Mechanisms of antihyperglycemic effect of p-methoxycinnamic acid in normal and streptozotocin-induced diabetic rats

We investigated the antihyperglycemic effect of p-methoxycinnamic acid (p-MCA), a cinnamic acid derivative, on plasma glucose and insulin concentrations, activities of hepatic glucose-regulating enzymes and hepatic glycogen content in normal and streptozotocin (STZ)-induced diabetic rats. p-MCA (10-100 mg/kg, PO) dose-dependently decreased plasma glucose concentration in both normal and diabetic rats in the oral glucose tolerance test. To investigate the chronic effects of p-MCA on glucose metabolism, p-MCA (40 mg/kg, PO) was administered to normal and diabetic rats once a day for 4 weeks. p-MCA reduced plasma glucose concentration in diabetic rats, which was observed during the 4-week study. However, p-MCA treatment did not change plasma glucose concentrations in normal rats during the 4-week study. p-MCA also reduced the excessive activities of hepatic glucose-6-phosphatase, hepatic hexokinase, glucokinase and phosphofructokinase in diabetic rats and increased hepatic glycogen in these rats. In p-MCA-treated normal rats, there were no changes in the activities of hepatic glucose-regulating enzymes, hepatic glycogen and glucose-6-phosphate. Our findings suggested that p-MCA exert its antihyperglycemic effect by increasing insulin secretion and glycolysis, and by decreasing gluconeogenesis.     

alpha-Glucosidase inhibitory activity of cyanidin-3-galactoside and synergistic effect with acarbose

Cyanidin-3-galactoside, a natural anthocyanin, was investigated for its alpha-glucosidase inhibitory activity. The IC(50) value of cyanidin-3-galactoside was 0.50 +/- 0.05 mM against intestinal sucrase. A low dose of cyanidin-3-galactoside showed a synergistic inhibition on intestinal alpha-glucosidase (maltase and sucrase) when combined with acarbose. A kinetic analysis showed that cyanidin-3-galactoside gave a mixed type inhibition against intestinal sucrase. The results indicated that cyanidin-3-galactoside was an alpha-glucosidase inhibitor and could be used in combination with acarbose for treatment of diabetes.     

The role of arginine vasopressin in diabetes-associated increase in glucagon secretion

The purpose of this study was to investigate the role of arginine vasopressin (AVP) on glucagon secretion in both normal and diabetic rats. Diabetes was induced by intravenous administration of 50 mg/kg streptozotocin, 14 days before pancreatic perfusion. Diabetic rats were maintained on insulin replacement therapy until approximately 48 h before the perfusion experiments. Both glucagon and AVP were determined in the effluent of the perfused pancreas using RIA. Both normal and diabetic rats had similar basal glucagon secretion. AVP (3-30 pM) increased glucagon secretion from both normal and diabetic rats in a concentration-dependent manner. However, diabetic subjects were more sensitive to AVP administration than normal subjects with regard to glucagon secretion. By comparison of the areas under the curves, AVP-induced glucagon secretion in diabetic rats was approximately 2-fold that of the normal rats. In addition, immunoreactive AVP was detected in the effluent of the perfused pancreas, and diabetic rats had 70% higher AVP concentrations in the pancreatic effluent than normal rats. We conclude that AVP is secreted from the pancreas and diabetic rats can secrete more AVP from the pancreas than normal rats. Consequently, AVP may have a greater impact on glucagon secretion in diabetic subjects than normal ones. AVP might play an important role in the hypersecretion of glucagon in diabetic subjects.     

Inhibitory activity of cyanidin-3-rutinoside on alpha-glucosidase

Cyanidin-3-rutinoside, a natural anthocyanin, inhibited alpha-glucosidase from baker's yeast in dose-responsive manner. The IC50 value was 19.7 microM +/- 0.24 microM, compared with the IC50 value of voglibose (IC50 = 23.4 +/- 0.30 microM). Cyanidin-3-rutinoside was found to be a non-competitive inhibitor for yeast alpha-glucosidase with a Ki value in the range of 1.31-1.56 x 10(-5)M. These results indicated that cyanidin-3-rutinoside could be classed as a new alpha-glucosidase inhibitor.     

Structure-activity relationships of trans-cinnamic acid derivatives on alpha-glucosidase inhibition

trans-Cinnamic acid and its derivatives were investigated for the alpha-glucosidase inhibitory activity. 4-Methoxy-trans-cinnamic acid and 4-methoxy-trans-cinnamic acid ethyl ester showed the highest potent inhibitory activity among those of trans-cinnamic acid derivatives. The presence of substituents at 4-position in trans-cinnamic acid altered the alpha-glucosidase inhibitory activity. Increasing of bulkiness and the chain length of 4-alkoxy substituents as well as the increasing of the electron withdrawing group have been shown to decrease the inhibitory activity. 4-Methoxy-trans-cinnamic acid was a noncompetitive inhibitor for alpha-glucosidase, whereas, 4-methoxy-trans-cinnamic acid ethyl ester was a competitive inhibitor. These results indicated that trans-cinnamic acid derivatives could be classified as a new group of alpha-glucosidase inhibitors.     

A series of cinnamic acid derivatives and their inhibitory activity on intestinal α-glucosidase

Inhibition of α-glucosidase and α-amylase delays the digestion of starch and disaccharides to absorbable monosaccharides, resulting in a reduction of postprandial hyperglycemia. Finding effective mammalian α-glucosidase inhibitors from natural sources can be beneficial in the prevention and treatment of diabetes mellitus. We investigated the inhibitory activity of cinnamic acid derivatives against rat intestinal α-glucosidase and porcine pancreatic α-amylase in vitro. Among 11 cinnamic acid derivatives, caffeic acid, ferulic acid, and isoferulic acid were the most potent inhibitors against intestinal maltase with IC₅₀ values of 0.74?±?0.01, 0.79?±?0.04, and 0.76?±?0.03?mM, respectively, whereas ferulic acid (IC₅₀?=?0.45?±?0.01?mM) and isoferulic acid (IC₅₀?=?0.45?±?0.01?mM) were effective intestinal sucrase inhibitors. However, all cinnamic acid derivatives were found to be inactive in pancreatic α-amylase inhibition. Kinetic analysis revealed that intestinal maltase was inhibited by caffeic acid, ferulic acid, and isoferulic acid in a mixed-inhibition manner. In addition, ferulic acid and isoferulic acid inhibited intestinal sucrase in a mixed type manner, whereas caffeic acid was a non-competitive inhibitor. The combination of isoferulic acid and acarbose showed an additive inhibition on intestinal sucrase. This study could provide a new insight into naturally occurring intestinal α-glucosidase inhibitors that could be useful for treatment of diabetes and its complications.     

SSTR2 mediates the somatostatin-induced increase in intracellular Ca(2+) concentration and insulin secretion in the presence of arginine vasopressin in clonal beta-cell HIT-T15

The effects of somatostatin (SRIF) are mediated through the seven transmembrane receptor family that signals via Gi/Go. To date, five distinct SRIF receptors have been characterized and designated SSTR1-5. We have characterized the SRIF receptor that mediates the increase in [Ca(2+)](i) and insulin secretion in HIT-T15 cells (Simian virus 40-transformed Syrian hamster islets) using high affinity, subtype selective agonists for SSTR1 (L-797,591), SSTR2 (L-779,976), SSTR3 (L-796,778), SSTR4 (L-803,087), SSTR5 (L-817,818) and PRL-2903, a specific SSTR2 antagonist. In the presence of arginine vasopressin (AVP), SRIF increased [Ca(2+)](i) and insulin secretion. Treatment with the SSTR2 agonist L-779,976 resulted in similar responses to SRIF. In addition, L-779,976 increased both [Ca(2+)](i) and insulin secretion in a dose-dependent manner. Treatment with L-779,976 alone did not alter [Ca(2+)](i) or basal insulin secretion. In the presence of AVP, all other SRIF receptor agonists failed to increase [Ca(2+)](i) and insulin secretion. The effects of SRIF and L-779,976 were abolished by the SSTR2 antagonist PRL-2903. Our results suggest that the mechanism underlying SRIF-induced insulin secretion in HIT-T15 cells be mediated through the SSTR2.