Antidiabetic effects, mechanisms of of p-methoxy-trans-cinnamic acid

Abstract

p-Methoxycinnamic acid (p-MCA) is a cinnamic acid derivative that shows various pharmacologic actions such as neuroprotective and hepatoprotective activities. To examine the insulinotropic activity of p-MCA, the perfused rat pancreas and a pancreatic β-cell line, INS-1 were used in the studies. P-MCA increased insulin secretion from the perfused rat pancreas and INS-1 cells in a concentration-dependent manner. In addition, p-MCA increased intracellular Ca²⁺ concentration ([Ca²⁺]i) in INS-1 cells. The p-MCA-induced insulin secretion and rise in [Ca²⁺]i were markedly inhibited in the absence of extracellular Ca²⁺ or in the presence of an L-type Ca²⁺ channel blocker, nimodipine. These results suggested that p-MCA increased Ca²⁺ influx via the L-type Ca²⁺ channels. Diazoxide, and ATP-sensitive K⁺ channel opener, did not alter p-MCA-induced insulin secretion, nor [Ca²⁺]i response. In addition, p-MCA enhanced glucose and glyburide-induced insulin secretion and it also potentiated the increase in insulin secretion and a rise of [Ca²⁺]i induced by KCI-and Bay K 8644, an L-type Ca²⁺ channel. Furthermore, p-MCA increased cyclic AMP content of INS-1 cells and enhanced the increase of cyclic AMP content induced by an adenylyl cyclase activator forskolin; however, p-MCA failed to enhance the effect of a phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Taken together, our results suggested that p-MCA stimulated insulin secretion from pancreatic β-cells by increasing Ca²⁺ influx via the L-type Ca²⁺ channels, but not through the closure of ATP-sensitive K+ channels. In addition, p-MCA may increase cyclic AMP content by inhibiting phosphodiesterase. P-MCA was a potent competitive inhibitor against yeast α-glucosidase However, it had no inhibitory activities on mammalian α-glucosidase and α-amylase. In the acute toxicity test, oral administration of p-MCA (100-2000 mg/kg) produced neither mortality nor significant differences in blood chemistry analysis when compared to the control group, which was fed with sunflower oil. In addition, neither gross abnormalities nor histopathological changes of brain, pancreas, heart and lung were observed.