Introduction

Type 2 diabetes is a complex metabolic disorder associated with develo** insulin resistance, impaired insulin signaling and β-cell dysfunction, abnormal glucose and lipid metabolism, sub-clinical inflammation and increased oxidative stress; these metabolic disorders lead to long-term pathogenic conditions including micro- and macro-vascular complications, neuropathy, retinopathy, nephropathy, and a consequent decrease in quality of life and an increase in the rate of mortality [1–3]. Among the multiple risk factors underling the incidence and progression of type 2 diabetes, diet is the main modifiable factor. An increasing number of epidemiological investigations show that diet rich in foods with high-content of phytochemicals, high total antioxidant capacity and polyphenolic compounds may be related to lower risk of diabetes and predisposing factors [4–9].

Based on the current understanding of pathophysiology of insulin resistance and type 2 diabetes, multiple pharmacological and non-pharmacological interventions have been developed with the aim of improving glycemic control and prevention of diabetes complications; in this area, recently the use of functional foods and their bioactive components have been considered as a new approach in the prevention and management of diabetes and its complications [10–13].

Due to their biological properties, polyphenols may be appropriate nutraceuticals and supplementary treatments for various aspects of diabetes mellitus. Our aim here is to review the current evidences in relation to several potential efficacies of these bioactive components on type 2 diabetes mellitus and related metabolic disorders. We obtained relevant articles, including in vitro, animal models and human studies with appropriate design, as well as review articles with good quality, published between 1990 to 2013, through searches of the Medline and PubMed databases. We first describe a brief introduction on dietary polyphenols, food sources and properties, and then summarize the evidence from in vitro, animal models and clinical studies.

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 8000 polyphenolic compounds, including phenolic acids, flavonoids, stilbenes, lignans and polymeric lignans have been identified in whole plant foods [5]. These compounds are secondary metabolites of the plants that act as a defense against ultraviolet radiation, oxidants and pathogens [14].

Polyphenols may be classified into several categories based on the number of phenol rings and structural elements that bind these rings to one another [15]. Phenolic acids are approximately a third of the polyphenolic compounds in the diet and include two main classes hydroxybenzoic acid derivatives (protocatechuic acid, gallic acid, p-hydroxybenzoic acid) and hydroxycinnamic acid derivatives (caffeic acid, chlorogenic acid, coumaric acid, Ferulic acid, sinapic acid); berry fruits, kiwi, cherry, apple, pear, chicory and coffee are the foods with high content of these phenolic acids [16]. Flavonoids are the most abundant polyphenols in the human diet and more than 4000 types of these compounds have been identified. There are six subclasses of flavonoids including anthocyanins, flavonols, flavanols, flavanones, flavones and isoflavones; anthocyanins (cyanidin, pelargonidin, delphinidin, malvidin) are found in the berries family, red wine, red cabbage, cherry, black grape and strawberry. Flavonols, including quercetin, kampferol and myricetin, have been mainly detected in onion, curly kale, leeks, broccoli and blueberries. Isoflavones are other most important dietary flavonoids that include daidzein, genistein and glycitein; soybeans and soy products are the richest sources of these estrogen-like structure compounds. Lignans, diphenoilc components with phytoesterogenic activity, have been found in high concentrations in linseed and other grains and cereals. Stilbenes occur in the human diet in low quantities; resveratrol, one of the well studied compounds of these groups, is largely detected in grapes and red wine [5, 16, 17].

It is estimated that dietary intake of polyphenols is approximately 1 g/day [18, 19]. Bioavailability of these bioactive components is dependent on food preparation processes, gastrointestinal digestion, absorption and metabolism [20]. During the absorption pathway, dietary polyphenols must be hydrolyzed by the intestinal enzymes or colonic microflora, and then be conjugated in the intestinal cells and later in the liver by methylation, sulfation or glucuronidation [21]. Polyphenols consequently reach and accumulate in the target tissue and induce biological properties; the polyphenol derivates mainly excrete through bile and urine. Several studies showed rapid absorption of the polyphenolic compounds, such as procyanidins, quercetin and flavanols into plasma, with plasma concentrations peaking at 2 or 3 hours after ingestion [16].

Several biological activities and beneficial properties have been documented for dietary polyphenols, and some of the more well known ones include antioxidant, anti-allergic, anti-inflammatory, anti-viral and anti-microbial, anti-proliferative, anti-mutagenic, anti-carcinogenic, free radical scavenging, regulation of cell cycle arrest, apoptosis, and induction of antioxidant enzymes; more interestingly, dietary polyphenols could modulate some important cell signaling pathways such as nuclear factor kappa-B (NF-κB), activator protein-1 DNA binding (AP-1), extracellular signal-regulated protein kinase (ERK), phosphoinositide 3 (PI3) kinase/protein kinase B (Akt), mitogen-activated protein kinases (MAPK), and nuclear factor erythroid 2 related factor 2 (Nrf2) [22].

Anti-hyperglycemic effects of polyphenols with regard to carbohydrate metabolism, β-cell function and insulin resistance

Impaired carbohydrate metabolism and develo** insulin resistance is the main metabolic disorder in non-insulin dependent diabetes mellitus leading to hyperglycemia. Altered digestion and absorption of dietary carbohydrate, depletion of glycogen storage, increased gluconeogenesis and over output hepatic glucose, β-cell dysfunction, insulin resistance of peripheral tissue and defect in insulin signaling pathways are more important causes of hyperglycemia [23]. Although the use of oral anti-diabetic drugs including α-glucosidase inhibitors, biguanides, meglitinides, sulfonylureas, thiazolidindiones or insulin therapies are common clinical options in management of type 2 diabetes and hyperglycemia, but traditionally used natural agents have been considered for a long period of time. Among the known natural bioactive components and phytochemicals, recently polyphenols are very popular because of their anti-hyperglycemic effects, safety and non side-effects. Potential efficacy of polyphenols on carbohydrate metabolism and glucose homeostasis has been well investigated in in vitro, animal models and some clinical trials [24].

In Figure 1 beneficial effects of polyphenols on management of blood glucose in diabetes are summarized. The hypoglycemic effects of polyphenols are mainly attributed to reduce intestinal absorption of dietary carbohydrate, modulation of the enzymes involved in glucose metabolism, improvement of β-cell function and insulin action, stimulation of insulin secretion, and the antioxidative and anti-inflammatory properties of these components [25–27].

Figure 1
figure 1

Beneficial effects of polyphenols on management of blood glucose in diabetes. The hypoglycemic effects of polyphenols are mainly attributed to reduce intestinal absorption of dietary carbohydrate, modulation of the enzymes involved in glucose metabolism, improvement of β-cell function and insulin action, and stimulation of insulin secretion.

Full size image

One of the most well known properties of the polyphenols, especially flavonoids, phenolic acids and tannins, on carbohydrate metabolism is inhibition of α-glucosidase and α-amylase, the key enzymes responsible for digestion of dietary carbohydrates to glucose [26, 28]. Some polyphenols, including green tea catechins and epicatechins, chlorogenic acids, Ferulic acids, caffeic and tannic acids, quercetin and naringenin, could interact with absorption of glucose from intestine via inhibition of Na+-dependent glucose transporters, SGLT1 and SGLT2 [29, 30]. 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 glucose-6-phosphatase 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 [85]. Purple corn extract containing cyanidin 3-glucoside and cyanidin-3-(6″-malonylglucoside) attenuated hyperglycemia-induced mesangial cell proliferation and matrix accumulation, and inhibited over-expression intracellular cell adhesion molecule-1 and monocyte chemoattractant protein-1, as major features of diabetic mesangial fibrosis and glomerulosclerosis [86]. 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, epicatechin-3-gallat, 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].

Conclusion

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.