Studies on the hypoglycemic effect of DHH-105 and its mechanisms involved
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AbstractCompounds synthesized on the basis of the chemical structure isolated from green tea were screened for their ability to increase glucose transport in isolated rat epididymal adipocytes. DHH-105 was the most effective at increasing glucose transport (392% over control). We examined the hypoglycemic effect ofDHH-105 in diabetic animals, STZinduced diabetic C57BL/6 mice or obese ob/ob mice. Animals that received daily intraperitoneal injections ofDHH-105 (150mg/kg) for two weeks showed lower blood glucose levels than those of untreated control STZ-diabetic mice (467 ± 6.7 vs. 285 ± 46mg/dl) and ob/ob mice (258 ± 44mg/dl vs. 155±18g/dl) and showed significantly improved glucose tolerance. To study the mechanisms of the hypoglycemic action of DHH-105, we further investigated the effect ofDHH-105 on glucose transport and the signal transduction pathways involved. DHH-105 increased glucose transport in a doseand time-dependent manner. DHH-105 increased the Vmax of glucose transport and translocation of GLUT 4. Phenylarsine oxide inhibited glucose transport was increased by DHH-105 while protein synthesis inhibitors did not affect DHH-105 induced glucose transport. Phosphatidylinositol 3-kinase inhibitors abolished the effect of DHH-105 on glucose transport. DHH-105 bound to the insulin receptor and increased the phosphorylation of the insulin receptor �� subunit and IRS-1, activated phosphatidylinositol 3-kinase and increased the phosphorylation of Akt. These results indicate that DHH-105 lowers blood glucose levels in diabetic animals through the enhancement of glucose transport mediated by the increase of insulin receptor signaling pathways.
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