Department of Clinical Nutrition and Food and Health Research Centre, University of Eastern Finland, P.O. Polyphenols, including flavonoids, phenolic acids, proanthocyanidins and resveratrol, are a large and heterogeneous group of phytochemicals in plant-based foods, such as tea, coffee, wine, cocoa, cereal grains, soy, fruits and berries.
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Growing evidence indicates that various dietary polyphenols may influence carbohydrate metabolism at many levels. IntroductionPolyphenols are a large and heterogeneous group of phytochemicals of plant-based foods, such as tea, coffee, wine, cereal grains, vegetables, legumes, fruits and berries.
In animal models and a limited number of human studies carried out so far, polyphenols and foods or beverages rich in polyphenols have attenuated postprandial glycemic responses and fasting hyperglycemia, and improved acute insulin secretion and insulin sensitivity.
The structural diversity of polyphenols extends from simple one-phenol hydroxybenzoic and hydroxycinnamic acids to large polymeric macromolecules like proanthocyanidins and ellagitannins. The possible mechanisms include inhibition of carbohydrate digestion and glucose absorption in the intestine, stimulation of insulin secretion from the pancreatic ?–cells, modulation of glucose release from the liver, activation of insulin receptors and glucose uptake in the insulin-sensitive tissues, and modulation of intracellular signalling pathways and gene expression.
An essential group of phenolic compounds are flavonoids encompassing structural classes like flavonols, flavones, flavanols, flavanones, anthocyanidins and isoflavones.
The positive effects of polyphenols on glucose homeostasis observed in a large number of in vitro and animal models are supported by epidemiological evidence on polyphenol-rich diets.
Consumption of plant foods is associated with lowered risk of major chronic diseases including diabetes, cardiovascular diseases and cancer [2–5]. In vitro and in vivo studies on polyphenols show that polyphenols possess anti-inflammatory, antioxidative, chemopreventive and neuroprotective activities, suggesting that they could contribute to the health-protective properties of plant foods. Growing evidence indicates that dietary polyphenols also influence glucose and lipid metabolismThe majority of dietary polyphenols are metabolised by colonic microbiota before absorption, only smaller amount being absorbed directly from upper gastrointestinal tract [6].
Gut bacteria modulate polyphenols by various mechanisms including hydrolysis, ring-cleavage, reduction, decarboxylation and demethylation. The microbial metabolism is a pre-requisite for absorption, and it also modulates the biological activity of the compounds.
The systemic effects of dietary polyphenols depend largely on the synergistic action that polyphenols may exert after entering circulation, and are affected by other constituents present in the diet as well as endogenous factors [7,8].Starch and sucrose are the most important dietary carbohydrates. Their digestion, absorption and metabolism may be influenced by dietary polyphenols and their metabolites. Most dietary carbohydrate is digested in the upper gastrointestinal tract to monosaccharides which are then absorbed to the circulation. The elevated glucose concentration in blood promotes secretion of insulin from the ?-cells of the islets of Langerhans in the pancreas, and insulin mediates the uptake of glucose in peripheral tissues including muscle, adipose tissue and kidney, promotes storage of glucose in liver as glycogen, and inhibits lipolysis in adipose tissue. Another essential hormone in maintaining the glucose homeostasis is glucagon that is secreted from the pancreatic ?-cells once the blood glucose level begins to fall below normal. Glucagon promotes liver glucose production by inducing glycogenolysis and gluconeogenesis to ensure adequate circulating glucose to fuel the body functions.Maintenance of glucose homeostasis is of utmost importance to human physiology, being under strict hormonal control.
Failure of this control can result in the metabolic syndrome, a multi-symptom disorder of energy homeostasis encompassing obesity, hyperglycemia, impaired glucose tolerance, hypertension and dyslipidemia [9]. The most characteristic abnormality in the metabolic syndrome is insulin resistance, which results from interactions between genetic and environmental factors, including diet and sedentary lifestyle [10,11].
Metabolic syndrome is the major predisposing factor to type 2 diabetes, where defects in both insulin action and insulin secretion are present, but their relative contribution varies individually. The disturbance of glucose metabolism is often related to the increase of fat mass, especially in the abdominal area and ectopically, to the tissues where fat is not stored in normal energy homeostasis [12]. This in turn results in inflammation and exacerbated oxidative stress at the whole body level, and malfunction in several organs including pancreas, liver, muscle and adipose tissue [13].The prevalence of type 2 diabetes is rising exponentially, estimated to reach over 300 million cases by year 2030 [14]. Presently, the treatment of metabolic syndrome and prevention of type 2 diabetes involves lifestyle modifications like increased physical activity and weight control by reduced caloric intake [15,16]. Increasingly, the dietary recommendations for individuals at risk of type 2 diabetes emphasise the intake of plant food products, such as whole grains, berries, fruits and vegetables, all known to be excellent sources of dietary fibre, but also good sources of variable polyphenolic compounds. These compounds may influence glucose metabolism by several mechanisms, such as inhibition of carbohydrate digestion and glucose absorption in the intestine, stimulation of insulin secretion from the pancreatic ?–cells, modulation of glucose release from liver, activation of insulin receptors and glucose uptake in the insulin-sensitive tissues, and modulation of hepatic glucose output (Figure 1).Dietary polyphenols are found in distinctive combinations of metabolites from different chemical classes.
The biochemical properties and resulting health-beneficial bioactivities in different plant groups or even different species are thus discrete, having different impact on different health conditions [3].
Also different berry species like cranberry, strawberry and blueberry have been addressed to possess capacity to protect from diabetes, and the studies have most often focused on the anthocyanin metabolite class [23].
Similarly, the whole grain products are intensively studied not only for the high fibre content but also for the rich phenolic compound repertoire that may have beneficial effect on glucose homeostasis [24].
Whilst the results from dietary human interventions are still scarce, there is a wealthy of data published with different diabetic animal models. The most common ones are rat and mice models with diet-induced diabetes, thereby resembling the type 2 diabetes in humans, and the models with destruction of pancreas by allozan or streptotozin treatment resulting in insulin deficiency. Various in vitro studies have been performed by different cell lines of adipose, hepatic, pancreatic and myotube origin.This review will demonstrate the potential of dietary phenolic phytochemicals in maintenance of glucose and energy homeostasis and in suppression of metabolic syndrome and type 2 diabetes as evidenced by rapidly expanding literature. However, the antioxidant role of these compounds in metabolic syndrome, extensively reviewed recently [25,26], is not discussed herein. Influence of Polyphenols on Carbohydrate Digestion and Glucose Absorption in the IntestineFood and beverages high in available carbohydrates such as starch or sucrose induce postprandial hyperglycemia, hyperinsulinemia and other hormonal and metabolic disturbances. The rapid absorption of glucose challenges the regulatory mechanisms of glucose homeostasis, and habitual consumption of high-glycemic diets may therefore increase the risk for obesity, type 2 diabetes and cardiovascular disease [27].
Carbohydrate digestion and glucose absorption are obvious targets for better glycemia control after high-carbohydrate meals. The liberated glucose is absorbed across the intestinal enterocytes via specific transporters.
Inhibition of the digestive enzymes or glucose transporters would reduce the rate of glucose release and absorption in the small intestine and consequently suppress postprandial hyperglycemia.
Carbohydrate DigestionStarch is composed of amylose, which is a linear ?-1,4-linked glucose polymer, and highly branched amylopectin consisting of linear ?-1,4-linked glucose chains with ?-1,6-linked branch chains.
Salivary and pancreatic ?-amylases catalyze the endo-hydrolysis of ?-1,4-glucosidic linkages releasing mainly maltose, maltotriose and related ?-1,6-oligomers. Further digestion takes place in the small intestinal brush border by ?-glucosidases, which hydrolyze the terminal ?-1,4-linked glucose residues as the final step in the digestion of dietary carbohydrates to release glucose. The ?-glucosidase activities, first described as maltases, are associated with maltase-glucoamylase and sucrase-isomaltase [28–30]. In addition to ?-1,4-glucosidic activity, sucrase-isomaltase displays specific activities against the ?-1,2 linkages of sucrose and ?-1,6 linkages of isomaltose.A variety of polyphenols have been shown to inhibit ?-amylase and ?-glucosidase activities in vitro (Table 1).
The inhibitory polyphenols include flavonoids (anthocyanins, catechins, flavanones, flavonols, flavones and isoflavones), phenolic acids and tannins (proanthocyanidins and ellagitannins).
In addition, in vitro inhibitory activities have been reported for polyphenolic extracts of foods, including berries (strawberries, raspberries, blueberries and blackcurrants), vegetables (pumpkin, beans, maize and eggplant), colored grains such as black rice, green and black tea, and red wine (Table 2).
In the studies, maltose, sucrose or p-nitrophenyl-?-d-glucopyranoside have been used as substrate for ?-glucosidase activity. Glucose AbsorptionIntestinal absorption of glucose is mediated by active transport via the sodium-dependent glucose transporter SGLT1 and by facilitated sodium-independent transport via the glucose transporter GLUT2 [31,32].

On the luminal side of the intestinal brush border membrane, two Na+ ions bind to SGLT1 and produce a conformational change that permits glucose binding, followed by another conformational change to allow glucose and Na+ to enter the enterocyte. Glucose is released from the enterocyte via GLUT2, a high capacity facilitative transporter in the basolateral membrane, to enter the circulation.The influence of polyphenols on glucose transporters has been studied in vitro by using intestinal brush border membrane vesicles or everted sacs and Caco-2 cells.
Several flavonoids and phenolic acids have been shown to inhibit glucose transport (Table 2). The Na+-dependent SGLT1-mediated glucose transport was inhibited by chlorogenic, ferulic, caffeic and tannic acids [33], quercetin monoglucosides [34], tea catechins [35–37] and naringenin [38]. The glucose transport by GLUT2 was inhibited by quercetin, myricetin, apigenin and tea catechins [37,39]. Postprandial GlycemiaEffects of polyphenols, polyphenolic food fractions, and foods and beverages rich in polyphenols on postprandial blood glucose responses have been investigated in animal models and in human studies. Either glucose, maltose, sucrose, starch or various meals have been used as the carbohydrate challenge.Animal studies. Diacylated anthocyanin as well as an anthocyanin extract from purple sweet potato reduced the blood glucose and insulin responses to maltose administration in rats [40]. The lack of effect after sucrose or glucose administration indicates that the anti-hyperglycemic effect was achieved by maltase inhibition, and not by inhibition of intestinal sucrase activity or glucose transport. Also a tea polyphenol, theaflavin 3-O-gallate, was effective in suppressing the postprandial glucose response to maltose [41].A crude Acerola polyphenol fraction (containing anthocyanins) significantly reduced the plasma glucose level after administration of maltose or glucose in mice, suggesting inhibition of ?-glucosidase and intestinal glucose transport [42]. A leaf extract of Nerium indicum, a plant used as a folk remedy for type 2 diabetes in Pakistan, was found to reduce the postprandial rise in blood glucose in maltose-or sucrose-loaded rats [43].
A similar response was obtained with chlorogenic acid, which was identified as the major ?-glucosidase inhibitor in the leaf extract.Gingko biloba extracts and their flavonoid fraction reduced the elevation of rat plasma glucose level after oral administration of starch, maltose, sucrose or glucose [44].
Also in diabetic rats, the flavonoid fraction attenuated the glucose response to sucrose and glucose administration. When diabetic rats were administered glucose with quercetin, hyperglycemia was significantly decreased compared to administration of glucose alone [39].Human studies. Apple juice contains polyphenols such as chlorogenic acid and phloridzin, with higher levels in cloudy juice compared to clear juice. When nine healthy subjects consumed a 25 g glucose load in 400 mL of commercial apple juices, the mean plasma glucose concentrations were significantly lower at 15 and 30 min after ingestion of clear apple juice, and significantly lower at 15 min but significantly higher at 45 and 60 min after ingestion of cloudy apple juice compared to control drink [45]. The effects of apple juices on plasma glucose, insulin, GIP and GLP-1 concentrations were consistent with delayed absorption of glucose.Berries are rich sources of polyphenols, especially anthocyanins, flavonols, proanthocyanidins and phenolic acids.
In twelve healthy subjects, ingestion of sucrose (35 g) with berries (150 g of puree made of bilberries, blackcurrants, cranberries and strawberries providing nearly 800 mg polyphenols) produced a different postprandial glycemic response compared to the control without berries but with comparable profile of available carbohydrates [46]. The shape of the plasma glucose curve with reduced concentrations in the early phase and a slightly elevated concentration in the later phase indicates delayed response due to berry consumption. In another study, consumption of cranberry juice sweetened with high-fructose corn syrup resulted in different (but not statistically significant) pattern of postprandial glycemia compared to the similar amount of the sweetener in water [47].In ten type 2 diabetic patients, red wine (200 mL) taken during a midday meal induced a smaller increase in blood glucose versus the same meal accompanied by an equivalent amount of water, with no effect of plasma insulin levels [48].
In ten healthy young adults, sugar cane bioflavonoid extract reduced the postprandial glycemic response to a high-glycemic starchy meal composed of wheat biscuits and milk [49]. Ingestion of cinnamon (6 g) with rice pudding significantly lowered blood glucose response in the postprandial phase (15, 30 and 45 min) in 14 healthy subjects [50,51].
However, in another study of the same group [51], cinnamon (3 g) reduced postprandial serum insulin and increased GLP-1 concentrations without significantly affecting blood glucose response. Cinnamon has high content of proanthocyanidins.Gastrointestinal hormone (GIP and GLP-1) profiles after consumption of 25 g glucose with coffee (400 mL containing 350 mg chlorogenic acid) indicated delayed intestinal absorption of glucose in nine healthy subjects [52]. The authors concluded that chlorogenic acid, the major polyphenol of coffee, might attenuate the intestinal glucose absorption rates and shift the site of glucose absorption to more distal parts of the intestine. In overweight men, chlorogenic acid (1 g) reduced early glucose and insulin responses during an oral glucose tolerance test [53]. Attenuated glycemic response has also been observed when sucrose (25 g) was consumed in chlorogenic acid enriched instant coffee [54].When either 250 mL of coffee or tea was consumed with test meals, they increased the overall mean peak blood glucose concentration, but did not significantly affect the incremental area under the glucose response curve of the meals [55]. Coffee and tea contain caffeine, which increases postprandial glycemia and impairs glucose tolerance [52,56,57].
Caffeinated coffee ingested with either a high or low glycemic meal significantly impaired acute blood glucose management and insulin sensitivity compared with ingestion of decaffeinated coffee [57]. Instant black tea consumed with glucose reduced the late phase plasma glucose response with a corresponding increase in insulin [58]. The attenuation of late postprandial glycemia may be explained by an elevated insulin response following stimulation of pancreatic ?-cells rather than by retarded absorption of glucose.In conclusion, the scientific evidence on the potential of polyphenolic compounds to retard carbohydrate digestion and absorption and to suppress hyperglycemia in the postprandial state is promising. Current evidence from human studies suggests that beverages such as apple juice, red wine and decaffeinated coffee as well as berries and cinnamon may improve short-term glycemic control. For substantiation of the benefits of polyphenols in the control of postprandial glucose homeostasis, more clinical studies involving subjects with normal and impaired glucose metabolism are needed. These studies should be focused on the effects of dietary polyphenols on glycemic responses induced by starch and sucrose, the main high-glycemic carbohydrates in our diet.
Influence of Polyphenols on Pancreatic ?-cell FunctionInsulin secretion by the pancreas involves numerous reactions which are potential targets for the action of polyphenols. Upon high blood glucose concentrations pancreatic ?-cells respond to the increased demand of insulin by various mechanisms including increased insulin secretion, hypertrophy, proliferation of existing ?-cells and formation of new ones from progenitor cells. The insulin release from ?-cells is a cascade starting from the uptake of glucose by the GLUT2 transporters. Glucose enters a cycle of enzymatic reactions involving phosphorylation, leading to increased ATP content in the cells, and causing inactivation of ATP-sensitive potassium channels on the cell membrane.
The membrane depolarizes and leads to calcium channel opening and subsequent flow of Ca2+ into cell. The rise in Ca2+ concentration promotes release of insulin by exocytosis from existing storage granules [59,60].Prolonged hyperglycemia and hyperlipidemia, typically within development of metabolic syndrome, leads to the dysfunction of the pancreatic ?-cells, reflected in autocrine insulin resistance, impaired insulin secretion, decreased expression of genes involved in insulin production and finally decrease in ?-cell mass caused by apoptosis.
Therefore the insulin deficiency related to metabolic syndrome in pancreas is due to both the cellular damage and the impaired efficiency in the synthesis of insulin [61].The most extensively studied sources of dietary polyphenols in terms of pancreatic function and insulin secretion is soy, and especially its isoflavonoids, genistein and daidzein. Many of these studies, reviewed below and summarized in Tables 1 and 2, examine also the molecular mechanisms behind the observed effects of polyphenols. In Vivo Studies with Animal ModelsThere are few recent studies where soy isoflavonoids at physically achievable concentrations have shown positive impact on ?-cell function.
In addition to enhancing the insulin production in pancreas the treatment also seemed to contribute to improved insulin sensitivity in peripheral tissues, thus necessitating smaller amounts of insulin and preventing pancreatic exhaustion [63].
The same line in results was obtained also by Lu et al on high-isoflavone soy protein fed STZ-diabetic rats [64]. Effects Observed in Cell Culture AnalysesEpigallocatechin gallate (EGCG) and rutin were examined for their ability to attenuate the glucotoxicity in rat insulinoma pancreatic ?-cells (RIN m5F) [65].
The treatment increased glucose dependent insulin secretion, and was able to promote effective secretion of insulin also under chronic high glucose incubation when insulin secretion is suppressed by glucotoxicity (33 mM, 48 h), suggesting that both EGCG and rutin might preserve the glucose- sensing ability during hyperglycemia. EGCG and rutin elevated the intracellular ATP, suggesting that the increase in insulin secretion is mediated by enhancing the normal, glucose induced insulin secretion that is dependent on ATP concentrations. Interestingly, epicatechin, the precursor of EGCG, was found to inhibit insulin secretion when tested on INS-1 cells [66].A very detailed study on the effects of dietary phenolic acids on pancreas function was carried out with cinnamic acid derivatives in INS-1 cell culture and perfused rat pancreas [67]. Among the differentially substituted cinnamic acid derivatives, the most prominent insulin releasing agents were the ones containing m-hydroxy and p-methoxy residues on the phenol ring structure, whereas cinnamic acid (no substituents in the phenol ring) was inactive.

The structure promoting insulin secretion most effectively was the one of ferulic acid, containing p-hydroxy and m-methoxy structure, as it enhanced insulin secretion in a dose-dependent manner (1–100 ?M), being significant already at 1 ?M concentrations. Notably, the assays were performed in absence of glucose, whereas the majority of other reports have focused on glucose dependent insulin release. The results were verified also with treatment of perfused rat pancreas and intravenous administration in normal rats, where the increase in plasma insulin was detected in fasting state. Interestingly, isoferulic acid, the stereoisomer of ferulic acid did not have any effect on insulin releasing properties.
This finding corroborated earlier results showing that plasma glucose lowering properties of isoferulic acid are due to increase in glucose uptake and retarding of hepatic gluconeogenesis, without any effect on pancreatic insulin output [68]In one of the most recent studies isoflavonoids were shown to improve glucose stimulated insulin secretion in INS-1E pancreatic cell line but this effect was not due to modulation of insulin synthesis, since there was no difference on the insulin concentration in the genistein treated and non-treated cells.
However, the insulin secretion upon glucose stimulation was significantly increased after 48h pre-treatment with genistein (1–5 ?M).
Ethanol extracts from the root, stem, leaf and fruit of the Canadian lowbush blueberry Vaccinium angustifolium, a very rich source of flavonoids, were analyzed for insulin secretagogue and proliferative effects [72]. The insulin secretion was measured from growth arrested (tetracycline-treated) ?-cells in order to distinguish the insulinotropic effect from the cell proliferative effect.
Only slight enhancement was observed in the glucose stimulated insulin secretion with the treatment by leaf and stem extracts, but the effect on the cell proliferation rate was found to be significantly increased by the treatment with the fruit extract when compared to vehicle-only control, suggesting a potential capability to restrain ?-cell damage in metabolic syndrome.Another study showing ?-cell protective effect of flavonoids was performed by mixtures of flavonoids quercetin, luteolin and apigenin in RINmF5 cells [73]. Flavonoids showed anti-inflammatory action in a treatment with interleukin 1? (IL-1?) and interferon ? (IFN- ?), and the effect was verified at transcriptional analysis of inflammation-related genes, suggesting a role for flavonoids in the restoration of insulin secretion capacity by preventing the cytokine-induced ?-cell damage. It was suggested that the ?-cell restoring effect of rutin was due to enhanced ability to scavenge free radicals and mediate antioxidant enzyme activity in the pancreas. Similarily, quercetin, the aglycon molecule of rutin, showed ?-cell restoration when used as dietary supplement (0.5% of diet for 14 days) in STZ induced diabetic mice [75].
Gene expression analysis showed that quercetin restored the cell proliferation capacity inhibited by STZ treatment, and resulted in higher plasma insulin levels.
In addition oxidative stress markers were reduced in pancreas, further ameliorating the oxidative damage associated with diabetes. Quercetin has been studied also in STZ-diabetic rats by intraperitoneal injection, and the preservation of islet cells and restoration of insulin production has been observed in two studies [76,77].Intraperitoneal injection of (?)epicatechin in alloxan treated mice demonstrated ?-cell- regenerative capacity [78].
Similarily, (?)epicatechin or quercetin promoted increased release of insulin when isolated rat islets were exposed to them, whereas naringenin and chrysin inhibited it [79].
Additional observations with dietary sources of polyphenols include the protection of non-obese diabetic mice pancreatic islets from infiltration of immune cells and induction of insulitis by feeding grape powder and high vitamin A supplement [80].
An interesting approach was taken to study olive mill waste which is a rich source of phenolic compounds, especially phenylethanol compound hydroxytyrosol. Fractions of olive mill waste were studied for a range of hypoglycemic and antioxidative effects, including the effect in insulin secretion in alloxan- induced diabetic rats administered by intraperitonial injection.
Mainly the purified hydroxytyrosol fraction showed protective action on alloxan-damaged ?-cells [81].Phytochemical- rich extracts from other than dietary plants have also been studied for their impact on pancreatic insulin production and release. A fraction containing apigenin and rutin from Teucrium polium, a medicinal plant from Iran, mediated insulin secretion increase in the presence of STZ on isolated rat pancreatic islets [85].In conclusion, it is obvious that the pancreas is one of the targets of dietary polyphenol bioactivity, as several of the studied plant extracts and purified compounds exhibit beneficial effects on ?-cell function and insulin release in different diabetic models. For instance, in INS-1E cells genistein did not increase the level of intracellular ATP upon the glucose stimulation, whereas treatment of the RIN-m5F cells with EGCG and rutin elevated the ATP level [65]. This suggests that the latter treatment enhanced the signaling route mediated normally by glucose, whereas the genistein treatment had effect on alternative mechanism of insulin secretion. A range of different compounds and plant food extracts studied show various activities relevant for insulin secretion, and the activities are different on normoglycaemic controls and the subjects with symptoms of metabolic syndrome.
The studies have been made mainly using cell cultures and animal models, and motivate to proceed to human controlled trials. Influence of Polyphenols on Tissue Uptake of GlucoseDietary polyphenols may also influence glucose metabolism by stimulating peripheral glucose uptake in insulin-sensitive and non-insulin sensitive tissues.
Glucose transport pathways can be classified either as insulin or non-insulin mediated pathways. Non-insulin mediated glucose uptake takes place in all tissues and is responsible for the basic glucose transport into the cells in post-absorptive state. In contrast the insulin mediated glucose uptake takes place only in insulin sensitive tissues. Insulin stimulates the glucose uptake in skeletal muscle, which is the largest site for disposal of dietary glucose, and in adipose tissue, whereas in the liver it decreases the hepatic glucose output rate by increasing the storage of glucose as glycogen.Glucose uptake is mediated by the action of glucose transporters (GLUTs) on the cell surface [86]. It is important to point out that among the 13 GLUTs identified so far [87], only GLUT4 is an insulin sensitive glucose transporter. Class I comprises GLUT1–4; class II, GLUT6, 8, 10, and 12 and class III, GLUT5, 7, 9, 11 and H+-myo-inositol cotransporter (HMIT) [88]. Tissue- and cell-specific expression of the well-characterized GLUT isoforms underlies their specific role in the control of whole-body glucose homeostasis. Numerous studies with transgenic or knockout mice support an important role for these transporters in the control of glucose utilization, glucose storage and glucose sensing, but more studies are needed to elucidate the mechanisms behind.Glucose transporters from class I are actively involved in glucose mobilization and uptake. GLUT1 and GLUT3 are responsible for maintaining the basal glucose uptake, and contrary to GLUT4 are abundant in several tissues [89].
GLUT1 is widely distributed in fetal tissues and it is expressed at high levels in erythrocytes and endothelial cells of barrier tissues in adults, while GLUT 3 is mostly expressed in neurons and placenta. Glucose is transported into and out of liver cells by the concentration-driven GLUT2 [90], which is also expressed by renal tubular cells, small intestinal epithelial cells that transport glucose and pancreatic beta cells. The cascade promotes GLUT4 glucose transporter translocation from an intracellular pool to the plasma membrane [91,92]. In addition to PI3K activity, there are also other signalling routes involved in the cellular response to insulin stimulation and a detailed overview of the basic insulin signalling and regulation of glucose metabolism was reviewed some years ago by Saltiel and Kahn [93]. In this sense, a molecular mathematical model of glucose mobilization and glucose uptake has been recently developed considering the kinetics of GLUT2, GLUT3 and GLUT4, the process of glucose mobilization by glycogen phosphorylase and glycogen synthase in liver, as well as the dynamics of the insulin signalling pathway [90].Among the potential compounds stimulating glucose uptake, several foods and plant extracts rich in polyphenols have been the object of extensive research during the last years (Tables 1 and 2).
The methods most commonly used to study the effects of phenolic compounds on peripheral glucose uptake are cell culture assays in rat skeletal muscle (rat L6 myotubes) and adipose (3T3-L1) cell lines.
Effects of Pure Compounds on Glucose UptakeChlorogenic acid and ferulic acid caused a modest, but significant increase in 2-deoxy-d-glucose transport into L6 myotubes, showing comparable performance to metformin and 2,4-thiazolodinedione, two common commercial oral hypoglycemic drugs [94].
Purified aspalathin from green roiboos extract increased dose-dependently and significantly glucose uptake by L6 myotubes at concentrations 1–100 ?M, irrespective of insulin absence [71].
As aspalathin is capable of scavenging intracellular reactive oxygen species (ROS), its antioxidative function may be involved in the stimulation of glucose uptake and insulin secretion, and hence glucose homeostasis.
An inhibitory effect of EGCG was observed in L6 skeletal muscle cells on insulin resistance induced by dexamethasone, a glucocorticoid [95]. A 24 h- treatment with EGCG attenuated the effect of dexamethasone on glucose uptake and improved insulin-stimulated glucose uptake in a dose-dependent manner by increasing GLUT4 translocation to plasma membrane [95].
EGCG was able to increase the phosphorylation of AMPK, suggesting that the AMPK signalling pathway is likely responsible for the EGCG-stimulated GLUT4 translocation.Resveratrol increased glucose uptake in C2C12 skeletal muscle cells by activating AMPK [96].
In the absence of insulin, the effect of resveratrol on glucose uptake was primarily dependent on AMPK activation, without involving PI3K.

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