactivity of PGG was confirmed by comparison of plant-derived and chemically synthesized PGG, a mechanism study was conducted in an attempt to identify the molecular target and pathway used by PGG. Cell studies found that, similar to insulin, PGG stimulates glucose transport in adipocytes. But, surprisingly, PGG inhibits insulin-induced adipogenesis in preadipocytes. Protein studies using adipocytes revealed that PGG induces phosphorylation of insulin receptor and Akt, and translocation of glucose transporter 4, the protein factors involved in the insulin-mediated glucose transport signaling pathway. Control experiments using different cell lines, chemicals and signaling pathway inhibitors showed that PGG's activity is cell type-, chemical- and pathway-specific. Animal studies indicated that PGG was effective in reducing blood glucose and insulin in diabetic and obese mouse models. These results suggest that PGG may be used as a new compound model to dissect glucose transport signaling pathway and adipogenesis for a better understanding of the relationship of the two processes with respect to the progress of T2D. PGG can also be used as a prototype for development of a new generation of anti-diabetic therapeutics that effectively treats hyperglycemia of T2D without increasing adiposity or weight gain.