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The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Toggle navigation. Login Register Login using.

You can login by using one of your existing accounts. We will be provided with an authorization token please note: passwords are not shared with us and will sync your accounts for you. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button. Forgot Password? Beneficial effects of polyphenols on management of blood glucose in diabetes. Some investigations have shown that polyphenolic compounds are also able to regulate postprandial glycemia and inhibit the development of glucose intolerance by a facilitated insulin response and attenuated secretion of glucose-dependent insulinotropic polypeptide GIP and glucagon-like polypeptide-1 GLP-1 [ 31 , 32 ].

Some polyphenols are able to regulate the key pathways of carbohydrate metabolism and hepatic glucose homeostasis including glycolysis, glycogenesis and gluconeogenesis, usually impaired in diabetes. Ferulic acid, a hydroxycinnamic acid derivate, effectively suppresses blood glucose by elevating glucokinase activity and production of glycogen in the liver and increased plasma insulin levels in diabetic rats [ 33 ]. Supplementation of diabetic rats with hesperidin and naringin, two main citrus bioflavonoids, was accompanied with increased hepatic glucokinase activity and glycogen content, attenuated hepatic gluconeogenesis via decrease the activity of glucosephosphatase and phosphoenolpyruvate carboxykinase PEPCK , and subsequent improvement of glycemic control [ 34 , 35 ].

Green tea polyphenols, mainly catechins and epicatechins have been shown to attenuate hyperglycemia and hepatic glucose output via downregulation the expression of liver glucokinase and upregulation of PEPCK [ 36 ]; in an in vitro study, epigallocatechin gallate EGCG , one of the most abundant catechins in green tea, could activate AMP-activated protein kinase as a required pathway for the inhibition of gluconeogenic enzymes expression [ 37 ].

Dietary polyphenols also influence peripheral glucose uptake in both insulin sensitive and non-insulin sensitive tissues; one study showed that phenolic acids stimulated glucose uptake by comparable performance to metformin and thiazolodinedione, main common oral hypoglycemic drugs [ 38 ]. The results from the in vitro studies showed that some polyphenolic compounds such as quercetin, resveratrol and EGCG improved insulin-dependent glucose uptake in muscle cells and adipocytes by translocation of glucose transporter, GLUT4, to plasma membrane mainly through induction of the AMP-activated protein kinase AMPK pathway [ 39 , 40 ].

AMPK, an important sensor of cellular energy status, has a key role in metabolic control; activation of this pathway is considered as a new treatment for obesity, type 2 diabetes, metabolic syndrome and a main target for anti-diabetic drugs including metformin [ 41 , 42 ]. Interestingly, effect of polyphenols in activation of AMPK has been reported times more than metformin [ 43 ].

Some polyphenols also have potential to induce phosphatidylinositide 3-kinase PI3k as a key signaling pathway for up-regulation of glucose uptake [ 44 ]. In summary, results of the studies acknowledge that plant polyphenols favorably affect several aspects of diabetes-induced metabolic disorders and modulate carbohydrate metabolism, glucose homeostasis, insulin secretion and insulin resistance.

Progressive insulin resistance is mainly accompanied with pro-atherogenic cardiovascular risk profiles and consequently atherosclerotic coronary artery disease and other forms of cardiovascular disease are the major causes of mortality in type 2 diabetic patients [ 53 ]. Dyslipidemia, undesirable changes in vascular endothelial and smooth muscle cells, lipid peroxidation especially oxidized low-density lipoprotein particles, oxidative damage and increased inflammatory mediators including chemokines and cytokines, hyper-coagulation and platelet activation have been considered as the main metabolic abnormalities in diabetes mellitus leading to cardiovascular disease [ 54 ].

There is growing evidence suggesting that dietary intake of polyphenol-rich foods and supplementation with these bioactive components could have protective effects against diabetes-induced cardiovascular pathogenesis; the mechanisms involved in these properties mainly include regulation of lipid metabolism, attenuation of oxidative damage and scavenging of free radicals, improvement of the endothelial function and vascular tone, enhancement the production of vasodilating factors such as nitric oxide, and inhibition the synthesis of vasoconstrictors such as endothelin-1 in endothelial cells [ 55 , 56 , 57 ].

One of the most important favorable effects of polyphenols on cardiovascular system in diabetes probably is regulation of lipid and lipoprotein metabolism, and improvement of dyslipidemia. Based on research conducted in this area, polyphenolic compounds are capable of reducing digestion and absorption of dietary lipids.

Oligomeric procyanidins, contained in apples had inhibitory effects on pancreatic lipase and triglyceride absorption [ 58 ]. Apple procyanidins also induce hypolipidemic effects by decreasing of apolipoprotein B synthesis and secretion, inhibition of cholesterol estrification and intestinal lipoprotein production [ 59 ]. The hypolipidemic effects of catechins and proanthcyanidins are related to inhibition of key enzymes in lipid biosynthesis pathways, reduce intestinal lipid absorption.

Catechins also interact with proteins involved in cholesterol translocation from the enterocyte brush border ATP-binding cassette proteins, multidrug resistance P-glycoprotein 1, B type1-scavenger receptors, Niemann Pick C-1 like 1 protein , change their function and effectively reduce cholesterol absorption [ 60 ]. Endothelial dysfunction, proliferation and migration of smooth muscle cells of the vessels are central events in the pathogenesis of diabetes-induced atherosclerosis.

Some cardiovascular protective properties of polyphenols are attributed to modulatory effects on the vascular structure and function. Interestingly, some polyphenols inhibit the expression of major proangiogenic, prothrombotic and proatherosclerotic factors such as monocyte chemoattractant protein-1, vascular endothelial growth factor VEGF and matrix metalloproteinase-2 MMP-2 in smooth muscle cells, by redox-sensitive and redox-insensitive mechanisms [ 62 , 63 , 64 ].

Oligomeric proanthcyanidins, found in red apple, cinnamon, cocoa, and grapes have the potential to protect vascular cell against diabetes-induced oxidative stress via increase in activity of superoxide, dismutase inhibition of NADPH oxidase and production of free radicals as well as decrease proliferation of smooth muscle cells [ 65 ].

Flananols modulate platelet hyperactivity and aggregation, regulate coronary blood flow, reduce endothelial inflammatory cytokines and free radicals, increase production and bioavailability of nitric oxide, and consequently atherosclerosis development [ 66 ]. In human trials, consumption of high-polyphenol dark chocolate was accompanied with improvement of endothelial function in individuals with stage 1 hypertension, and attenuation acute transient hyperglycemia-induced endothelial dysfunction and oxidative stress in type 2 diabetic patients [ 67 , 68 ].

Administration of other polyphenol-rich products such as grape seed extract, cranberry juice, grape and pomegranate juice also had a therapeutic role in decreasing cardiovascular risk factors in patients with type 2 diabetes and metabolic syndrome [ 69 , 70 ]. Catechins, quercetin and anthocyanins have potent platelet-inhibitory properties and are considered as inhibitors of platelet cell signaling and thrombus formation [ 71 ]. As reviewed by Pascul-Tresa, bioactive anthocyanins including delphinidinrotinoside, cyanidinglucoside, cyanidinrutinoside, malvidinglucoside and intestinal metabolites such as dihydroferulic acid and 3- hydroxyphenyl propionic acid prevent platelet hyper-activation and aggregation through inhibition of peptides activating thrombin receptor [ 66 ].

Undoubtedly, one of the main protective properties of polyphenols in the development of cardiovascular dysfunction in diabetic condition is related to the ability of these bioactive components to prevent lipoproteins oxidation and production of advanced glycation end products. Dietary polyphenolic compounds also protect myocardial tissue against several undesirable changes and diabetic cardiomyopathy. In summary, results of the studies confirm that polyphenolic compounds attenuate several cardiovascular risk factors in diabetes; dietary polyphenols modulate lipid metabolism and dyslipidemia, improve vascular function, decrease oxidative and inflammatory-induced vascular damage, and regulate blood pressure.

Inhibition of these oxidative processes could prevent the onset and development of long-term diabetic complications [ 76 ]. Most polyphenolic compounds and their active metabolites have been known as potent antioxidant phytochemicals due to their unique structure. As reviewed by Dembinska-Kiec, these compounds could scavenge free radicals, quench electronically excited compounds, reduce hydroperoxide formation, and attenuate production of reactive oxygen species ROS through modulation of several enzymes involved in the development of ROS including xanthine oxidase, cyclooxygenase, lipoxygenase, microsomal monooxygenase, NADH oxidase and mitochondrial succinoxidase [ 77 ].

Some experts believe that polyphenols beyond the direct antioxidant capacities in scavenging of free radicals mainly act by direct interactions with important cellular receptors or key signaling pathways, which may result in modification of the redox status of the cell and may trigger a series of redox-dependent reactions [ 78 ].

Plant polyphenols can enhance the endogenous antioxidative system, improve oxidant antioxidant balance, and effectively prevent oxidative damage; green tea catechins are the polyphenolic compounds most studied polyphenolic compounds in this area; these bioactive components decreased lipid peroxidation and increased plasma total antioxidant capacity; they also attenuated of stress-sensitive signaling pathways, prooxidant enzymes, and inducted of antioxidant enzymes including superoxide dismutase, catalase and glutathione peroxidase [ 79 ].

Polyphenolic compounds have wonderful modulatory effects on many aspects of metabolic, endocrine and cellular signaling transduction of adipose tissue.

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Some polyphenols, up-regulate lipolysis pathways via induction of hormone sensitive lipase, adipose tissue lipase, increased gene expression of mitochondrial uncoupling protein 2 UCP-2 and carnitin palmitoyl transferase-1 CPT-1 in adipocytes [ 81 , 82 ]. Cyanidin and cyanidinglucoside have shown several therapeutic effects on adipocyte dysfunction through decrease in plasminogen activator inhibitor-1 and interleukin-6, induction of mitochondrial uncoupling proteins, acetyl CoA oxidase, perlipin and adiponectin gene expression [ 84 ].

One of the most important properties of polyphenols recently identified is its preventive effect against long-term diabetes complications including retinopathy, nephropathy and neuropathy; based on research conducted in this area administration of anthocyanins, flavonoids and other polyphenolic compounds in diabetic conditions may facilitate new approaches for improving the quality of life in diabetic patients.

As reviewed by Ghosh et al, anthocyanins and anthocyanins-rich extracts have the potential to alleviate the developing pathways of some pathologic conditions related to diabetes; anthocyanins facilitate blood flow and prevent diabetes-induced microangiopathy, increase microvascular permeability, decrease leucocytes aggregation in vascular cell wall and improve capillary filtration of albumin [ 85 ]. Recently there has been increasing interest in grape seed proanthcyanidin extracts as a natural treatment for some important diabetes complications; proanthcyanidin-rich grape seed extract inhibited the development of retinopathy, nephropathy and neurodegenerative damage in diabetic condition [ 87 , 88 ].

Flavanols surprisingly have the potential to improve cognitive disorders and cholinergic dysfunction related to diabetes and other secondary consequence of changes in the nervous system induced by hyperglycemia and diabetes oxidative stress; administration of quercetin in diabetic rats improved mental function and memory via inhibition of acetylcholine esterase and attenuation of oxidative damage in nervous system [ 89 ].

Green tea catechins including epicatechin, epicatechingallat, and epigalocatechin gallat decreased the synthesis of thromboxane A2 TXA2 and increased prostacyclin I2 PGI2 , modulate the impaired balance between these ecosanoids as accelerators of thrombogenesis in the renal tubules, leading consequently improved glomerular filtration and kidney function [ 90 ].

Type 2 diabetes, a clustering of metabolic disorder, is accompanied with other pathogenic conditions including sub-clinical inflammation and oxidative stress that subsequently leads to insulin resistance and long-term diabetes complications. The rising trend in the prevalence of diabetes complications suggests that current medical treatments for the management of diabetes are not sufficient and use of supplementary treatments, including functional foods and their nutraceuticals, could increase the effectiveness of diabetes management. Plant polyphenols including phenolic acids, flavonoids, stilbenes and lignans, based on in vitro studies , animal models and some clinical trials, have been proposed as effective supplements for diabetes management and prevention of its long-term complications.

Further investigations using human clinical studies are needed to confirm the beneficial effects of polyphenolic compounds as supplementary treatments for diabetic patients. The authors express to acknowledge the assistance given by Ms N. Shiva in language editing of the manuscript. This article is published under license to BioMed Central Ltd. Skip to main content Skip to sections. Advertisement Hide. Download PDF. Dietary polyphenols as potential nutraceuticals in management of diabetes: a review.

Open Access. First Online: 13 August Dietary polyphenols: food sources, bioavailability and metabolism Polyphenols are natural phytochemical compounds in plant-based foods, such as fruits, vegetables, whole grains, cereal, legumes, tea, coffee, wine and cocoa; more than polyphenolic compounds, including phenolic acids, flavonoids, stilbenes, lignans and polymeric lignans have been identified in whole plant foods [ 5 ].

Open image in new window. Figure 1 Beneficial effects of polyphenols on management of blood glucose in diabetes. Diabetes mellitus is a highly prevalent disease worldwide and is associated with increased rates of morbidity and mortality. Diabetes-associated metabolic disorders manifest as hyperglycemia and increased advanced glycated hemoglobin HbA1c through disturbances of insulin secretion or action efficiency, and these disorders play a central role in diabetes clinical care and pathophysiology.

In addition, dyslipidemia with high levels of triglycerides TG , cholesterol, low-density lipoprotein LDL and a low level of high-density lipoprotein HDL are frequently noted in patients with diabetes. Type 2 diabetes is the most prevalent form of diabetes.

Nutraceuticals, Glycemic Health and Type 2 Diabetes

Obesity is known to be an important morbidity factor in the pathogenesis of type 2 diabetes, and it is associated with an overproduction of free fatty acid FFA [ 1 ]. Abelmoschus esculentus AE; also known as okra is one flowering plant of the mallow family [ 2 ]. The fruit of AE is consumed as a popular vegetable in many countries.

In addition to its high fiber, vitamin, and trace element contents [ 3 ], AE is also known for its medicinal value, especially with regards to an anti-hyperglycemic effect.

Although AE is generally viewed as being advantageous for diabetic patients, few scientific reports have identified the clinical targets that AE acts on. A previous work of Sabitha et al. Possessing a good anti-oxidation ability, AE has been shown to decrease lipid peroxidation, increase the levels of superoxide dismutase, catalase, and glutathione peroxidase, and the reduced glutathione in the liver, kidney and pancreas of diabetic rats [ 5 ].

However, in these reports, the experimental animals were fed with AE powder of the seeds and peel which was crude, preventing the bioactive components from being identified. In fact, AE contains abundant mucilage which increases the difficulty in isolation, analysis and further tests with bio-models.

Our previous report successfully demonstrated extraction steps and obtained a series of subfractions from AE which were analyzed for their chemical composition, and tested for their individual effects and molecular targets to prevent diabetic renal epithelial to mesenchymal transition [ 6 ]. Based on this, in the present study, we used modified extraction steps and tested AE subfractions on type 2 diabetic rats with insulin resistance [ 8 , 9 ]. We aimed to explore whether AE subfractions can improve the metabolic disturbances caused by insulin resistance. AE was purchased from Chuchi Chiayi, Taiwan.

The yields of dry base of F1, F2 and FR were 1. F1 was composed of at least 10 compounds, including quercetin glucosides and pentacyclic triterpene ester [ S1 Table ]. The F2 portion of AE contained a large amount of carbohydrates and polysaccharides. Monosaccharide analysis and uronic determination revealed that F2 was rich in uronic acid All animals had free access to food and water.

The protocol described by Yang et al 8 was used to induce type 2 diabetes in the rats. Using the formulation described in AIN, normal and high-fat diets HFD were prepared and rationed according to the formula previously reported [ S3 Table ]. The other rats received only the same amount of 0. About 2 weeks later, when the hyperglycemic status was confirmed, the rats were tube-fed with or without different doses of AE subfractions. Briefly, the rats were divided into the following groups: control normal diet , C1-C3 normal diet with 0. The body weight, serum glucose and insulin were measured every 2 weeks.

At the end of the experiment, the animals were sacrificed under 4—8 psi of CO 2.

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Although unconsciousness often occurred within 1 minute, the rats were left in the container for at least 3—5 minutes to ensure death, which was verified no cardiac pulse. Plasma glucose was measured by enzymatic colorimetric methods using an automatic analyzer Olympus AU, Olympus Co. A synthetic polymer containing multiple copies of the immunoreactive portion of HbA1c caused agglutination of latex coated with HbA1c-specific mouse monoclonal antibodies.

The agglutination reaction increased scattering of light, which was measured as an increased absorbance at nm. HbA1c in whole blood specimens competed for the limited number of antibody latex binding sites, thus inhibiting agglutination and decreasing the absorbance. The HbA1c concentration was then quantified using a calibration curve of absorbance versus HbA1c concentration.

Dietary polyphenols as potential nutraceuticals in management of diabetes: a review | SpringerLink

The statistical software SPSS version Four weeks later, F2 H was the first subfraction to show an anti-hyperglycemic effect. F2 H continued to decrease serum glucose until the end of the experiments. F1 H also decreased serum glucose at 6, 8 and 10 weeks, but not as effectively as F2 H. Among all of the subfractions, FR had the least potent anti-hyperglycemic effect, with an effect only at 8 and 10 weeks Table 1. The insulin secretion of the diabetic rats continued until 8 weeks and decreased thereafter. All of the diabetic rats had insulin resistance in the first 2 weeks.

Among all of the subfractions, F2 H was superior in decreasing insulin resistance at 4—12 weeks. F1 and FR were also effective in attenuating insulin resistance, showing an effect from 6 weeks to the end of the experiments Fig 2. Serum from the experimental animals was collected. At the end of the experiments, HbA1C had doubled in the untreated diabetic group. F1 H also showed good potency, reducing HbA1C from 8. Serum from the experimental animals was collected after sacrifice.

The percentage of serum HbA1C was estimated by agglutination assay. The serum level of TG more than doubled in the untreated diabetic group. Serum cholesterol was also elevated in the diabetic group. However, total cholesterol was not altered by AE treatment Fig 4B. The markers of lipid parameters were analyzed using enzymatic colorimetric methods. FFA is an important morbidity factor associated with obesity and metabolic syndrome.

These data suggested that all of the AE subfractions possessed a good ability to improve dyslipidemia in the diabetic rats. AE subfractions seemed to attenuate the high level of LDL accompanied with diabetes, although the effect was not statistically significant. HDL was decreased by nearly half in the diabetic group, but was elevated with AE treatment and especially with FR, which increased the level in a dose-dependent manner.

All of the diabetic rats were much fatter at baseline.