Plasma Glucose Lowering Action Research Articles

Antihyperglycemic action of rhodiola-aqeous extract in type1-like diabetic rats

BackgroundRhodiola rosea (Rhodiola) is a plant in the Crassulaceae family that grows in cold regions of the world. It is mainly used in clinics as an adaptogen. Recently, it has been mentioned that Rhodiola increases plasma β-endorphin to lower blood pressure. Thus, the present study aims to investigate the antidiabetic action of Rhodiola in relation to opioids in streptozotocin-induced diabetic rats (STZ-diabetic rats).MethodsIn the present study, the plasma glucose was analyzed with glucose oxidase method, and the determination of plasma β-endorphin was carried out using a commercially available enzyme-linked immunosorbent assay. The adrenalectomy of STZ-diabetic rats was used to evaluate the role of β-endorphin. In addition, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting analysis were performed to investigate mRNA and protein expressions.ResultsRhodiola-water extract dose-dependently lowered the plasma glucose in STZ-diabetic rats and this action was reversed by blockade of opioid μ-receptors using cyprodime. An increase of plasma β-endorphin by rhodiola-water extract was also observed in same manner. The plasma glucose lowering action of rhodiola-water extract was attenuated in bilateral adrenalectomized rats. In addition, continuous administration of rhodiola-water extract for 3 days in STZ-diabetic rats resulted in an increased expression of glucose transporter subtype 4 (GLUT 4) in skeletal muscle and a marked reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression in liver. These effects were also reversed by blockade of opioid μ-receptors.ConclusionsTaken together, rhodiola-water extract improves hyperglycemia via an increase of β-endorphin secretion from adrenal gland to activate opioid μ-receptors in STZ-diabetic rats.

Decrease of Plasma Glucose byHibiscus taiwanensisin Type-1-Like Diabetic Rats

Hibiscus taiwanensis (Malvaceae) is widely used as an alternative herb to treat disorders in Taiwan. In the present study, it is used to screen the effect on diabetic hyperglycemia in streptozotocin-induced diabetic rats (STZ-diabetic rats). The extract of Hibiscus taiwanensis showed a significant plasma glucose-lowering action in STZ-diabetic rats. Stems of Hibiscus taiwanensis are more effective than other parts to decrease the plasma glucose in a dose-dependent manner. Oral administration of Hibiscus taiwanensis three times daily for 3 days into STZ-diabetic rats increased the sensitivity to exogenous insulin showing an increase in insulin sensitivity. Moreover, similar repeated administration of Hibiscus taiwanensis for 3 days in STZ-diabetic rats produced a marked reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression in liver and an increased expression of glucose transporter subtype 4 (GLUT 4) in skeletal muscle. Taken together, our results suggest that Hibiscus taiwanensis has the ability to lower plasma glucose through an increase in glucose utilization via elevation of skeletal GLUT 4 and decrease of hepatic PEPCK in STZ-diabetic rats.

Plasma Glucose-lowering Action of Allantoin is Induced by Activation of Imidazoline I-2 Receptors in Streptozotocin-induced Diabetic Rats

Allantoin, an active principle of yam, is documented to lower plasma glucose in diabetic rats. However, action mechanisms of allantoin remain obscure. It has been indicated that metformin shows ability to activate imidazoline I-2 receptors (I-2R) to lower blood sugar. Allantoin has also a chemical structure similar to metformin; both belong to guanidinium derivative. Thus, it is of special interest to know the effect of allantoin on I-2R. In the present study, the marked plasma glucose-lowering action of allantoin in streptozotocin-induced type-1 like diabetic rats was blocked by specific I-2R antagonist, BU224, in a dose-dependent manner. Also, the increase of β-endorphin release by allantoin was blocked by BU224 in the same manner. Otherwise, amiloride at the dose sufficient to block I-2AR abolished the allantoin-induced β-endorphin release and inhibited the blood glucose-lowering action of allantoin markedly but not completely. The direct effect of allantoin on glucose uptake in isolated skeletal muscle was also blocked by BU224. Also, the phosphorylation of AMPK in isolated skeletal muscle was raised by allantoin in a concentration-dependent manner. More-over, insulin sensitivity in diabetic rats was markedly increased by allantoin and this action was also blocked by BU224. These results suggest that allantoin has an ability to activate imidazoline I-2R while I-2AR is linked to the increase of β-endorphin release and I-2BR is related to other actions including the influence in skeletal muscle for lowering of blood glucose in type-1 like diabetic rats. Thus, allantoin can be developed to treat diabetic disorders in the future.

Evaluation of antidiabetic potential of selected traditional Chinese medicines in STZ-induced diabetic mice

AimsTraditional Chinese medicine (TCM) has been used for treating complex chronic diseases owing to their fewer side-effects, better patient tolerance and relatively less cost. The present work was carried out to study the anti-diabetic efficacy and mechanisms of 34 TCMs. Materials and methodsStreptozotocin (STZ)-diabetic mice were orally administrated with corresponding herbal solution once a day for 4 weeks. At the end of experiment, the level of plasma glucose, malondialdehyde (MDA), the activity of superoxide dismutase (SOD) and the serum aldose reductase (AR) were determined, the effects of TCM extract on α-glucosidase and angiotensin-converting enzyme (ACE) in vitro were also evaluated. Results13 out of the 34 herbs showed a statistically significant plasma glucose lowering action compared with the diabetic control group. Biochemical analysis revealed that Atractylodes macrocephala, Codonopsis pilosula, Dioscorea opposite, Flos lonicerae and Pueraria lobata may retard the progression of diabetes via reduce the blood glucose level and prevent the increase of AR activity. Other tested herbs, such as Ramulus cinnamomi, Cinnamomum cassia, and Eucommia ulmoides, showed the antidiabetic ability by either prevent the decrease in SOD activity or suppress the increase of MDA. Zymologic assay reveals that Pueraria lobata and Anemarrhena asphodeloides showed the highest inhibition against α-glucosidase and ACE respectively. Interestingly, the post-treatment glucose levels and AR activity were positively correlated with kidney/body weight of 34 herbs treated diabetic mice (p=0.02, 0.04 respectively). ConclusionsSeveral potential antidiabetic herbs derived from Chinese traditional pharmacopeia such as Dioscorea opposite, Pueraria lobata, Codonopsis pilosula and Ramulus cinnamomi, have been found to exert a beneficial action on diabetes and diabetic complications via multi-mechanisms.

Novel Hormonal Delivery Method Using the Ink-Jet Technology: Application to Pulmonary Insulin Therapies

A device developed based on ink-jet printer technology can precisely control the size and volume of droplets ejected. Here, we evaluated the application of this technology to the pulmonary administration of insulin mist as a therapeutic measure for diabetes. Insulin ejected from the ink-jet device was initially characterized by high-performance liquid chromatography (HPLC) and mass spectrometry. Its effects on D-glucose uptake rate by L6 cells were then investigated. Next, different insulin solutions (with or without additives or ink-jet processing) were subcutaneously administered, and their pharmacodynamic features were evaluated. Finally, decreases in plasma glucose level in rats were examined after ventilator-assisted pulmonary administration of insulin mist. Neither the HPLC nor the mass spectrometry profile of insulin was altered by the ink-jet process. The D-glucose uptake rate by L6 cells that received the recovered aerosolized insulin solution was similar to that of cells treated with control insulin, at 107%. Neither the addition of additives nor the ink-jet process used for insulin aerosolization impaired the plasma glucose-lowering action of subcutaneously injected insulin. Similarly, the efficacy of pulmonary insulin administration was not affected by the additives or the ink-jet process. Plasma glucose levels showed a trend towards decreasing after ventilator-assisted pulmonary administration of insulin mist. Plasma insulin level increased 30 min after the inhalation. The ink-jet process did not affect the quality or biological activity of insulin, suggesting the potential use of the ink-jet device for insulin inhalation therapy for diabetes.

Plasma Glucose Lowering Mechanisms of Catalpol, an Active Principle from Roots of Rehmannia glutinosa, in Streptozotocin-Induced Diabetic Rats

Catalpol is one of the active principles from roots of Rehmannia glutinosa Steud (Scrophulariaceae) that is widely used to treat diabetic disorders in Chinese traditional medicine using the name of Di-Huang, which is used to investigate the mechanisms for lowering of plasma glucose in streptozotocin-induced diabetic rats (STZ-diabetic rats). Catalpol decreased plasma glucose in a dose-related manner, and this action was reduced by pretreatment with naloxone or naloxonazine. An increase of plasma β-endorphin by catalpol was also observed in parallel. The plasma glucose lowering action of catalpol was deleted in bilateral adrenalectomized rats. Moreover, catalpol enhanced β-endorphin release from the isolated adrenal medulla of STZ-diabetic rats. Otherwise, plasma glucose lowering action of catalpol failed to produce in opioid μ-receptor knockout mice. Also, repeated administration of catalpol for 3 days in STZ-diabetic rats resulted in a marked reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression in liver and an increased expression of glucose transporter subtype 4 (GLUT 4) in skeletal muscle. These effects were also reversed by blockade of opioid μ-receptors. Our results suggested that catalpol increased glucose utilization through increase of β-endorphin secretion from adrenal gland in STZ-diabetic rats.

Improvement of Insulin Resistance by Chlorella in Fructose‐rich Chow‐fed Rats

Chlorella is a type of unicellular fresh water algae. In an attempt to develop new agents for handling insulin resistance, Chlorella was employed to screen the effect on insulin resistance in rats induced by fructose-rich chow. A single oral administration of Chlorella for 90 min decreased the plasma glucose in a dose-dependent manner in rats receiving 4-week fructose-rich chow. In addition, chronic treatment with Chlorella for 15 days also lowered plasma glucose in the same manner. Then, the insulin action on glucose disposal rate was measured using the glucose-insulin index, values of the areas under the curves of glucose and insulin during the intraperitoneal glucose tolerance test (IPGTT). Oral administration (three times daily for 5 days) of Chlorella to rats receiving 4 weeks of fructose-rich chow abolished the elevated value of the glucose-insulin index, indicating that Chlorella has an ability to improve insulin resistance. An increase of insulin sensitivity by Chlorella was further evaluated using the plasma glucose lowering action of exogenous insulin in streptozotocin-induced diabetic rats (STZ-diabetic rats). Oral administration of Chlorella three times daily to STZ-diabetic rats increased the response to exogenous insulin 15 days later. The obtained results suggest that oral administration of Chlorella has the ability to improve insulin sensitivity, which may be used as an adjuvant therapy for patients with insulin resistance.

Decrease of Plasma Glucose by Allantoin, an Active Principle of Yam (Dioscorea spp.), in Streptozotocin-Induced Diabetic Rats

The effect of allantoin, an active component of yam, on plasma glucose of streptozotocin-induced diabetic rats (STZ-diabetic rats) is investigated. Allantoin decreased plasma glucose levels in a dose-related manner, which was reduced by pretreatment with naloxone or naloxonazine. A concomitant increase in plasma β-endorphin, detected by enzyme-linked immunosorbent assay, was observed. Moreover, allantoin enhanced β-endorphin release from the isolated adrenal medulla of STZ-diabetic rat in a dose-related manner. However, its plasma glucose lowering action was reduced but not totally abolished by bilateral adrenalectomy. Furthermore, allantoin directly increased radioactive glucose uptake in isolated skeletal muscle, and repeated administration for 3 days increased GLUT4 mRNA and protein levels in muscle. This effect was markedly reduced in STZ-diabetic rats with bilateral adrenalectomy. This study suggests that allantoin increases GLUT4 gene expression in muscle by increasing β-endorphin secretion from the adrenal gland in STZ-diabetic rats.

Mediation of Endogenous β‐Endorphin in the Plasma Glucose‐Lowering Action of Herbal Products Observed in Type 1‐Like Diabetic Rats

Recently, there have been advances in the development of new substances effective in managing diabetic disorders. Opioid receptors couple multiple systems to result in various biological effects, although opioids are best known for analgesia. In the present review, we used our recent data to describe the advance in plasma glucose-lowering action of herbal products, especially the mediation of β-endorphin in glucose homeostasis of insulin-deficient diabetes. In type 1-like streptozotocin-induced diabetic rats, we identified many products purified from herbs that show a dose-dependent plasma glucose-lowering action. Increase in β-endorphin secretion from the adrenal gland may activate peripheral opioid μ-receptors (MOR) to enhance the expression of muscle glucose transporters and/or to reduce hepatic gluconeogenesis at the gene level, thereby leading to improved glucose utilization in peripheral tissues for amelioration of severe hyperglycemia. It has also been observed that stimulation of α 1-adrenoceptors (α 1-ARs) in the adrenal gland by some herbal products is responsible for the increase in β-endorphin secretion via a phospholipase C-protein kinase dependent pathway. However, an increase in β-endorphin secretion from the adrenal gland by herbal products can function via another receptor. New insights into the mediation of endogenous β-endorphin activation of peripheral MOR by herbal products for regulation of glucose homeostasis without the presence of insulin have been established. Therefore, an increase in β-endorphin secretion and/or direct stimulation of peripheral MOR via an insulin-independent action might serve as the potential target for development of a therapeutic agent or promising adjuvant in intensive plasma glucose control.

Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist.

GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic β-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclization of the phenylpropanoic acid moiety of lead compound 1 produced fused phenylalkanoic acids with favorable in vitro agonist activities and pharmacokinetic profiles. Further optimization led to the discovery of dihydrobenzofuran derivative 9a ([(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate, TAK-875) as a potent, selective, and orally bioavailable GPR40 agonist, with a pharmacokinetic profile enabling long-acting drug efficacy. Compound 9a showed potent plasma glucose-lowering action and insulinotropic action during an oral glucose tolerance test in female Wistar fatty rats with impaired glucose tolerance. Compound 9a is currently in clinical trials for the treatment of type 2 diabetes mellitus.

The plasma glucose lowering action of tetrandrine in streptozotocin-induced diabetic rats.

The effect of tetrandrine, an active principle of Stephaniae tetrandrae, on the plasma glucose level in streptozotocin-induced diabetic rats (STZ-diabetic rats) was investigated. A single intravenous injection of tetrandrine decreased the plasma glucose in a dose-dependent manner in STZ-diabetic rats. Moreover, tetrandrine (1.0 mg x kg(-1)) significantly attenuated the rise in plasma glucose induced by the intravenous glucose challenge test in normal rats. A stimulatory effect of tetrandrine on glucose uptake was obtained in soleus muscles isolated from STZ-diabetic rats with a concentration-dependent manner from 0.01 to 10.0 micromol L(-1). The increase in glucose utilization by tetrandrine was further characterized using the enhancement of glycogen synthesis in the hepatocytes of STZ-diabetic rats. These results suggest that tetrandrine has the ability to enhance glucose utilization in peripheral tissue, resulting in the lowering of plasma glucose in diabetic rats lacking insulin.

Corni fructus as the major herb of Die-Huang-Wan for lowering plasma glucose in Wistar rats

Die-Huang-Wan is a mixture of six herbs used to lower plasma glucose by increasing insulin secretion in normal rats. Die-Huang-Wan contains the herbs dioscorea (Dioscoreae rhizoma), cornus (Corni fructus), alisma (Rhizoma alismatis), holelen (Poria), rehmannia (Rehmanniae radix) and tree peony bark (Moutan radicis cortex). The present study was designed to clarify the major herb contributing to the plasma glucose-lowering action of Die-Huang-Wan in rats. A decrease in plasma glucose was not observed in Wistar rats treated with the cornus-deleted formula of Die-Huang-Wan; however, the action was retained in the other herb-deleted formulas containing cornus. In normal rats, the decrease in plasma glucose and increase in plasma insulin concentrations were dependent on the dose of cornus and were similar to those produced by Die-Huang-Wan. Treatment of Wistar rats with each of the other five herbs separately did not result in a decrease in plasma glucose. Moreover, the increase in plasma insulin or reduction in plasma glucose resulting from cornus treatment was blocked by atropine or 4-diphenylacetoxy-N-methylpiperidine methiodide mustard, indicating mediation of muscarinic M(3) receptors similar to that caused by Die-Huang-Wan. These results suggest that cornus is the major contributor to the plasma glucose-lowering action in Die-Huang-Wan in normal rats.

Opening of ATP-sensitive Potassium Channel by Insulin in the Brain-induced Insulin Secretion in Wistar Rats

Cerebral insulin can regulate glucose homeostasis via activation of the parasympathetic nervous system, which results in the reduction of hepatic glucose output. However, the precise mechanism(s) through which cerebral insulin directly exerts an effect on insulin secretion remains unclear. In the present study, we found that cerebral administration of insulin caused an increase of plasma insulin concentration and a concomitant decrease in plasma glucose levels within one hour. These effects were blocked by vagotomy or intraperitoneal injection of 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide, a specific M (3) antagonist. The mediating influence of parasympathetic activation can thus be considered. The adenosine triphosphate-sensitive potassium (K-ATP) channel is a key mediator of the cerebral action of insulin. The plasma glucose-lowering action of insulin was abolished by cerebral administration of glibenclamide or repaglinide at concentrations sufficient to block K-ATP channels. In conclusion, our findings suggest that cerebral insulin may induce insulin release by stimulating the opening of K-ATP channels, which in turn activate parasympathetic tone in pancreatic tissue.

Increase in Plasma Glucose Lowering Action of Rosiglitazone by Electroacupuncture at Bilateral Zusanli Acupoints (ST.36) in Rats

Objectives Hypoglycemia induced by electroacupuncture (EA) is due to an increase of insulin secretion and/or mediation of β-endorphin. We applied EA at the Zusanli (ST.36) acupuncture point (acupoint) in combination with rosiglitazone (TZD) administration to evaluate their effect on plasma glucose and to explore possible mechanisms of action. Methods Thirty six normal adult Wistar rats were randomly divided into four groups: the 0.1 mg/kg TZD group (0.1TZD), 0.1 mg/kg TZD and EA group (0.1TZD + EA), EA group, and control group. In other experiments, streptozotocin was used to induce type 2 diabetes mellitus in neonatal rats; these were then randomly divided into a 0.1TZD group, 0.1TZD + EA group, and EA group and changes in plasma glucose and insulin concentrations evaluated. Results A marked hypoglycemic response was observed in the normal rat 0.1TZD, 0.1TZD + EA and EA groups, with the response more significant in the 0.1TZD + EA group than in the 0.1TZD group. Among the diabetic animals, the hypoglycemic responses in the 0.1TZD + EA and EA groups were greater than in the 0.1TZD group. In both the normal and diabetic rats, insulin secretion was increased by EA or 0.1TZD + EA treatment, but not by 0.1TZD. Conclusions The plasma glucose lowering action of rosiglitazone was increased by EA in both normal and diabetic rats, indicating that the application of EA may enhance the hypoglycemic action of this insulin sensitizer.

The amelioration of streptozotocin diabetes-induced renal damage by Wu-Ling-San (Hoelen Five Herb Formula), a traditional Chinese prescription

Ethnopharmacological relevance Wu-Ling-San (Hoelen Five Herb Formula) is a Chinese prescription used to promote water metabolism. Aim of the study The present study was undertaken to characterize the effects of Wu-Ling-San on diabetic nephropathy. Materials and methods Streptozotocin (STZ)-diabetic rats were orally administrated with Wu-Ling-San (0.5, 1.5, 2.5 g/(kg day)) once a day for 10 weeks. Changes in the renal function related parameters in plasma and urine were analyzed at the end of 10-week administration. Kidney was isolated for pathology histology, immunohistochemistry staining and Western blot analyses. Results Wu-Ling-San (2.5 g/(kg day)) partially decreased the high plasma glucose level in diabetic rats. Diabetic-dependent alterations in urinary albumin, 24-h urinary albumin excretion rate, creatinine clearance, and glomerular mesangial matrix expansion were ameliorated by Wu-Ling-San. The increased expression of nuclear factor-kB as well as transforming growth factor-β 1 and the progressive accumulation of fibronectin in kidney of diabetic rats were attenuated by Wu-Ling-San. Not only the elevated levels of advanced glycation end products (AGEs) and mitochondrial thiobarbituric acid-reactive substance, but also the higher levels of N ɛ-(carboxymethyl)lysine and receptor for AGEs in kidney of diabetic rats were ameliorated by Wu-Ling-San. Conclusions : Wu-Ling-San posses an anti-diabetic property with plasma glucose lowering action accompanied with amelioration of glycation-mediated renal damage.

Synthesis and biological evaluation of sulfonylurea and thiourea derivatives substituted with benzenesulfonamide groups as potential hypoglycemic agents

A novel class of sulfonylurea and thiourea derivatives substituted with benzenesulfonamide groups were designed and synthesized. The target compounds were assayed for the effects on the insulin release of isolated rat pancreatic islets and the glucose transport in adipocytes of rats. Some of them exhibited high potency. Compound 10 also had potent antiplatelet activity and showed an excellent property to protect collagen–epinephrine-induced mice mortality as well as plasma glucose-lowering activity in vivo. The preliminary pharmacological profile of compound 10 showed that it might be useful in the treatment of diabetics with cardiovascular and nephropathy complications.

Plasma Glucose Lowering Effect of the Wild Satureja khuzestanica Jamzad Essential Oil in Diabetic Rats: Role of Decreased Gluconeogenesis

This study was to evaluate the effect of the wild SKEO on activities and genes expression of hepatic Glycogen Phosphorylase (GP) and phosphoenolpyruvate carboxykinase (PEPCK) in normal and diabetic rats. The wild SKEO was orally administered at different doses (50 and 100 mg/kg/day) to normal as well as diabetic rats for 21 days. The levels of mRNA were determined using the quantitative real-time RT-PCR technique. The plasma glucose concentrations of diabetic rats receiving SKEO (100 mg kg(-1)) compared with diabetic control were significantly decreased. Hepatic GP activity and its mRNA levels of diabetic rats treated with SKEO moderately increased. The activity of hepatic PEPCK and its mRNA levels were significantly decreased in normal rats treated with SKEO (100 mg kg(-1)). The enhancement of PEPCK activity and its mRNA levels of diabetic treated rats with SEKO (100 mg kg(-1)) was significantly decreased compared with diabetic control. In conclusion, an excessive inhibition of PEPCK in liver of diabetic rats treated with the wild SKEO may contribute to the plasma glucose lowering action of SKEO that seems to be in relation with antioxidant properties of SKEO.

Activation of I2-imidazoline receptors may ameliorate insulin resistance in fructose-rich chow-fed rats

Agmatine, an endogenous ligand of imidazoline receptors, was employed to screen the effect on insulin resistance in rats induced by a diet containing 60% fructose. Single intravenous (i.v.) injection of agmatine sulfate for 30min decreased the plasma glucose concentrations in a dose-dependent manner from 0.5mg/kg to 3mg/kg in rats received 4-week fructose-rich chow without an alteration of systolic blood pressure. The plasma glucose lowering action of agmatine (1mg/kg, i.v.) was abolished by the pretreatment with BU224 (1mg/kg, i.v.) at sufficient dosage to block I2-imidazoline receptors. In addition, the value of glucose–insulin index, the areas under the curve of glucose and insulin during the intraperitoneal glucose tolerance test, showing an index of in vivo insulin sensitivity was reversed by the same treatment with agmatine in fructose-rich chow-fed rats; this action was also blocked by BU224. Our results suggest that activation of I2-imidazoline receptor to improve insulin action on glucose disposal can be considered for targeting glucose metabolism under insulin-resistant state.

Role of sympathetic tone in the loss of syringin-induced plasma glucose lowering action in conscious Wistar rats

Syringin is an active principle purified from the rhizome and root parts of Eleutherococcus senticosus (Araliaceae). The present study is designed to clarify the role of sympathetic activation in the insulinotropic effect of syringin. Plasma glucose lowering effect accompanying with the increase of plasma insulin and C-peptide were obtained in pentobarbital anesthetized Wistar rats 60 min after an intravenous (i.v.) injection of syringin (100 μg/kg). However, neither the plasma glucose lowering action, nor the raised plasma levels of insulin and C-peptide can be obtained in conscious rats received same syringin treatment. Otherwise, the insulin-releasing and plasma glucose lowering actions of syringin (100 μg/kg, i.v.) were appeared in conscious rats under chemical sympathectomy using an intraperitoneal injection of guanethidine. In addition, plasma glucose lowering action of syringin (100 μg/kg, i.v.) was observed in conscious rats with α 1-adrenoceptor blockade by prazosin. The stimulatory actions of syringin on the secretion of plasma insulin and C-peptide were also obtained in prazosin-treated conscious rats. The obtained results suggest that insulinotropic effect of syringin on the plasma glucose regulation is impaired in conscious rats with a regular sympathetic tone; decrease of sympathetic tone as observed in anesthetized animal might be helpful in the therapeutic benefit of syringin.

Release of acetylcholine by syringin, an active principle of Eleutherococcus senticosus, to raise insulin secretion in Wistar rats

The present study is designed to screen the effect of syringin, an active principle purified from the rhizome and root parts of Eleutherococcus senticosus (Araliaceae), on the plasma glucose and investigate the possible mechanisms. Plasma glucose decreased in a dose-dependent manner 60 min after intravenous injection of syringin into fasting Wistar rats. In parallel to the decrease of plasma glucose, increases of plasma insulin level as well as the plasma C-peptide was also observed in rats receiving same treatment. Both the plasma glucose lowering action and the raised plasma levels of insulin and C-peptide induced by syringin were also inhibited by 4-diphenylacetoxy-N-methylpiperdine methiodide (4-DAMP), the antagonist of the muscarinic M3 receptors, but not affected by the ganglionic nicotinic antagonist, pentolinium or hexamethonium. Moreover, disruption of synaptic available acetylcholine (ACh) using an inhibitor of choline uptake, hemicholinium-3, or vesicular acetylcholine transport, vesamicol, abolished these actions of syringin. Also, physostigmine at concentration sufficient to inhibit acetylcholinesterase enhanced the actions of syringin. Mediation of ACh release from the nerve terminals to enhance insulin secretion by syringin can thus be considered. The results suggest that syringin has an ability to raise the release of ACh from nerve terminals, which in turn to stimulate muscarinic M3 receptors in pancreatic cells and augment the insulin release to result in plasma glucose lowering action.