Amelioration of the oxidative stress

Diabetes is associated with oxidative stress due to hyperglycemia and hyperlipidemia⁽Reference Baynes and Thorpe⁴⁾. Hyperglycemia and dyslipidemia (increased level of fatty acids and TAG-rich and modified lipoproteins) induce inflammatory-immune responses and oxidative stress reactions, and generation of free radicals accounts for the cardiovascular complications and mortality of obesity and type 2 diabetes⁽Reference Baynes and Thorpe^4, Reference Pickup⁵⁾.

The depletion of antioxidants and its contribution to cardiovascular complications in diabetes is well documented⁽Reference Baynes and Thorpe^4–Reference Chertow⁶⁾. Several studies have demonstrated significant decrease of plasma antioxidants such as of α- and γ-tocopherol, β- and α-carotene, lycopene, β-cryptoxanthin, lutein, zeaxanthin, retinol, as well as ascorbic acid in the course of diabetes and its associated complications such as endothelial dysfunction and atherosclerosis⁽Reference Polidori, Mecocci and Stahl^7–Reference Valabhji, McColi and Richmond¹⁰⁾. Low levels of plasma antioxidants are even more pronounced in elderly diabetic subjects⁽Reference Polidori, Stahl and Eichler⁸⁾. Thus the rationale for the therapeutic use of antioxidants in the treatment and prevention of diabetic complications is strong.

Flavonoids, carotenoids, ascorbic acid and tocopherols are the main antioxidants recommended based on the results from experimental models⁽Reference Pietta^11, Reference Middleton, Kandaswami and Theoharides¹²⁾. They have been shown to inhibit ROS production by inhibiting several ROS producing enzymes (i.e. xanthine oxidase, cyclooxygenase, lipoxygenase, microsomal monooxygenase, glutathione-S-transferase, mitochondrial succinoxidase, NADH oxidase), and by chelating trace metals and inhibiting phospholipases A2 and C⁽Reference Manach, Mazur and Scalbert¹⁷⁾. They act by donating a hydrogen atom/electron to the superoxide anion and also to hydroxyl, alkoxyl and peroxyl radicals thereby protecting lipoproteins, proteins as well as DNA molecules against oxidative damage⁽Reference Pietta^11, Reference Noguchi and Nikki¹³⁾. However, free radicals as well as some antioxidative vitamin derivatives (i.e. retinoic acid) are also important regulators of cellular functions including gene expression, differentiation, preconditioning (mitochondrial function) and apoptosis etc⁽Reference Chertow⁶⁾.

Although many earlier epidemiological studies have reported lower risk of cardiovascular disease and cancer in populations with higher intakes and higher blood levels of antioxidants, the large scale trials with antioxidant supplementation have failed to confirm any protective effect by antioxidants on cardiovascular mortality in spite improving the biochemical parameters of lipoprotein oxidation (reviewed by Clarke & Armitage⁽Reference Clarke and Armitage¹⁴⁾). Nevertheless, the available evidence does not contradict the advice to increase consumption of fruit and vegetables to reduce the risk of cardiovascular disease especially in patients with diabetes⁽Reference Chertow⁶⁾.

Anti-inflammatory and antiatherogenic effects

Low-grade inflammation (also called a sub-clinical inflammatory condition) and the activation of the innate immune system are closely involved in the pathogenesis of type 2 diabetes and associated complications such as dyslipidemia and atherosclerosis⁽Reference Pickup¹⁵⁾. Especially the development of obesity related insulin resistance have been linked to cytokines tumour necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) produced by the adipose tissue. Major tissue specific pathways involved in the inflammatory process have been suggested to depend on nuclear factor-kappa B (NF-κB) and c-jun terminal NH2-kinase (JNK) signalling pathways⁽Reference Bastard, Maachi, Lagathu, Kim, Caron, Vidal, Capeau and Feve¹⁶⁾. A strong negative correlation between polyphenols consumption and CAD and stroke has been documented⁽Reference Manach, Mazur and Scalbert¹⁷⁾. However, a major difficulty with these correlative studies is the extreme complexity of the polyphenols in food and beverages. Several hundreds of phenolic compounds have been described in foods including flavonoids and non-flavonoids (phenolic acids, stilbenes and lignans).

There is increasing evidence of potential benefits of polyphenols in the regulation of cellular processes such as redox control and inflammatory responses as established in animal models or cultured cells. In the apoE KO mice model, polyphenols from red wine and green tea were shown to prevent the formation of atherosclerotic plaques⁽Reference Norata, Marchesi and Passamonti¹⁸⁾. This antiatherosclerotic effect may be associated both with modification of oxidative stress and/or with lipid-lowering effect of the polyphenols⁽Reference Hayek, Fuhrman and Vaya^19, Reference Waddington, Puddey and Croft²⁰⁾. The anti-inflammatory effect is due to decreased recruitment of monocyte-macrophages and T-lymphocytes and decreased chemokines and cytokines or its receptors. Resveratrol, catechin and quercetin interact with the NF-κB signalling pathway by inhibiting the expression of the adhesion molecules, ICAM-1 and VCAM, in endothelial cells as well as expression of MCP-1, MIP-1α and MIP-1β and the chemokine receptors CCR1 and CCR2⁽Reference Norata, Marchesi and Passamonti^18, Reference Pellegatta, Bertelli and Staels²¹⁾. The latter inhibit the chemotaxis and leukocyte recruitment resulting in decrease of IL-6, VEGF, TGFβ, but also IL-10 indicating decreased Th1 and Th2 recruitment.

Metabolites of blueberry polyphenols produced by gut flora have been shown to decrease the inflammation in vitro as measured by prostanoid production⁽Reference Russell^22, Reference Youdim, McDonald, Kalt and Joseph²³⁾. Beneficial immune responses have been shown in human endothelial cells upon exposure to these anthocyanin metabolites at doses comparable to those found in plasma after blueberry and cranberry administration⁽Reference Youdim, McDonald, Kalt and Joseph²³⁾. Anthocyanin metabolites reduced TNF-alpha induced expression of IL-8, MCP-1 and ICAM-1 while reducing the oxidative damage. Inhibition of COX-2 by anthocyanidins was mediated with MAPK-pathway in LPS-evoked macrophages in vitro ⁽Reference Hou, Yanagita, Uto, Masuzaki and Fujii^24, Reference Pergola, Rossi, Dugo, Cuzzocrea and Sautebin²⁵⁾. The main anthocyanin in the blackberry extract, cyanidine-3-O-glucoside, was shown to inhibit the iNOS biosynthesis⁽Reference Pergola, Rossi, Dugo, Cuzzocrea and Sautebin²⁵⁾. Asthma related inflammation can also be reduced by anthocyanins via COX-2 inhibition as shown in a murine model (in vivo). In this asthma model anthocyanins were also found to reduce Th2 regulated cytokine expressions (mRNA of TNF-alpha, IL-6, IL-13, IL-13 R2alpha). One key transcription factor in obesity related inflammation is NF-κB. The effects of anthocyanins in inhibition of NF-κB has been studied in a human intervention study using a blackcurrant and bilberry supplementation product “Medox” with 300 mg/d⁽Reference Karlsen, Retterstøl, Laake, Paur, Kjølsrud-Bøhn, Sandvik and Blomhoff²⁶⁾. In addition to inhibition of NF-κB in a cell culture model, NF-κB mediated cytokines IL-8 and INF alpha was significantly reduced.

Glucose and lipid metabolism

A number of regulatory mechanisms help the body to maintain glucose and lipid homeostasis and stable levels of energy stores. Such mechanisms involve control of metabolic fluxes among various organs and energy metabolism within individual tissues and cells⁽Reference Chertow⁶⁾. Many types of mammalian cells can directly sense changes in the levels of variety of macronutrients (glucose, fatty acids and amino acids) or the related enzymes etc of their catabolism, such as AMP-activated protein kinase (AMPK, the metabolic stress sensor); mammalian target of rapamycin (mTOR), protein kinase (MAPK, the amino-acid and metabolic state sensor), Per-Arnt-Sin (PAS) kinase (sensor of oxygen/redox status), hexosamine synthetic pathway flux (HBP) (insulin sensing), or NAD⁺-dependent protein deacetylase SIRT2 (sensor of the long-term energy restriction) involved in longevity⁽Reference McCue, Kwon and Shetty²⁸⁾ (Figs. 1 and 2).

Fig. 1 Some of common mechanisms regulating the cellular response to “nutrient-energy sensing” pathway including AMP-regulating kinase and mammalian target of rapamycin (mTOR) pathways.

Fig. 2 The main transcriptor factors induced by insulin, glucocorticosteroids, cAMP and mitogens during adipogenesis.

Regulation of the postprandial glucose by inhibiting starch digestion, delaying the gastric emptying rate and reducing active transport of glucose across intestinal brush border membrane is one of the mechanisms by which diet can reduce the risk of type 2 diabetes. Thus inhibition of intestine sodium–glucose cotransporter-1 (Na-Glut-1) along with inhibition of α-amylase and α-glucosidase activity by plant phenols make them a potential candidate in the management of hyperglycemia⁽Reference Heilbronn, Smith and Ravussin^29, Reference Kobayashi, Saito, Nakazawa and Yoshizaki³⁰⁾.

Tea and several plant polyphenols were reported to inhibit α-amylase and sucrase activity, decreasing postprandial glycemia⁽Reference Kobayashi, Saito, Nakazawa and Yoshizaki³⁰⁾. Individual polyphenols, such as (+)catechin, ( − )epicatechin, ( − )epigallocatechin, epicatechin gallate, isoflavones from soyabeans, tannic acid, glycyrrhizin from licorice root, chlorogenic acid and saponins also decrease S-Glut-1 mediated intestinal transport of glucose (reviewed by Tiwari⁽Reference Tiwari and Rao³¹⁾). Saponins additionally delay the transfer of glucose from stomach to the small intestine⁽Reference Francis, Kerem, Makkar and Becker³²⁾. The water-soluble dietary fibres, guar gum, pectins and polysaccharides contained in plants are known to slow the rate of gastric emptying and thus absorption of glucose. The α-glucosidase inhibitors (acarbose and the others) are presently recommended for the treatment of obesity and diabetes. Phytochemicals have been shown to demonstrate such as activity⁽Reference Watanabe, Kawabata, Kurihara and Niki³³⁾.

Anthocyanins, a significant group of polyphenols in bilberries and other berries, may also prevent type 2 diabetes and obesity. Anthocyanins from different sources have been shown to affect glucose absorption and insulin level/secretion/action and lipid metabolism in vitro and in vivo ⁽Reference Tsuda, Ueno, Kojo, Yoshikawa and Osawa^35–Reference Martineau, Couture, Spoor, Benhaddou-Andaloussi, Harris, Meddah, Leduc, Burt, Vuong, Mai Le, Prentki, Bennett, Arnason and Haddad³⁷⁾. Blueberry extracts were found to be potent inhibitors of starch digestion, and more effective inhibitors of the α-glucosidase/maltase activity than extracts from strawberry and raspberry. Martineau and his group (2006) reported that extracts from the high bush blueberry (V. angustifolium) also increase glucose uptake by the muscle cells in the presence of insulin and protect the neural cells from the toxic effects of high glucose levels in vitro ⁽Reference Martineau, Couture, Spoor, Benhaddou-Andaloussi, Harris, Meddah, Leduc, Burt, Vuong, Mai Le, Prentki, Bennett, Arnason and Haddad³⁷⁾. Other in vitro studies with pancreatic cells have shown that pure anthocyanins (glucose conjugates) such as delfinidin glucosides, cyanidin glycosides and cyanidin galactosides can increase the excretion of insulin in primary cell cultures⁽Reference Martineau, Couture, Spoor, Benhaddou-Andaloussi, Harris, Meddah, Leduc, Burt, Vuong, Mai Le, Prentki, Bennett, Arnason and Haddad³⁷⁾. Anthocyanins also influence the expression of genes involved in cell cycle, signal transduction, lipid and carbohydrate metabolism in adipocytes isolated from rats⁽Reference Jayaprakasam, Vareed, Olson and Nair³⁶⁾ and human tissues⁽Reference Xia, Ling, Ma, Xia, Hou, Wang, Zhu and Tang³⁹⁾. These in vitro studies suggest that the anthocyanins may decrease the intestinal absorption of glucose by retarding the release of glucose during digestion.

Tsuda and his co-workers have also studied the colourful extract of purple corn (PCC) containing anthocyanins with respect of its possible effects in obesity and diabetes⁽Reference Tsuda, Horio, Uchida, Aoki and Osawa³⁴⁾. Purple corn colour contains high amounts of cyanidin glucoside (70 g/kg) and it is used as a food colouring agent in beverages. They fed mice for 12 weeks with a high fat diet (HFD) or a normal diet with or without 2 g/kg cyanidin glucosides. The animals fed with HFD had higher body weight and weights of brown and white adipose tissues (hypertrophy) and increased triglycerides and total fat content in liver, but not in serum. Serum insulin, leptin and TNF-α (mRNA) were also increased after feeding with this diet. All of these effects of HFD feeding were decreased in mice fed a diet with PCC. Similar effects have been observed with high fat diets rich in anthocyanins from Cornelian cherries and black rice⁽Reference Martineau, Couture, Spoor, Benhaddou-Andaloussi, Harris, Meddah, Leduc, Burt, Vuong, Mai Le, Prentki, Bennett, Arnason and Haddad^37, Reference Johnston, Clifford and Morgan⁴⁰⁾. In many of the studies utilizing the HFD model the sources of anthocyanins are not fully described. Therefore, a detailed analysis of the contents of extracts as well as the contents of diets could provide valuable information to further evaluate the effective components in these diets. Thus far only one other human study on anthocyanins has been reported and it showed that consumption of chokeberry, a berry that contains as much antocyanins as bilberries, decreases fasting glucose and serum cholesterol and decreases Hb_A1C in type 2 diabetic patients⁽Reference Jahromi and Ray⁴²⁾.

In addition to anthocyanins, chlorogenic acid also present in wild berries may also explain some of their potential health effects in obesity related diseases. Indeed, several studies on coffee rich in chlorogenic acid suggested some beneficial effects of this compound. Johnston and his co-workers studied the effect of coffee on the absorption of glucose from a single dose (25 g, 2·5 mmol/l chlorogenic acid) in humans⁽Reference Johnston, Clifford and Morgan⁴⁰⁾. They suggested that chlorogenic acid could disrupt the Na-gradient that is needed in the transport of glucose from the proximal duodenum.

Cytoprotection of pancreatic β-cells (maintaining of insulin secretion)

Cytoprotection of pancreatic β-cells was demonstrated for the extracts containing phytochemicals (liquiritigenin, pterosupin) from several medicinal plants: Pterocarpus marsupium, Gymnemaq sylvestre ⁽Reference Chakravarthy, Gupta and Gode^43, Reference Ignacimuthy and Amalraj⁴⁴⁾, as well as Zizyphus jujuba or Trigonella foenum-graceum L. fenugreek seeds⁽Reference Ravicumar and Anuradha^45, Reference Young, Dragstedt, Haraldsdottir, Daneshvar, Kal, Loft, Nilsson, Nielsen, Mayer, Skibsted, Huynh-Ba, Hermetter and Sandstrom⁴⁶⁾ in streptozotocin or alloxan-induced model of diabetic rats. The antioxidant effects of the above flavonoids were demonstrated by the decrease of lipid peroxidation, as well as by increased plasma levels of glutathione and beta-carotene⁽Reference Young, Dragstedt, Haraldsdottir, Daneshvar, Kal, Loft, Nilsson, Nielsen, Mayer, Skibsted, Huynh-Ba, Hermetter and Sandstrom⁴⁶⁾. Water-soluble extracts of the Gymnema sylvestre leaves given for 10–12 months to control glycemia and lipidemia enhanced endogenous insulin secretion in 27 IDDM patients⁽Reference Shanmugasundaram, Rajeswari and Baskaran⁴⁷⁾. Also the fenugreed seeds have been reported to exert hypoglycemic and lipid normalizing effects⁽Reference Sharma and Raghuram^48, Reference Sharma, Raghuram and Dayasagar Rao⁴⁹⁾.

Inhibition of aldose reductase (the polyol pathway)

Accumulation of sorbitol, the metabolite of polyol reductase pathway, plays an important role in diabetic complications such as retinopathy, cataract, neuropathy and nephropathy. Apart from their common antioxidant activity, several plant-derived flavonoids can increase aldose reductase activity, ameliorating the complications of diabetes in experimental models⁽Reference Iwata, Nagat and Omae^50, Reference Yoshikawa, Morikawa and Murakami⁵¹⁾. Recently butein (tetrahydrochalcone) was reported to be a potent antioxidant and a compound that inhibits aldose reductase in the treatment of the side effects observed in rats with streptozotocin-induced diabetes⁽Reference Lim, Jung, Shin and Keum⁵²⁾.

Improvement of endothelial dysfunction

Plant polyphenols exert also vasorelaxant, anti-angiogenic and anti-proliferative effects on cells of the vascular wall such as endothelium or vascular smooth muscle⁽Reference Stoclet, Chataigneau and Ndiaye⁵³⁾. Epigallocatechin gallate decreases vascular smooth muscle cell proliferation and thereby reduces the capillary thickness and inhibits vessel remodeling⁽Reference Flesch, Schwarz and Bohm⁵⁵⁾. Plant phenols induce vasorelaxation by the induction of endothelial nitric oxide synthesis or increased bioavailability and the NO-cGMP pathway⁽Reference Chyu, Babbidge and Zhayo^54, Reference Liu, Chen and Chan⁵⁶⁾. The inhibition of vasoconstrictory endothelin-1 by polyphenols in human and bovine endothelium has been also reported⁽Reference Rupnick, Panigrahy and Zhang⁵⁷⁾. Thus the beneficial effects of phytochemicals on endothelial function are well documented.

Inhibition of angiogenesis

Without the appropriate blood supply by blood and lymph capillary network, tissues cannot survive because the circulatory system is essential for the oxygen and nutrient distribution between tissues and for the removal of by-products of metabolism. Vasculogenesis and angiogenesis play an essential role in a number of physiologic and pathologic events such as fetal development, vascular and tissue remodeling in ischemia, inflammation and proliferative diabetic retinopathy. Vascularity is critical also for the function of adipose tissue as a metabolic and an endocrine organ. It has been shown recently that treatment of animals with antiangiogenic factors, (such as anti VEGF or its receptor antibody) dose-dependently and reversibly decreases the adipose tissue depot and body weight⁽Reference Higami, Barger and Page⁵⁸⁾. Angiogenesis may play an important role in the diabetic microangiopathy and inflammation (macrophage infiltration) of the adipose tissue and also in the control of adipose tissue mass⁽Reference Fain, Madan and Hiler^59, Reference Losso⁶⁰⁾ (Fig. 3).

Fig. 3 Some of corregulators involved in adipogenesis and the possible regulation by PPARγ ligands, glucocorticoides, insulin/Akt and histone deacetylases including sirtuin-1. TRAP – thyroid-hormone receptor-associated protein, FoxO1 – forkhead transcription factor.

The possibility of the control of pathological angiogenesis (including age-related macular degeneration (AMD) and diabetes) by nutraceuticals has been reviewed by Losso⁽Reference Losso⁶⁰⁾. Several classes of compounds including catechins, curcumin, isoflavones, polymeric proanthocyanidins and flavonoids, saponins and terpenes, vitamins, and their possible mechanisms of function have been discussed in this review. Anti-angiogenic effect of polyphenols depends mainly on the inhibition of the p38 MAPK-mediated expression of the VEGF gene⁽Reference Dembinska-Kiec, Polus and Kiec-Wilk⁶²⁾. On the other hand, our experimental results indicate that carotenoids such as β-carotene may promote angiogenesis by activating chemotaxis of endothelial cells and its progenitors⁽Reference Brakenhielm, Cao and Cao⁶³⁾. Thus in diabetes which displays both excessive and insufficient angiogenesis, compounds that may inhibit excessive angiogenesis and exacerbate insufficient angiogenesis need to be identified. Brakenhielm et al. ⁽Reference Brakenhielm, Cao and Cao⁶³⁾ demonstrated that the resveratrol, a red wine compound with beneficial antioxidative effects and stimulator of the sirtuin (“the longevity gene”), caused wound enlargement in the diabetic rat model. Delayed wound healing is a known complication of diabetes caused by microangiopathy and endothelial dysfunction. Retinoids prevent angiogenesis and with green tea catechins inhibit angiogenesis. Compounds exerting the thermogenic, as well as anti-angiogenic activity also demonstrate the antiobesity effects⁽Reference Cao⁶⁵⁾.