Inhibition of advanced glycation end products by red grape skin extract and its antioxidant activity.

BACKGROUND: The objective of the present study was to determine the phytochemical content and the protective effect of red grape skin extract (RGSE) against fructose-mediated protein oxidation. In addition, RGSE was screened for its potential as an antioxidant using various in vitro models. METHODS: Antioxidant activity was measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl radical scavenging activity, superoxide radical scavenging activity, trolox equivalent antioxidant capacity, ferric reducing antioxidant power (FRAP), ferrous ion chelating power. The total phenols content was measured by Folin-Ciocalteu assay, the flavonoids content by the AlCl3 colorimetric method. Antiglycation activity was determined using the formation of AGE fluorescence intensity, Nε-(carboxymethyl)lysine, and the level of fructosamine. The protein oxidation was examined using the level of protein carbonyl content and thiol group. RESULTS: The results showed that the content of total phenolics, flavonoids and total anthocyanins in RGSE was 246.3 ± 0.9 mg gallic acid equivalent/g dried extract, 215.9 ± 1.3 mg catechin equivalent/g dried extract, and 36.7 ± 0.8 mg cyanidin-3-glucoside equivalent/g dried extract, respectively. In the DPPH radical scavenging activity, hydroxyl radical scavenging activity, and superoxide radical scavenging activity, RGSE had the IC50 values of 0.03 ± 0.01 mg/ml, 5.40 ± 0.01 mg/ml, and 0.58 ± 0.01 mg/ml, respectively. In addition, RGSE had trolox equivalent antioxidant capacity assay (395.65 ± 1.61 mg trolox equivalent/g dried extract), ferric reducing antioxidant power (114.24 ± 0.03 mM FeSO4/g dried extract), and ferrous ion chelating power (3,474.05 ± 5.55 mg EDTA/g dried extract), respectively. The results showed that RGSE at different concentrations (0.031-0.500 mg/ml) has significantly inhibited the formation of AGEs in terms of the fluorescence intensity of glycated BSA during 4 weeks of study. The RGSE markedly decreased the level of fructosamine, which is directly associated with the reduction of AGE formation and Nε-(carboxymethyl)lysine (CML). The results demonstrated the significant effect of RGSE on preventing protein oxidative damages, including effects on the thiol and protein carbonyl oxidation. CONCLUSIONS: The present study revealed that RGSE would exert beneficial effects by virtue of its antioxidants and antiglycation. The findings could provide a new insight into the naturally occurring antiglycation properties of RGSE for preventing AGE-mediated diabetic complication.

In vitro effects of cinnamic acid derivatives on protein tyrosine phosphatase 1B.

Protein Tyrosine Phosphatase 1B (PTP1B) is a major negative regulator of insulin signaling pathways. Finding selective PTP1B inhibitors from natural sources has been widely recognized as a potential drug target for the treatment of diabetes mellitus and obesity. In the present study, we evaluated the inhibitory activity of cinnamic acid derivatives against PTP1B in vitro. Among 14 cinnamic acid derivatives and related compounds, the most potent inhibitor PTP1Bs were o-hydroxycinnamic acid and p-hydroxycinnamic acid, which had IC50 values of 137.67 ± 13.37 and 181.60 ± 9.34 µM, respectively. The kinetics analysis revealed that PTP1B was inhibited by o-hydroxycinnamic acid and p-hydroxycinnamic acid in a non-competitive manner. o-Hydroxycinnamic acid (25 µM) and p-hydroxycinnamic acid (25 µM), in combination with sodium orthovanadate (0.0125 µM), demonstrated a synergistic effect to inhibit PTP1B activity. In conclusion, the findings provide a new insight into naturally occurring PTP1B inhibitors that could be useful for treatment of diabetes and obesity.

Cinnamic acid and its derivatives inhibit fructose-mediated protein glycation.

Cinnamic acid and its derivatives have shown a variety of pharmacologic properties. However, little is known about the antiglycation properties of cinnamic acid and its derivatives. The present study sought to characterize the protein glycation inhibitory activity of cinnamic acid and its derivatives in a bovine serum albumin (BSA)/fructose system. The results demonstrated that cinnamic acid and its derivatives significantly inhibited the formation of advanced glycation end products (AGEs) by approximately 11.96-63.36% at a concentration of 1 mM. The strongest inhibitory activity against the formation of AGEs was shown by cinnamic acid. Furthermore, cinnamic acid and its derivatives reduced the level of fructosamine, the formation of N(ɛ)-(carboxymethyl) lysine (CML), and the level of amyloid cross ß-structure. Cinnamic acid and its derivatives also prevented oxidative protein damages, including effects on protein carbonyl formation and thiol oxidation of BSA. Our findings may lead to the possibility of using cinnamic acid and its derivatives for preventing AGE-mediated diabetic complications.

Grape seed extract supplementation prevents high-fructose diet-induced insulin resistance in rats by improving insulin and adiponectin signalling pathways.

Recent evidence strongly supports the contention that grape seed extract (GSE) improves hyperglycaemia and hyperinsulinaemia in high-fructose-fed rats. To explore the underlying molecular mechanisms of action, we examined the effects of GSE on the expression of muscle proteins related to the insulin signalling pathway and of mRNA for genes involved in the adiponectin signalling pathway. Compared with rats fed on a normal diet, high-fructose-fed rats developed pathological changes, including insulin resistance, hyperinsulinaemia, hypertriacylglycerolaemia, a low level of plasma adiponectin and a high level of plasma fructosamine. These disorders were effectively attenuated in high-fructose-fed rats supplemented with GSE. A high-fructose diet causes insulin resistance by significantly reducing the protein expression of insulin receptor, insulin receptor substrate-1, Akt and GLUT4, and the mRNA expression of adiponectin, adiponectin receptor R1 (AdipoR1) and AMP-activated protein kinase (AMPK)-α in the skeletal muscle. Supplementation of GSE enhanced the expression of insulin signalling pathway-related proteins, including Akt and GLUT4. GSE also increased the mRNA expression of adiponectin, AdipoR1 and AMPK-α. In addition, GSE increased the mRNA levels of glycogen synthase and suppressed the mRNA expression of glycogen synthase kinase-3-α, causing an increase in glycogen accumulation in the skeletal muscle. These results suggest that GSE ameliorates the defective insulin and adiponectin signalling pathways in the skeletal muscle, resulting in improved insulin resistance in fructose-fed rats.

Cyanidin-3-rutinoside alleviates postprandial hyperglycemia and its synergism with acarbose by inhibition of intestinal α-glucosidase.

The inhibitory activity on intestinal α-glucosidase by cyanidin-3-rutinoside was examined in vitro and in vivo. The IC(50) values of cyanidin-3-rutinoside against intestinal maltase, and sucrase were 2,323 ± 14.8 and 250.2 ± 8.1 µM, respectively. The kinetic analysis revealed that intestinal sucrase was inhibited by cyanidin-3-rutinoside in a mixed-type manner. The synergistic inhibition also found in combination of cyanidin-3-rutinoside with acarbose against intestinal maltase and sucrase. The oral administration of cyanidin-3-rutinoside (100 and 300 mg/kg) plus maltose or sucrose to normal rats, postprandial plasma glucose was markedly suppressed at 30-90 min after loading. Furthermore, the normal rats treated with acarbose and cyanidin-3-rutinoside (30 mg/kg) showed greater reduction of postprandial plasma glucose than the group treated with acarbose alone. These results suggest that cyanidin-3-rutinoside retards absorption of carbohydrates by inhibition of α-glucosidase which may be useful as a potential inhibitor for prevention and treatment of diabetes mellitus.

In vitro inhibitory effects of cyandin-3-rutinoside on pancreatic α-amylase and its combined effect with acarbose.

The inhibitory activity on pancreatic α-amylase by cyanidin-3-rutinoside was examined in vitro. The IC50 value of cyanidin-3-rutinoside against pancreatic α-amylase was 24.4 ± 0.1 µM. The kinetic analysis revealed that pancreatic α-amylase was inhibited by cyanidin-3-rutinoside in a non-competitive manner. The additive inhibition of a combination of cyanidin-3-rutinoside with acarbose against pancreatic α-amylase was also found. These results provide the first evidence for the effect of cyanidin-3-rutinoside in a retarded absorption of carbohydrates by inhibition of pancreatic α-amylase which may be useful as a potential inhibitor for prevention and treatment of diabetes mellitus.

Inhibitory activities of cyanidin and its glycosides and synergistic effect with acarbose against intestinal α-glucosidase and pancreatic α-amylase.

Cyanidin and its glycosides are naturally dietary pigments which have been indicated as promising candidates to have potential benefits to humans, especially in the prevention and treatment of diabetes mellitus. We investigated the structure activity relationships of cyanidin and its glycosides to inhibit intestinal α-glucosidases and pancreatic α-amylase in vitro. The results found that cyanidin and its glycosides are more specific inhibitors of intestinal sucrase than intestinal maltase. Cyanidin-3-galactoside and cyanidin-3-glucoside were the most potent inhibitors against intestinal sucrase and pancreatic α-amylase with IC(50) values of 0.50 ± 0.05 and 0.30 ± 0.01 mM, respectively. Our findings indicate that the structural difference between glucose and galactose at the 3-O-position of cyanidin was an important factor for modulating the inhibition of intestinal sucrase and pancreatic α-amylase. The combination of cyandin-3-glucoside, cyanidin-3- galactoside or cyanidin-3,5-diglucosides with a low concentration of acarbose showed synergistic inhibition on intestinal maltase and sucrase. The synergistic inhibition was also found for a combination of cyanidin or cyanidin-3-glucoside with a low concentration of acarbose. The findings could provide a new insight into a use for the naturally occurring intestinal α-glucosidase and pancreatic α-amylase inhibitors for the prevention and treatment of diabetes and its complications.

Preventive effect of grape seed extract against high-fructose diet-induced insulin resistance and oxidative stress in rats.

The purpose of the present study was to investigate the preventive effect of grape seed extract (GSE) on insulin resistance and oxidative stress in rats fed a high-fructose diet. After 8 weeks of the experiment, the fasting plasma glucose, insulin concentrations, and the homeostasis model assessment of basal insulin resistance (HOMA-IR) of rats fed a high-fructose diet supplemented with 1% GSE were significantly lower than that of a high-fructose diet group. In the oral glucose tolerance test, rats fed a high-fructose diet supplemented with 1% GSE had a significantly reduced plasma glucose and insulin concentrations after 15 min of glucose loading, indicating that GSE improved glucose intolerance. In addition, fed rats fed a high-fructose diet supplemented with 1% GSE markedly increased activity of hepatic superoxide dismutase, catalase, and suppressed lipid peroxidation when compared to rats fed a high-fructose diet. However, rats fed a high-fructose diet supplemented with GSE were not found to have a significant change in the activity of hepatic glutathione peroxidase. In conclusion, intake of GSE may be a feasible therapeutic strategy for prevention of a high-fructose diet-induced insulin resistance and oxidative stress.

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

Inhibition of alpha-glucosidase and alpha-amylase delays the digestion of starch and disaccharides to absorbable monosaccharides, resulting in a reduction of postprandial hyperglycemia. Finding effective mammalian alpha-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 alpha-glucosidase and porcine pancreatic alpha-amylase in vitro. Among 11 cinnamic acid derivatives, caffeic acid, ferulic acid, and isoferulic acid were the most potent inhibitors against intestinal maltase with IC(50) values of 0.74 +/- 0.01, 0.79 +/- 0.04, and 0.76 +/- 0.03 mM, respectively, whereas ferulic acid (IC(50) = 0.45 +/- 0.01 mM) and isoferulic acid (IC(50) = 0.45 +/- 0.01 mM) were effective intestinal sucrase inhibitors. However, all cinnamic acid derivatives were found to be inactive in pancreatic alpha-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 alpha-glucosidase inhibitors that could be useful for treatment of diabetes and its complications.

Anti-inflammatory effects of topical supernatant from human amniotic membrane cell culture on canine deep corneal ulcer after human amniotic membrane transplantation.

The objective of this study was to examine the effect of topically applied human amniotic epithelial cell (HAEC) culture supernatant on corneal inflammatory reaction in dogs. Twenty-five dogs were randomly assigned into five groups. The control group consisted of five dogs with normal cornea. Inductions of corneal ulcers were performed using 0.45 cm trephine and human amniotic membrane was transplanted in 20 dogs. These 20 dogs were assigned into four treatment groups: topical antibiotic, topical corticosteroid, topical mock media and topical culture supernatant from HAEC, respectively. Administrations of the testing agents started at 24 h (h) after transplantation four times daily for nine consecutive days. Tears were collected before an operation 24 h after transplantation, but before application of the testing agents on consecutive odd days following transplantation. The concentrations of interleukin-1beta (IL-1beta) and nitric oxide (NO) in tear fluid were measured using canine IL-1beta ELISA kit and Griess assay, respectively. Our analysis indicates that elevations of IL-1beta and NO concentrations are associated with inflammatory conditions in the eyes. Corticosteroid, a reference anti-inflammatory drug, and the culture supernatant from HAEC significantly decreased IL-1beta and NO concentrations. In addition, the clinical signs such as conjunctivitis and neovascularization were decreased in both topical corticosteroid and supernatant from HAEC treated groups. Mock and antibiotic solutions failed to decrease NO and IL-1beta concentrations. In conclusion, topical application of the culture supernatant from HAEC alleviated inflammation in induced-corneal ulcer of dogs, possibly via inhibition of IL-1beta and NO production.

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.

Insulin-releasing properties of a series of cinnamic acid derivatives in vitro and in vivo.

Cinnamic acid derivatives are naturally occurring substances found in fruits, vegetables, and flowers and are consumed as dietary phenolic compounds. In the present study, cinnamic acid and its derivatives were evaluated for insulin secreting activity in perfused rat pancreas and pancreatic beta-cells (INS-1) as well as an increase in [Ca(2+)]i in vitro. The presence of m-hydroxy or p-methoxy residues on cinnamic acid was a significantly important substituent as an effective insulin releasing agent. The introduction of p-hydroxy and m-methoxy-substituted groups in cinnamic acid structure (ferulic acid) displayed the most potent insulin secreting agent among those of cinnamic acid derivatives. In particular, the stimulatory insulin secreting activities of test compounds were associated with a rise of [Ca(2+)]i in INS-1. In perfused rat pancreas, m-hydroxycinnamic acid, p-methoxycinnamic acid, and ferulic acid (100 microM) significantly stimulated insulin secretion during 10 min of administration. The onset time of insulin secretion of those compounds was less than 1 min and reached its peak at 4 min that was about 2.8-, 3.3-, and 3.4-fold of the baseline level, respectively. Intravenous administration of p-methoxycinnamic acid and ferulic acid (5 mg/kg) significantly decreased plasma glucose and increased insulin concentration in normal rats and maintained its level for 15 min until the end of experiment. Meanwhile, m-hydroxycinnamic acid induced a significant lowering of plasma glucose after 6 min, but the effects were transient with plasma glucose concentration, rapidly returning to basal levels. Our findings suggested that p-methoxycinnamic acid and ferulic acid may be beneficial for the treatment of diabetes mellitus because they regulated blood glucose level by stimulating insulin secretion from pancreatic beta-cells.

Insulin-secretagogue activity of p-methoxycinnamic acid in rats, perfused rat pancreas and pancreatic beta-cell line.

This study investigated the effect of p-methoxycinnamic acid (p-MCA) on plasma glucose and insulin concentrations in normal and streptozotocin-induced diabetic rats. In both fasting and glucose-loading conditions, an oral administration of p-MCA (40-100 mg/kg) significantly decreased plasma glucose and also increased plasma insulin concentrations in both normal and diabetic rats. The onset of the p-MCA-induced antihyperglycaemia/hypoglycaemia was observed at 1 hr after administration. In perfused rat pancreas, p-MCA (10-100 microM) stimulated insulin secretion about 1.4- and 3.1-fold of basal-control group. In addition, p-MCA (10 microM) enhanced glucose-induced insulin secretion. Moreover, p-MCA stimulated insulin secretion and increased intracellular Ca(2+) concentration ([Ca(2+)](i)) in insulinoma-1 cells. Taken together, our findings suggested that p-MCA exerted antihyperglycaemic/hypoglycaemic effect by stimulating insulin secretion from pancreas and could be developed into a new potential for therapeutic agent used in type 2 diabetic patients.

Synthesis of N-phenylphthalimide derivatives as alpha-glucosidase inhibitors.

Sixteen N-phenylphthalimide derivatives were synthesized and their ability to inhibit alpha-glucosidase was investigated. N-(2,4-dinitrophenyl)phthalimide was a potent inhibitor of yeast alpha-glucosidase (IC50; 0.158 +/- 0.005 mM) and maltase (IC50; 0.051 +/- 0.008 mM), whereas it did not inhibit sucrase. From a Lineweaver-Burk plot of alpha-glucosidase kinetics, N-(2,4-dichlorophenyl)phthalimide was found to be a competitive inhibitor of yeast alpha-glucosidase. These results indicate that N-(2,4-dinitrophenyl)phthalimide could be a representative of a new group of alpha-glucosidase inhibitors.

Slow acting protein extract from fruit pulp of Momordica charantia with insulin secretagogue and insulinomimetic activities.

The protein from Thai bitter gourd (Momordica charantia) fruit pulp was extracted and studied for its hypoglycemic effect. Subcutaneous administration of the protein extract (5, 10 mg/kg) significantly and markedly decreased plasma glucose concentrations in both normal and streptozotocin-induced diabetic rats in a dose-dependent manner. The onset of the protein extract-induced antihyperglycemia/hypoglycemia was observed at 4 and 6 h in diabetic and normal rats, respectively. This protein extract also raised plasma insulin concentrations by 2 fold 4 h following subcutaneous administration. In perfused rat pancreas, the protein extract (10 microg/ml) increased insulin secretion, but not glucagon secretion. The increase in insulin secretion was apparent within 5 min of administration and was persistent during 30 min of administration. Furthermore, the protein extract enhanced glucose uptake into C2C12 myocytes and 3T3-L1 adipocytes. Time course experiments performed in rat adipocytes revealed that M. charantia protein extract significantly increased glucose uptake after 4 and 6 h of incubation. Thus, the M. charantia protein extract, a slow acting chemical, exerted both insulin secretagogue and insulinomimetic activities to lower blood glucose concentrations in vivo.

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.

Somatostatin increases phospholipase D activity and phosphatidylinositol 4,5-bisphosphate synthesis in clonal beta cells HIT-T15.

In the presence of arginine vasopressin (AVP), somatostatin increases [Ca(2+)](i), leading to a transient increase in insulin release from clonal beta cells HIT-T15 via G(i/o) and phospholipase C (PLC) pathway (Cheng et al., 2002a). The present study was to elucidate the mechanisms underlying somatostatin-induced [Ca(2+)](i) increase in the presence of AVP. We found that the effect of somatostatin was mediated by betagamma subunits but not by the alpha subunit of G(i/o). Because somatostatin alone failed to increase [Ca(2+)](i), we hypothesized that somatostatin increases phosphatidylinositol 4,5-bisphosphate (PIP(2)) synthesis, providing extra substrate for preactivated PLC-beta to generate inositol 1,4,5-trisphosphate (IP(3)). Somatostatin alone did not increase IP(3) levels, but AVP + somatostatin did. Somatostatin increased PIP(2) levels but decreased phosphatidylinositol 4-phosphate levels. We further hypothesized that PLD mediates somatostatin-induced changes in PIP(2) levels. Both the phospholipase D (PLD) inhibitors and antibody versus PLD1 antagonized AVP-somatostatin-induced increases in [Ca(2+)](i). PLD inhibitor also antagonized somatostatin-induced increase in PIP(2) levels. In addition, somatostatin increased PLD activity. These results suggest that activation of somatostatin receptors that are coupled to the betagamma dimer of G(i/o) led to PLD1 activation, thus promoting the synthesis of phosphatidic acid. Phosphatidic acid activates PIP-5 kinase, which evokes an increase in PIP(2) synthesis. The PIP(2) generated by somatostatin administration increases substrate for preactivated phospholipase C-beta, which hydrolyzes PIP(2) to form IP(3), leading to an increase in [Ca(2+)](i). The regulation of PIP(2) synthesis by G(i/o)-coupled receptors via PLD activation represents a novel signaling mechanism for somatostatin and a novel concept in the cross-talk between G(q)- and G(i/o)-coupled receptors in beta cells.

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.

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.

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.