Yarrowia lipolytica biomass-a potential additive to boost metabolic and physiological responses of Nile tilapia.

We studied the effects of Yarrowia lipolytica biomass on digestive enzymes, blood biochemical profile, energy metabolism enzymes, and proximate meat composition of Nile tilapias. The experiment was entirely randomized with four replications. The animals (n = 20 per repetition) were fed with 0%, 3%, 5%, and 7% of biomass for 40 days and then blood and liver were analyzed. There was an increase in the activities of chymotrypsin (5, 7% groups), trypsin (3, 5% groups), and sucrase (7% group) compared to the respective control groups. On the other hand, maltase activity was significantly reduced for all yeast biomass treatments, while the supplementation did not influence lipase and amylase activities. Moreover, the blood triacylglycerol concentrations were increased in the 7% group, while any treatment modified blood total cholesterol, glycemia, and hepatic glycogen content. Y. lipolytica biomass promoted significant increases in meat protein and lipid contents without changes in moisture and ash parameters. Furthermore, Y. lipolytica biomass promoted increases in hexokinase (3% group), phosphofructokinase (5, 7% groups), glucose-6-phosphate dehydrogenase (5% group), citrate synthase (3% group), aspartate aminotransferase and alanine aminotransferase (3% group), and glutamate dehydrogenase (3, 5% groups) compared to the respective control groups. At the same time, no changes were observed in the activity of glucose-6-phosphatase. Y. lipolytica biomass supplementation in tilapias' diet can modulate the digestive system and improve nutrient disponibility to the cells. Moreover, the changes in the metabolic profile and in energy metabolism can be correlated with the improvement of meat composition. Therefore, the Y. lipolytica biomass has a great potential to be used as a feed ingredient for Nile tilapias.

Immunomodulatory effects of Yarrowia lipolytica as a food additive in the diet of Nile tilapia.

The use of yeasts as a dietary additive for fish can act as a source of nutrients and as an immunostimulant. This work aimed to evaluate the effects of the fermented biomass of the yeast Yarrowia lipolytica as a food additive on zootechnical and hematological parameters, and on immune response in the plasma and kidney of Nile Tilapia (Oreochromis niloticus). After supplementation with 3, 5, and 7% of the yeast biomass for 35 days, the blood and tissues of the animals of each experimental group were collected for analysis. The addition of this biomass in the feed promoted an improvement of zootechnical parameters in tilapia. There was also a rise in the number of neutrophils (groups with 3, 5, and 7%) and monocytes (group 3, 5, and 7%) compared with the control group. Moreover, there was an increase in the levels of lysozyme, myeloperoxidase, and nitrite/nitrate content in the blood of animals fed with yeast biomass. On the other hand, there were no observed alterations in survival and hematological parameters of animals fed with yeast biomass. In the analysis of the kidney, the addition of biomass in feed promoted an increase in levels of myeloperoxidase (group with 3%) but did not alter the levels of lysozyme and nitrite/nitrate content. In conclusion, this study demonstrated that Y. lipolytica had growth and immunostimulatory effects on Nile tilapia. These findings strongly suggest the potential application of a Y. lipolytica-based immunostimulant for tilapia aquaculture.

Biological activity of 2α,3ß,23-trihydroxyolean-12-ene on glucose homeostasis.

We studied the effect and the mechanisms of action of 2α,3ß,23-trihydroxyolean-12-ene (THO), from Croton heterodoxus Baill. (Euphorbiaceae), in glucose uptake in hyperglycemic rats. The effect of in vivo pretreatment with THO in hyperglycemic rats was analyzed. The in vitro effects of THO were observed in adipocytes and in adipose tissue. THO reduced glycemia, in part by increasing serum insulin and augmenting the disposal of glucose as glycogen in hepatocytes but did not change the serum concentration of glucagon-like peptide-1. THO increased glucose uptake in adipocytes and in adipose tissue by a mechanism dependent on phosphatidylinositol 3-kinase vesicular traffic and on the process of vesicle fusion at the plasma membrane in regions containing cholesterol, indicating the involvement of glucose transporter-4 (GLUT4). This triterpene may act solely via the activation and translocation of GLUT4 (rather than via nuclear actions, such as upregulation of GLUT4 synthesis), since THO did not alter the amount of GLUT4 mRNA or the content of GLUT4. Consistent with these data, the stimulatory effect of this triterpene on the quantity of GLUT4 in the membrane fraction was dependent upon p38 phosphorylation. In this experimental model, orally administered 10 mg/kg THO did not modulate extracellular serum lactate dehydrogenase. In conclusion, THO decreases hyperglycemia by increasing serum insulin and hepatic glycogen content. The THO mechanism of action on adipose tissue for glucose uptake is suggested to be via GLUT4 translocation stimulation mediated by a p38-dependent mechanism. THO is a potential antihyperglycemic agent that acts in a target tissue for glucose homeostasis.

Fern-9(11)-ene-2α,3ß-diol Action on Insulin Secretion under Hyperglycemic Conditions.

The objective of this study was to investigate the effect and the mechanism of action of fernenediol as an insulin secretagogue. Wistar rats were treated with 0.1, 1, and 10 mg/kg fernenediol before inducing hyperglycemia by oral glucose. The glycaemia, insulin, LDH, calcium, and hepatic glycogen were analyzed. Considering the intestine and pancreas as targets for the triterpene action, the duodenum was used to verify the influence of fernenediol on intestinal glycosidases. Additionally, pancreatic islets were used for studies of 14C-deoxyglucose uptake and the influx of 45Ca2+ in hyperglycemic media with/without fernenediol in the presence/absence of an inhibitor/activator of KATP channels, glibenclamide, diazoxide, nifedipine, calcium chelator (BAPTA-AM), and H-89 and ST, the inhibitors of the PKA and PKC enzymes. Fernenediol significantly reduced glycaemia, potentiated glucose-induced insulin secretion, and stimulated liver glycogen deposition in hyperglycemic rats after an in vivo treatment without changing intestinal disaccharidases activities and showing no influence on intestinal glucose absorption. Also, it stimulated the glucose uptake and calcium influx in pancreatic islets. The involvement of voltage-dependent L-type calcium channels and ATP-dependent potassium channels and the release of calcium from intracellular stores are mandatory for the stimulatory effect of fernenediol on calcium influx. Fernenediol did not change PKA and PKC activities or modify calcium levels. This triterpene is a potent antihyperglycemic agent with a strong insulin secretagogue effect on glycogen accumulation as well. As a whole, this compound presents significant perspectives as a future new drug for the treatment of insulin resistance and/or diabetes.

The potent insulin secretagogue effect of betulinic acid is mediated by potassium and chloride channels.

Betulinic acid (BA) has been described as an insulin secretagogue which may explain its potent antihyperglycemic effect; however, the exact role of BA as an insulinogenic agent is not clear. The aim of this study was to investigate the mechanism of BA on calcium influx and static insulin secretion in pancreatic islets isolated from euglycemic rats. We found that BA triggers calcium influx by a mechanism dependent on ATP-dependent potassium channels and L-type voltage-dependent calcium channels. Additionally, the voltage-dependent and calcium-dependent chloride channels are also involved in the mechanism of BA, probably due to an indirect stimulation of calcium entry and increased intracellular calcium. Additionally, the downstream activation of PKC, which is necessary for the effect of BA on calcium influx, is involved in the full stimulatory response of the triterpene. BA stimulated the static secretion of insulin in pancreatic islets, indicating that the abrupt calcium influx may be a key step in its secretagogue effect. As such, BA stimulates insulin secretion through the activation of electrophysiological mechanisms, such as the closure of potassium channels and opening of calcium and chloride channels, inducing cellular depolarization associated with metabolic-biochemical effects, in turn activating PKC and ensuring the secretion of insulin.

Evaluation of the antioxidant system and neurotoxic effects observed in Rhamdia branneri (Teleostei: Heptapteridae) sampled from streams of the lower Iguazu River basin.

The use of multiple biomarkers has been shown to be an efficient method for evaluating environmental contamination. In this work, we evaluate neurotoxic effects and the antioxidant system responses of the R. branneri collected in two streams of lower Iguazu River basin, relating them with different percentage of vegetation coverture, presence of pesticides and fall and winter seasons. The biological samples were collected in March and August of 2015, from two streams that belong to the lower Iguazu River basin (Brazil): the Manoel Gomes River and the Arquimedes Stream. Soil analyses were performed, and the results showed the presence of the following organophosphates in the Manoel Gomes River and the Arquimedes Stream: disulfoton, methyl parathion, and ronnel. The present study detected inhibition of cholinesterase activity in the brain and muscle of fish samples during the fall from the Manoel Gomes River and the Arquimedes Stream. In the Manoel Gomes River, elevated lipoperoxidation was also observed during the fall. It was observed that the increase or decrease of biomarkers was related to temporal variation and, possibly, to the exposure of animals to agrochemicals. Although the Manoel Gomes River and the Arquimedes Stream are located in regions with large areas of vegetation, the soil analyses show that agrochemical residues are able to reach these locations, which suggests that the fauna are in contact with oxidant and anti-cholinesterase agents during the fall, in addition to respond differently during each season.

In vivo potential hypoglycemic and in vitro vasorelaxant effects of Cecropia glazioviistandardized extracts

ABSTRACTThe aim of this study is to investigate the effect of Cecropia glaziovii Snethl, Urticaceae, extracts on the oral glucose tolerance curve, on glycemia in alloxan-induced diabetic rats and vasorelaxant effect after the extraction process, and to standardize the extractive solutions. The effects of the process variables and their interactions were calculated in relation to dry residue, pH, total phenolic results and chemical marker content. Furthermore, the effect of the extracts (400 mg/kg), chlorogenic (2 or 15 mg/kg) and caffeic acids (2 mg/kg) were investigated on the oral glucose tolerance curve and on glycemia in alloxan-induced diabetic rats. Oral administration of ethanol extracts 4d20 and 8d20 significantly improved glucose tolerance in the hyperglycemic rats. Chlorogenic and caffeic acids, as well as the association of the compounds were able to significantly reduce glycemia after oral gavage treatments. On the other hand, the aqueous extracts did not alter the glycemia. The aqueous extracts (8020 and 9030) and only the higher dose of chlorogenic acid presented a significant effect on serum glucose lowering in diabetic rats. Additionally, the IC50 reveals that the ethanol extracts presented more potent vasodilator effects than the aqueous extracts in aortic rings. This study shows that C. glazioviistandardized extracts exhibits antihyperglycemic action, is able to improve glucose tolerance and has a potent vascular relaxing effect. These results are probably linked to concentrations of the main phenolic compounds of the extracts.

Acute effect of 3ß-hidroxihop-22(29)ene on insulin secretion is mediated by GLP-1, potassium and calcium channels for the glucose homeostasis.

The effect of 3ß-hidroxihop-22(29)ene (3-BHO) on insulin and glucagon-like peptide 1 (GLP-1) secretion as well as the mechanism of action of the compound in pancreatic islet on glucose homeostasis was investigated. The data from in vivo treatment show that 3-BHO significantly reduces the hyperglycemia by increasing the insulin and GLP-1 secretion, as well as by accumulating hepatic glycogen in hyperglycemic rats. In rat pancreatic ß-cell, 3-BHO stimulates the glucose uptake, insulin vesicles translocation to the plasma membrane and thus the insulin secretion through the involvement of potassium channels (ATP- and Ca(2+)-dependent K(+) channels) and calcium channels (L-type voltage-dependent calcium channels (L-VDCC)). Furthermore, this study also provides evidence for a crosstalk between intracellular high calcium concentration, PKA and PKC in the signal transduction of 3-BHO to stimulate insulin secretion. In conclusion, 3-BHO diminishes glycaemia, stimulates GLP-1 secretion and potentiates insulin secretion and increase hepatic glycogen content. Moreover, this triterpene modulates calcium influx characterizing ATP-K(+), Ca(2+)-K(+) and L-VDCC channels-dependent pathways as well as PKA and PKC activity in pancreatic islets underlying the signaling of 3-BHO for the secretory activity and contribution on glucose homeostasis.

The mechanism of action of ursolic acid as insulin secretagogue and insulinomimetic is mediated by cross-talk between calcium and kinases to regulate glucose balance.

BACKGROUND: The effect of in vivo treatment with ursolic acid (UA) on glycemia in hyperglycemic rats and its mechanism of action on muscle were studied. METHODS: The UA effects on glycemia, glycogen, LDH, calcium and on insulin levels were evaluated after glucose tolerance curve. The ß-cells were evaluated through the transmission electron microscopy. UA mechanism of action was studied on muscles through the glucose uptake with/without specific insulin signaling inhibitors. The nuclear effect of UA and the GLUT4 expression on muscle were studied using thymidine, GLUT4 immunocontent, immunofluorescence and RT-PCR. RESULTS: UA presented a potent antihyperglycemic effect, increased insulin vesicle translocation, insulin secretion and augmented glycogen content. Also, UA stimulates the glucose uptake through the involvement of the classical insulin signaling related to the GLUT4 translocation to the plasma membrane as well as the GLUT4 synthesis. These were characterized by increasing the GLUT4 mRNA expression, the activation of DNA transcription, the expression of GLUT4 and its presence at plasma membrane. Also, the modulation of calcium, phospholipase C, protein kinase C and PKCaM II is mandatory for the full stimulatory effect of UA on glucose uptake. UA did not change the serum LDH and serum calcium balance. CONCLUSIONS: The antihyperglycemic role of UA is mediated through insulin secretion and insulinomimetic effect on glucose uptake, synthesis and translocation of GLUT4 by a mechanism of cross-talk between calcium and protein kinases. GENERAL SIGNIFICANCE: UA is a potential anti-diabetic agent with pharmacological properties for insulin resistance and diabetes therapy.

Betulinic acid and 1,25(OH)2 vitamin D3 share intracellular signal transduction in glucose homeostasis in soleus muscle.

The effect of betulinic acid on glycemia and its mechanism of action compared with 1,25(OH)2 vitamin D3 in rat muscle were investigated. Betulinic acid improved glycemia, induced insulin secretion and increased the glycogen content and glucose uptake in muscle tissue. Additionally, the integrity of both PI3K and the cytoskeleton is necessary for the stimulatory action of betulinic acid in glucose uptake. The genomic effect was apparent, since cycloheximide and PD98059 nullified the stimulatory effect of betulinic acid on glucose uptake. Therefore, although this compound did not modify the DNA transcription, the protein translation was significantly improved. Also, betulinic acid increased the GLUT4 immunocontent and its translocation was corroborated by GLUT4 localization at the plasma membrane (after 180 min). On the other hand, the effect of 1,25(OH)2 vitamin D3 on glucose uptake is not mediated by PI3K and microtubule activity. In contrast, the nuclear activity of 1,25(OH)2 vitamin D3 is necessary to trigger glucose uptake. In addition, the increased DNA transcription and GLUT4 immunocontent provide evidence of a mechanism by which 1,25(OH)2 vitamin D3 contributes to glycemia. In conclusion, betulinic acid acts as an insulin secretagogue and insulinomimetic agent via PI3K, MAPK and mRNA translation and partially shares the genomic pathway with 1,25(OH)2 vitamin D3 to upregulate the GLUT4. In summary, betulinic acid regulates glycemia through classical insulin signaling by stimulating GLUT4 synthesis and translocation. In addition, it does not cause hypercalcemia, which is highly significant from the drug discovery perspective.

Involvement of GLUT-4 in the stimulatory effect of rutin on glucose uptake in rat soleus muscle.

OBJECTIVES: The aim of this study was to investigate the in-vitro effect of rutin on glucose uptake in an insulin target (soleus muscle) and the mechanism of action involved. METHODS: Isolated soleus muscles from rats were treated with rutin (500 µm) with or without the following inhibitors; hydroxy-2-naphthalenylmethylphosphonic acid trisacetoxymethyl ester (HNMPA(AM)3 ), an insulin receptor tyrosine kinase activity inhibitor, wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K), RO318220, an inhibitor of protein kinase C, colchicine, a microtubule-depolymerizing agent, PD98059, an inhibitor of mitogen-activated protein kinase kinase (MEK), and cycloheximide, an inhibitor of protein synthesis on fresh Krebs Ringer-bicarbonate plus [U-(14) C]-2-deoxy-d-glucose (0.1 µCi/ml). Samples of tissue medium were used for the radioactivity measurements. KEY FINDINGS: Rutin increased the glucose uptake in rat soleus muscle. In addition, the effect of rutin on glucose uptake was completely inhibited by pretreatment with HNMPA(AM)3 , wortmannin, RO318220, colchicine, PD98059, and cycloheximide. These results suggested that rutin stimulated glucose uptake in the rat soleus muscle via the PI3K, atypical protein kinase C and mitogen-activated protein kinase (MAPK) pathways. Also, rutin may have influenced glucose transporter translocation and may have directly activated the synthesis of the transporter GLUT-4. CONCLUSION: The similarities of rutin action on glucose uptake compared with the signalling pathways of insulin constitute strong evidence for the insulin-mimetic role of rutin in glucose homeostasis.

Insulin signaling: a potential signaling pathway for the stimulatory effect of kaempferitrin on glucose uptake in skeletal muscle.

The aim of the study was to investigate the in vitro effect and the mechanism of action of kaempferitrin on glucose uptake in an insulin target (soleus muscle). A stimulatory effect of kaempferitrin on glucose uptake was observed when rat soleus muscle was incubated with 10, 100 and 1000 ηM of this flavonoid glycoside. The presence of specific insulin signaling inhibitors, such as wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K), RO318220, an inhibitor of protein kinase C (PKC), PD98059, an inhibitor of mitogen-activated protein kinase (MEK), HNMPA(AM)3, an insulin receptor tyrosine kinase activity inhibitor, colchicine, a microtubule-depolymerizing agent, SB239063, an inhibitor of P38 MAPK and cycloheximide, an inhibitor of protein synthesis showed that kaempferitrin triggers different metabolic and nuclear pathways in skeletal muscle. Besides the influence on glycogen storage, the metabolic action involves the insulin receptor, PI3K, atypical PKC activity and the translocation of GLUT4. Additionally, the nuclear pathways (via MAPK and MEK) provide evidence of the stimulation of the expression of glucose transporters or other signaling proteins, reinforcing proposals that skeletal muscle represents a primary site at which kaempferitrin exerts its effect promoting glucose homeostasis. Also, these similarities with the signaling pathways of insulin constitute strong evidence for the insulin-mimetic role of kaempferitrin in glucose homeostasis.

Anti-hyperglycemic action of apigenin-6-C-ß-fucopyranoside from Averrhoa carambola.

A stimulatory effect of apigenin-6-C-ß-fucopyranoside (1) on glucose uptake was observed when rat soleus muscle was incubated with 1, 10 and 100 µM of this flavonoid glycoside. The presence of specific insulin signaling inhibitors, such as wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K), RO318220, an inhibitor of protein kinase C (PKC), PD98059, an inhibitor of mitogen-activated protein kinase (MEK), and HNMPA(AM)3, an insulin receptor tyrosine kinase activity inhibitor showed that apigenin-6-C-ß-fucopyranoside triggers different metabolic pathways in skeletal muscle. The oral administration of crude extract, fractions and isolated flavonoids (apigenin-6-C-ß-fucopyranoside (1) and apigenin-6-C-(2″-O-α-rhamnopyranosyl)-ß-fucopyranoside (2)) from Averrhoa carambola leaves exhibited a potential hypoglycemic activity in hyperglycemic normal rats. Additionally, both flavonoids significantly increased the muscle and liver glycogen content after an acute treatment. The results indicate that A. carambola can be regarded as a potent antihyperglycemic agent with insulin secretagogue and insulin mimetic properties.

Effects of flavonoids on α-glucosidase activity: potential targets for glucose homeostasis.

OBJECTIVE: Flavonoids are naturally occurring compounds widely distributed in plants, which have hypoglycemic potential and have been described as glucosidase inhibitors. This study evaluated the effect of flavonoids on intestinal glucosidase activity after in vivo and in vitro treatment. METHODS: For the in vivo studies animals received quercetin by gavage and for the in vitro assays a segment of the small intestine was used. To obtain the oral glucose tolerance curve fasted normal rats were loaded with glucose plus flavonoids. The glycemia was measured by the glucose oxidase method. RESULTS: Quercetin reduced the effect of sucrase and maltase in the in vivo and in vitro treatments. It was observed in the in vitro studies that the maximum inhibitory effect of kaempferitrin was around 23% for maltase activity. Also, for the sucrose substrate the specific enzyme activity was significantly decreased. Aglycone, flavonoids, and kaempferol decreased significantly the maltase activity at all concentrations assayed. Finally, rutin reduced maltase-specific activity at all concentrations studied. According to the oral glucose tolerance curve, rutin reduced the serum glucose levels at 15, 30, and 60 min when administered by oral gavage 30 min before glucose overload in rats. CONCLUSION: Based on these results, we can conclude that disaccharidases are targets of flavonoids in the regulation of glucose absorption and consequently glucose homeostasis.

Potential insulin secretagogue effects of isovitexin and swertisin isolated from Wilbrandia ebracteata roots in non-diabetic rats.

The antihyperglycemic effect and mechanism of action of extracts, fractions and compounds from Wilbrandia ebracteata was studied. The crude extract reduced the glycemia, increased glycogen content and serum insulin in hyperglycemic rats. Also, a significant effect was observed with the n-butanol and metanol subfraction. However, the antihyperglycemic effect of the n-butanol fraction was not observed in diabetic rats. The C-glycosylflavones isovitexin and swertisin showed a strong antihyperglycemic action compared with the extracts and fractions. These results show that the extracts, fractions, and isolated C-glycosylflavones have an antihyperglycemic action that was reinforced by the stimulation on in vivo insulin secretion.

Antihyperglycemic activity of naphthylchalcones.

The purpose of the present work was to investigate, following previous works, naphthylchalcones as antihyperglycemic agent in glucose loaded animal model, insulin secretion as well as the action of these compounds on glucose uptake in a target tissue of insulin. The naphthylchalcones were found to have an acute serum glucose-lowering effect in hyperglycemic normal rats. In addition, chalcones 2 and 4 stimulated significantly the insulin secretion induced by glucose. These results suggest that the presence of nitro group and their position in the phenyl rings are responsible for the antihyperglycemic activity of chalcones. Additionally, the effect of chalcones on serum glucose-lowering seems to be a consequence of insulin secretion and these chalcones represent potential compounds with strong antihyperglycemic properties.

Nitrochalcones: potential in vivo insulin secretagogues.

In this study, the in vivo and in vitro anti-hyperglycemic activity of chalcone derivatives of 3,4-methylenedioxy, with a substituent electron-acceptor nitro group in the A or B ring, was investigated. As expected, the second generation sulfonylurea glipizide stimulated insulin secretion and reduced glycemia over the study period. Also, it was demonstrated for the first time that chalcones are able to increase insulin secretion and this event was coincident with serum glucose-lowering in the oral glucose tolerance test. Additionally, the chalcones studied had a similar effect on insulin secretion and serum glucose-lowering as glipizide. The effect of chalcones in terms of inducing insulin secretion was greater than that of glipizide after 30 min. Moreover, chalcones were not able to stimulate glucose uptake in soleus muscle, either in the presence of insulin or in the absence of this hormone. In addition, the oral treatment with chalcones did not alter glycemia in diabetic rats. These reports indicate that the effect of chalcones on serum glucose-lowering in hyperglycemic-normal rats is mainly a consequence of insulin secretion, highlighting these chalcones as novel compounds with strong anti-hyperglycemic properties.

Stimulatory effect of apigenin-6-C-beta-L-fucopyranoside on insulin secretion and glycogen synthesis.

In vivo and in vitro treatments were carried out to investigate the effects of apigenin-6-C-beta-L-fucopyranoside (1), isolated from Averrhoa carambola L. (Oxalidaceae), on serum glucose and insulin levels in hyperglycemic rats as well as its effect on glycogen synthesis in normal rat soleus muscle. Apigenin-6-C-beta-L-fucopyranoside showed an acute effect on blood glucose lowering in hyperglycemic rats and stimulated glucose-induced insulin secretion. A stimulatory effect of 1 on glycogen synthesis was observed when muscles were incubated with this flavonoid and also its effect was completely nullified by pre-treatment with insulin signal transduction inhibitors. Taking this into account, the MAPK-PP1 and PI3K-GSK3 pathways are involved in the apigenin-6-C-beta-L-fucopyranoside-induced increase in glycogen synthesis in muscle. This study provides evidence for dual effects of apigenin-6-C-beta-L-fucopyranoside as an antihyperglycemic (insulin secretion) as well as an insulinomimetic (glycogen synthesis) agent.

Signaling pathways of kaempferol-3-neohesperidoside in glycogen synthesis in rat soleus muscle.

Kaempferol 3-neohesperidoside is one of the several compounds that have been reported to have insulin-like properties in terms of glucose lowering. We studied the effect of kaempferol 3-neohesperidoside in glycogen synthesis in rat soleus muscle through the incorporation of (14)C-d-glucose in glycogen. Kaempferol 3-neohesperidoside stimulates glycogen synthesis in rat soleus muscle by approximately 2.38-fold. Insulin at 100 nM showed a stimulatory effect on glycogen synthesis when compared with the control group. The stimulatory effect of kaempferol 3-neophesperidoside on glycogen synthesis was inhibited by wortmannin, the phosphatidylinositol 3-kinase (PI3K) inhibitor, and enhanced by lithium chloride, a glycogen synthase kinase 3 (GSK-3) inhibitor. Moreover, the stimulatory effect of kaempferol 3-neohesperidoside was also nullified by PD98059, a specific inhibitor of mitogen-activated protein kinase (MEK) and by calyculin A, an inhibitor of protein phosphatase 1 (PP1) activity. It was concluded that the PI3K - GSK-3 pathway and MAPK - PP1 pathway are involved in the stimulatory kaempferol 3-neohesperidoside effect on glycogen synthesis in rat soleus muscle.