ALLNatural Heart Health

Grape Seed Extract, a Highly Beneficial Health Factor

ALLNatural Heart Health is prepared from an extract of grape seeds. This product primarily contains oligomeric proanthocyanidins (OPCs) which have many health benefits.

The phenomenon, termed “The French Paradox”, has been attributed in part to the large intake of red wine in France, especially those wines containing high levels of OPCs. This effect is associated with a greatly reduced incidence of heart disease even though the French consume large amounts of saturated fats.

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The Health Benefits of ALLNatural Heart Health

OPCs are known for their significant antioxidant properties which are 20 and 50 times greater than those of vitamins E and C, respectively. Grape Seed Extract provides excellent protection against oxidative stress and free–radical mediated tissue injury including those associated with many diseases, some of which are indicated below.

Heart Disease

Inhibits the development of heart disease (atherosclerosis) and prevents oxidation of low density lipoprotein (LDL, bad cholesterol).

Blood Pressure

Reduces blood pressure and can help relive the sensation of swelling, heaviness and tingling of the legs caused by blockage of veins and inflammatory infection.


Protection against oxidative stress and high blood glucose levels in diabetics.

Brain and Alzheimer’s Diseases

Helps to inhibit oxidative DNA damage in the spinal cord and the brain. Can be beneficial for persons with Alzheimer’s by reducing inflammation in the brain.


Protects against skin, colorectal, prostate, breast and other cancers.

Anti-Fatigue During Exercise

OPCs reduce oxidative destruction of muscle and other tissue.


Authorized for Sale by Health Canada

ALLNatural Heart Health and Grape Seed Extract is of high quality and strength. ALLNatural Nutritional Products Inc. has been issued a Natural Product Number (NPN 80021102), a requirement by Health Canada for the sale of nutraceuticals. This number insures you that the product has been reviewed and approved by Health Canada and it is safe, effective and of high quality.

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Frequently Asked Questions

ALLNatural Nutritional Products are high quality, safe, effective and of great value. ALLNatural Grape Seed Extract uses Health Canada’s recommended dosage of 200 mg per capsule, with an 80% OPCs concentration. It is encapsulated in 100% vegetable capsules and produced at facilities with Good Manufacturing Practice (GMP) and associated site licenses. ALLNatural Grape Seed Extract is analyzed at state of the art laboratories to ensure its high quality and strength. Its price is also very competitive in the nutraceutical market.

OPC Diagram

Epicatechin (EC), one of the building blocks of proanthocyanidins

Proanthocyanidins, also known as OPCs (oligomeric proanthocyanidins) or condensed tannins, are a subgroup of the flavonoid class of polyphenols. In essence, they are oligomer chains of flavanols, such as the flavan-3-ol epicatechin.

OPCs are very complex and require specialized knowledge and technology in order to be accurately identified and quantified.

Yes! OPCs in Grape Seed Extract and red wines have been associated with many health benefits. Proanthocyanidins are almost completely non-toxic both in acute dosage (LD50>4,000 mg/kg in rats and mice) and high long-term dosage (no toxic effects at 60 mg/kg/day for 12 months in dogs and six months in rats). They have no potential for causing mutations or birth defects, and have no adverse effect on fertility, pregnancy, or nursing. Scientific studies have demonstrated that OPCs can be safely consumed at high levels but are not recommended for children. Consult a doctor before using.

Yes! OPCs exert a potent antioxidant capability (50 times greater than Vitamin E and 20 times greater than Vitamin C in vitro), and are highly effective anti-inflammatory and anti-aging substances. OPCs destroy free radicals and restore correct alignment of collagen fibers in aging or damaged connective tissue. Antioxidant supplementation is necessary if we are unable to reduce our exposure to free radicals, but wish to counter their effect. OPCs should be taken in conjunction with foods or dietary supplements rich in vitamin C, vitamin E, beta-carotene, and selenium, to name a few antioxidants. If you are not taking vitamin C and E with your OPC you are not getting the full effect. The combination helps remove harmful free radicals.

Science and Research

Grapes and their seed are a rich source of bioactive polyphenols which are mainly the flavan-3-ol. The main monomeric subunit derivatives of the flavan-3-ols are (+)-catechin, (-)-epicatechin, (-) – epicatechin-3-O-gallate, epigallocatechin and epigallacatechin-3-O-gallate. Each of these individual subunits link together (condense) to form diamers (2 monomers), trimers, tetramers, pentamers and the larger polymers (≥ 6 mers). Several different names are often used interchangeably to describe the polyphenolics in grape seed extract. Health Canada uses the name oligomeric proanthocyanidins (OPCs) to describe the bioactive flavan-3-ols in GSE.

Presumably they refer to OPCs with less than eight monomers (< 8 mers). Other or overlapping designations that appear in the literature are proanthocyanidins, procyanidins and condensed tannins. Overall the OPCs are polymeric chains of catechins, epicatechins or their derivatives. The amount of flavanols, mainly as catechin and epicatechin polymers in the seed, range from a low of less than 40% to over 90%. The level of OPCs in red wines are between 0.5 g/L and 1.5 g/L or even higher in certain wines from Sardina while those in white wines are from 10 to 50 mg/L. The average intake of OPCs in the USA is estimated to be about 95 mg/day/person while the Health Canada recommended intake of GSE (80% OPC’s) is 400 mg/day/person.

In general the flavanol monomers plus the 2 to 5 oligomers from GSE are absorbed from the digestive tract, while only the monomers and possibly the dimers are able to enter the brain and produce a beneficial effect. In contract to the shorter oligomers, the larger polymers, especially those ≥ 8 mers are not absorbed but are able to enhance the absorption of the smaller lower molecular weight OPCs.

The main reason why life expectancy is much longer in certain regions of France compared with other western countries, in spite of their high intake of saturated fats, is that the French, in contrast to people in the other countries, consume large quantities of red wines high in OPCs. This is referred to as the French Paradox.

It has been shown that the main compounds responsible for this effect are the OPC’s (similar to those in GSE) and to a lessor degree resveratrol. Numerous studies have demonstrated that grape seed extract OPC’s have a broad range of pharmaceutical and medicinal properties including their ability to protect the body against oxidative stress caused by free radicals. Free-radical production in the body has been implicated in more than 100 diseases such as atherosclerosis, AIDs, arthritis, brain and cardiovascular dysfunctions, carcinogenesis, cataracts, diabetes, ischemic and ocular dysfunctions, and tumor promotion.

The OPCs have been shown to be considerably more powerful antioxidants than either vitamins C or E and, as a result, more protective against the destructive effects of free-radicals. Some of the specific benefits of grape seed extract OPCs are:

  1. Atherosclerosis: The considerable benefits of the OPCs were first described as an explanation for the French Paradox.
  2. Anticancer and chemoprevention potential: GSE is a highly beneficial agent in the protection and fight against cancer.
  3. Alzheimer’s and related neurological diseases: The monomeric and dimeric forms of GSE OPCs have been shown to be effective in the protection and prevention of Alzheimer’s and related diseases in animal models.
  4. Type-2 diabetes; effects on glucose metabolism: Several clinical trials with humans have demonstrated that GSE can reduce blood glucose concentrations in both diabetic and non-diabetic populations by two different biochemical mechanisms.

Recommended Duration of Intake and Safety of Grape Seed Extract

Grape Seed Extract (80% OPCs) should be taken over long periods of time at the Health Canada recommended rate of 400 mg/day (2 × 200 mg/caps) in order to receive its full benefits.

ALLNatural Nutritional Products Inc. has been issued a licence from Health Canada to market its grape seed extract under the brand name of ALLNatural Heart Health, Grape Seed Extract. The Natural Health Product Number (NPN), a requirement for the sale of the product, is 80021102.

GSE even when taken at doses that are several fold greater than the Health Canada recommended dose is safe and rarely causes side effects.

The following selected scientific publications are reviews by international experts on the various beneficial effects of grape seed extract as outlined above. References to key publication are given in each section along with links to the abstracts and most of the full publication. Many of the complete publications can be accessed through the internet (Google Scholar).

Grapes are rich in polyphenols with 60 to 70% of the polyphenols of grapes being in the seed. The active phenolic compounds in grape seeds are the flavonoids and polyphenols.


Grape seeds contain flavonoids (4.5%) including kaemferol-3-O- glucosides, quercitin-3-0-glucosides, quercitin and myriceitin (Nassiri-Asl and Hosseinzadeh, 2009).


Grapes are rich in polyphenols with 60 to 70% being found in the seed. The polyphenols are mainly flavan-3-ol derivatives which occur as their monomeric and polymeric forms (1 to > mers). The monomeric of flavan-3-ol derivatives are (+)-catechin, (-)-epicatechin, (-)-epicatechin-3-O-gallate, epigallocatechin and epigallocatechin-3-O-gallate (Figure 1). The monomers of flavanol-3-ol condense to form dimers, trimers, tetramers, pentamers and longer chain polymers. Collectively the polyphenols of grape seed extract are referred to oligomeric proanthocyanidins (OPCs) or alternatively as procyanidins proanthocyanidins, or condensed tannin. As indicated above, proanthocyanidins are essentially polymeric chains of flavanoids such as catechins and epicatechins. (Figure 2).

Structures of the major flavan-3-ols identified in grape seed extract.

Figure 1.   Structures of the major flavan-3-ols identified in grape seed extract. The large number of hydroxyl groups are responsible for their powerful antioxidant and free-radical savaging ability (from Shoji et al., 2006).

Structures of proanthocyanidin oligomers.

Figure 2.   Structures of proanthocyanidin oligomers. The oligomeric proanthocyanidins are composed of flavan-3-ols units linked together from the C4 of one unit to either the C6 or C8 of the adjacent unit (from Shoji et al., 2006).

Total monomeric and polymeric amounts of OPCs

The total flavanol content of GSE has been reported to be 592 mg/g dry weight, including gallic acid (49 mg/g), catechin (41 mg/g), epicatechin (66 mg/g) and proanthocyanidins (437 mg catechin equivalents/g), (Wang et al., 2009). Wang et al. (2012) separated flavanols in GSE into catechin and epicatechins as monomers plus dimers, and into oligomers and polymers using HPLC analysis. The monomers plus dimers in their study was equal to 40% of the total proanthocyanidins.

Waterhouse (2002) reported that the proportion of flavanols, mostly as (+) – catechin and (-) – epicatechin, in the seed ranges from a low of less than 40% to a high of over 90%. Most GSE sold commercially contain 80% OPC’s. In typical red wines, the amount of polymer plus oligomer flavanols range from 25 to 50% for new wines and higher in older wines due to conversion of monomers into polymers.

The level of polymers in red wine are between 0.5 g/L and 1.5 g/L or even higher in red wines from Sardinia while in white wines, they range from 10 to 50 mg/L and are highly dependent on pressing techniques. The amount of total monomeric flavanols in typical red wine ranges from 40 to 120 mg/liter with the majority usually being catechin. The amount of the monomer flavanols vary from a low of 41 mg/kg seed for the variety Carigon to a high of 1,100 mg/kg seed for Pinot Noir.

Absorption and bioavailability of flavan-3-ol

In general most polyphenols are poorly absorbed compared with other nutrients. After absorption in the digestive tract, they are transported to the liver where they form glucuronide and/or sulfate or methyl conjugates, followed by transport to body tissues (Shoji et al., 2006 for citations).

Shoji et al. (2006) purified different proanthocyanidin (referred to us procyanidins)  fractions from apples including monomers of catechin and epicatechin, 2-5 mers (dimers, trimers, tetramers and pentomers) and those larger than the hexamers (> 7 mer). They reported that procyanidins (1 to 5 mers) were absorbed from the upper portion of the digestive tract such as the small intestine but unlike some reports were not degraded into compounds with lower molecular weights by the colonic microorganisms.

The dimers, trimers, tetramers and pentomers isolated from the procyanidin were all absorbed with that of the dimers being about one-third of that of the other compounds. Also, the procyanidin in each dimer to pentomer group were not reduced to compounds with molecular weight lower than those of the native procyanidins including the free monomers. Although procyanidins with molecular sizes, equal to or greater than 8-mers were not absorbed themselves, they were able to considerably enhance the absorption of the 1-5 mer procyanidins.

They proposed that the procyanidins with a high molecular weight (≥8-mers) were bound to mucosal protein of the digestive tract, thereby allowing the larger procyanidin oligomer (>5 mers) to be absorbed rather than being bound themselves to the numerous intestinal proteins. In another study, Wang et al. (2012) separated the propanthocyanidins (procyanidins) from GSE into two fractions, monomers plus dimers (Mo), and oligomers and polymers (Po).

The primary circulating forms of the polyphenols from Mo were the glucuronide conjugates of catachin (C) and epicatechin (EC). They reported that only the Mo fraction accumulated in the brain and that only this fraction from GSE was effective in treatment of Alzheimers disease in a mouse model of the disease.

In summary, the results of several studies have demonstrated that the flavanol monomers plus the 2-5 mer oliomers are absorbed from the digestive tract and are found in the plasma. In contrast, the larger oligomers (≥ 8 mers) are not absorbed but greatly increase the absorption of the smaller polymers (< 5 mers). Only the monomers and possibly the dimers are able to cross the blood brain barrier and produce a beneficial effect.

What is the estimated daily intake of proanthocyanidins (PA or OPCs) in the USA diet  (mainly wines, tea and daily legumes)?

The estimated intake of proanthocyanidins (PA) in the USA for adults over 19 years was estimated to be 95 mg/day, in order of polymers (30% or 29 mg/day), monomers (22% or 21 mg/day), dimers (16% or 15 mg/day), trimers (5% or 15 mg/day) and 4-6 mers (15% or 14 mg/day).  The major food sources, (tea, legume and wines,) contributed 45 mg (48%) to the daily intake (Wang et al., 2011).

The Health Canada recommended intake of GSE (80% OPCs) is 400 mg/day which would be equal to a total daily supplemental intake of OPCs (PAs) of 320 mg/day (400 × 0.8). Supplemental GSE would, therefore, greatly increase the average daily intake of OPCs from 95 mg/day/person to 415 mg/day/person (95 + 320).

An alternative means of increasing the intake of PA would be to consume additional red wine. This can be achieved by consuming 0.6 liters of red wine per day containing 0.5 g/liter of PA or smaller amounts if the PA content of the wine was higher. This may not be practical as most people do not consume wine on a daily bases and information is not generally available on the PA content of most red wines. White wines would not greatly increase the total intake of PA as they have low concentrations of these compounds. The best solution to ensure an adequate intake of PA (OPCs) is to take All Natural Nutritional Products GSE supplement.

The publication entitled “Wine, alcohol, and the French Paradox for coronary heart disease” by Renaud and De Lorgeril in 1992 has had a pronounced influence on the consumption of red wine world-wide and presumably will greatly promote an increased intake of GSE.

They proposed that a high intake of red wine was responsible for the much lower rate of coronary heart disease (CHD) in France (Toulouse, 50 per 100,000/ population) compared with that in other industrialized countries such as the USA (Stanford, 115/100,000/population) and UK (Glasgow, 256/100,000/population). This occurred despite intake of saturated fat and concentration of serum cholesterol that were similar in all three populations.

This finding constituted the French Paradox for CHD. They hypothesized that the much higher intake of red wine in France compared to the other countries was responsible for this difference. They also suggested that red wine intake does not prevent CHD through a direct effect on atherosclerosis, but through a direct hemostatic effect; that is, the inhibition of platelet reactivity (aggregation of blood platelets).

They proposed in a subsequent study that the protective effect of red wine was essentially associated with the tannin (proancythoanidin) present in red wine or grape seeds (Ruf et al., 1995). Tannins are synonymous with the terms polyphenols, oligomeric proanthocyanidins (OPCs), proanthocyanidins or procyanidins, all of which are used in the literature interchangeably.

They concluded that the main reason why a region in southern France has a high proportion of men over 75 years age was their intake of red wines which have two-to four-fold more OPCs than most wines. Corder et al. (2006) more recently provide strong evidence that the principal active component in red wine contributing to the French Paradox is its high content of procyanidins (OPCs).

Resveratrol is another compound found in red wines and has been shown to have a host of health benefits including the prolonging of life span in a number of different animal species. It may not, however, be primary responsible for health benefits of red wine since the amount of resveratrol that is available in red wines is one-hundredth to  one-thousandth the level of procyanidins.

The amounts of resveratrol required to obtain the same benefits as OPCs in red wine are approximately 100-fold greater than that which could be achieved by wine consumption. However, acceptable levels of intake of resveratrol can be achieved by taking supplements high in resveratrol. Under these conditions the many different and complementally benefits of resveratrol and OPCs can be achieved.

Grape seed OPCs have been shown to processes a broad spectrum of pharmacological and medicinal properties including their ability to protect the body against oxidative stress caused by free radicals. Free radicals have been implicated in more than one hundred disease conditions in humans, including atherosclerosis, AIDS, arthritis, brain and cardiovascular dysfunctions, carcinogenesis, cataracts, diabetes, ischemia and reperfusion injury of many tissues, ocular dysfunction, and tumor promotion.  Antioxidants/free radical scavengers function as inhibitors at the initiation and promotion/ propagation/ transformation stages of tumor promotion/carcinogenesis, and protect cells against oxidative damage.

Proanthocyanidins are powerful naturally occurring polyphenolic antioxidant that are especially high in certain red wines and GSE. Proanthocyanidins are known to possess antibacterial, antiviral, antiinflammatory, antiallergic and vasodilatory actions. They have also been shown to inhibit lipid peroxidation, platelet aggregation, capillary permeability and fragility. They are able to modulate the activity of regulatory enzymes including cyclooxygenase, lipooxygenase, protein kinase C, angiotensin-converting enzyme, hyaluronidase enzyme and cytochrome P450 activities (see Bagchi et al. 2000Bagchi et al. 2002 for general review).

Bagchi et al (2002) specific studies demonstrated the the GSE provided significantly better protection against free-radical damage than vitamins C and E, and β-carotene. Grape seed also provided selective protection against cytoxicity in cultured human breast, lung and astric adenocarcinoma cells, while enhancing the growth and viability of normal cells. They observed in their in vitro studies on the free radical scavenging abilities of GSE, vitamin E and vitamin C against biochemically generated superoxide anion and hydroxyl radical that GSE, under the condition of the experiment, exhibited 78-81% inhibition of superoxide anions and hydroxyl radicals while vitamin C inhibited these two free radical by approximately 12-19% and vitamin E by 36-44%, respectively. Bagchi et al. (1999), in another in vitro study, demonstrated that GSE reduced tobacco-treated in vitro cell deaths, by 85% while a combination of vitamins E and C only reduced cell deaths by 46%.

Altered expression of cell adhesion molecule expression has been implicated in a variety of clinical inflammatory conditions including those that cause coronary heart disease (CHD). Intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are major cell surface inducible glycoprotein that contribute to all adhesion processes. Sen and Bagchi (2001) demonstrated that GSE at low concentration down-regulated TNFδ-induced VCAM-1 expression but not ICAM-1 expression at the mRNA level. GSE also significantly decreased TNFδ-induced adhesion of T-cell to human umbilical vein endothelial cells.

The potent inhibitory effects of low concentration of GSE against-induced VCAM-1 expression suggests the potential of this extract for prevention of inflammatory conditions and other pathologies involving altered expression of VCAM-1. These studies demonstrate that GSE is highly bioavailable and can serve as a potential tool in protecting multiple target organs from structurally diverse drug-environmental and chemical induced toxic assaults. In summary, the consumption of flavanol rich compounds such as GSE that are high in OPC’s will contribute considerably to health and well being.

Free radicals, human diseases and OPCs as antioxidants

It was shown in the previous section entitled “Cellular protection with oligomeric proanthocyanidins (OPCs) from grape seeds” that GSE OPCs can play a major role in the amelioration of oxidative processes that have the potential to accelerate several diseases. Some of the specific beneficial effects of GSE OPCs are outlined below.


Strong evidence was shown in the section entitled “Red wine and grape seed extract and cardiovascular health (the French Paradox)” that OPCs from red wine and GSE have the potential to greatly reduce the incidence of coronary heart disease (CHD) and that this effect, in part, is attributed to the powerful antioxidative effects of the OPCs which among other actions greatly reduces the adherence of platelets onto the surface of blood vessels thereby reducing occlusions and incidence of CHD.

Wan et al (2001) in a highly controlled, double-blind randomized cross-over human study demonstrated the OPCs were effective in decreasing low density lipoprotein (LDL) oxidation and slightly increasing the levels of high density lipoprotein (HDL, good cholesterol). Sivaprakasapillai et al. (2009) demonstrated that an oral intake of 150 and 300 mg GSE/day/person considerably reduced both systolic and diastolic blood pressure in subjects with metabolic syndrome with the effects at the two dosage levels being similar.

The systolic blood pressure in the group receiving 150 mg/day of GSE decreased from 134 to 123 mm Hg (8.2% decrease) with the corresponding decrease in diastolic blood pressure being from 83 to 77 mm Hg (7.2% decrease). They also reported that GSE reduced oxidized LDL, particularly when its concentrations were high. Other studies have suggested that GSE lowers blood pressure by activation of endothelial nitric oxide synthetase (eNOS) causing an endothelium-dependent relaxation of blood vessals (Edirisinghe et al., 2008).

Anticancer and cancer chemoprevention potential of GSE

Cancer induction, growth and progression are multi-step events. Numerous studies have demonstrated that various dietary agents including GSE interfer with these stages of cancer, thus blocking malignancy. The transition of normal cells toward cancerous phenotype has been attributed to 6 basic defects in normal cell physiology, which culminate in giving an added growth advantage to the transformed cell (Hanahan and Weinberg, 2000).

Because these defects are mostly due to aberrant signal cascades involving numerous molecular players, targeting them by chemopreventative agents could be a rationalizated approach in cancer control. Kaur et al. (2009) in their review concluded that GSE targets these signalling cascades. They discuss the current literature related to the anticancer efficacy of GSE including its effects on skin-, colorectal-, prostate-, breast- and other cancers.

Preclinical and clinical studies have suggested that grapes and grape products including GSE are the source of many potential anticancer and cancer chmopreventative agents. They conclude “that the consumption of grapes and/or grape related products in diets along with maintaining an active and healthy lifestyle has practical and translation potential in the fight against cancer and is thus beneficial to the general population”.

Brain-target OPC metabolites for Alzheimer’s and related diseases

Alzheimer’s disease (AD) is the most common form of senile dementia occurring in later life. With the world population aging, it is estimated that the number of people affected by AD will double every 20 years from today’s estimate of 27 to 107 million. AD is characterized neuropathologically by deposits of amyloid-beta peptides (Aß) which are the primary factors driving this disease (Brookmeyer et al., 2007).

Wang et al. (2008) originally reported that a grape-derived polyphenolic preparation was capable of attenuating cognitive deterioration and reduced brain deterioration in an animal model. Wang et al. (2009) subsequently reported that polyphenol-rich GSE fed for 9 months as a food additive dramatically could prevent the development of AD and improve cognitive function in a general mouse model.

In another study, Wang et al. (2012) reported that only catechin and epicatechin in the monomeric and possibly the dimeric form of poanthocyanidin (PA) from GSE can selectively reach and accumulate in the brain. Most importantly; they reported for the first time that a biosynthetic epicatechin metabolite, 3’-O-methyl-epicatechin-5-O-ß glucuronide, one of the PA metabolites promotes basal synaptic transmission and long-term potentiation in hippocampus slices through metabolism associated with cAMP response element binding protein signaling.

These results suggest that only the monomeric and possibly the diameric forms of PA are taken up by the brain and that these forms, as their glycoside metabolites, benefit cognition by improving synaptic plasticity in the brain. As such these compounds are able to prevent AD and other forms of dementia.

Effect of GSE on glucose metabolism in Type-2 diabetic and non-diabetic individuals

Diabetes is a chronic metabolic disease that has a significant impact on the health and quality of life expectancy of patients. The prevalence of type-2 diabetes world-wide is 3% and is increasing in the developing countries as they adapt to western style diets. Diabetes is characterized by metabolic abnormalities in carbohydrate and lipid metabolsm resulted in postprandial and fasting hyperglycemia, dyslipidema and hyperinsulinema.

Sapwarobol et al. (2012) are the first to demonstrate that 100 and 300 mg GSE/day/subject reduced postpranlial plasma glucose levels in healthy individual 15 and 30 minutes after eating a high carbohydrate diet. The total estimated reduction in glucose uptake (AUC) was reduced by 46 and 75%, respectively, for individual given 100 and 300 mg GSE/day compared with those given the placebo. They proposed that the reduced postrandial glycemia abserved in their study can be explained by the known inhibitory activity of GSE against α glycoside and pancreatic amylase, key enzymes in the digestion of carbohydrates. They concluded that “the delayed and attenuated hyperglycemia may be a useful strategy to prevent development of diabetes in healthy populations.”

Kar et al. (2009) in an earlier study focused on the ability of GSE as modulators of novel markers of vascular risk, oxidative stress, and inflammation and insulin resistance in the pathogenesis of type-2 diabetes. Individuals at an average age of 62 with type 2 diabetes received GSE (600 mg/day) over a 4 week double-blind study. They reported that GSE significantly improved the concentration of metabolic markers of inflammation, glycemia and oxidative stress in obese type-2 subjects at high risk of having an adverse cardiovascular event.

Montagut et al. (2010) provide evidence on a second mechanism by which GSE brings about its beneficial effects in addition its ability to reduce the activity of digestive enzymes as proposed by Sapwarobol et al. (2012). Montagut et al. (2010) investigated the nature of the reaction of GSE with the insulin receptor.

They showed that a procyanidin extract from GSE interact with and induced the autophosphorylation of the insulin receptor which stimulated the uptake of glucose. However, this activation by GSE differs from insulin activation and results in differences in the downstream signaling. Oligomers of GSE phosphorylate protein kinase (AKT) induces phosphorylation at Thr308 to a lower degree than insulin does.

On the other hand, they phosphorylate Akt at Ser473 to the same extent as insulin. Moreover, they found that procyanidins phosphorylate p44/p42 and p38 MAPKs (mitogen activated protein kinase) much more than insulin does. These results provide further insight into the molecular signaling mechanisms used by procyanidins, pointing to Akt and MAPK proteins as key points for GSE-activated signaling pathways. Moreover, the differences in effects between GSE and insulin should help to understand the wide range of biological effects that procyanidins have.

The results of the studies reported in this section demonstrate that GSE has both an effect on glucose up take from the digestive system by its ability to inhibit the activity of carbohydrate digesting enzymes and by its ability to activate the insulin receptor and produce other effects.

Several studies with rodents have demonstrated the GSE when administered at a very high level was non toxic. Ray et al. (2001) carried out long term dose-dependent clinical studies (0 to 500 mg GSE/kg body weight/day) on mice vital target organs and serum chemistry changes.

They demonstrated that GSE was safe and did not cause any determinantal effects in vivo under the conditions of the study. The LD 50 of GSE was found to be greater than 5000 mg/kg body weight when administered once orally. Wren et al. (2002) carried out a 90-day toxicity study of in rats given 0, 0.5, 1 and 2% GSE in the diet (equal to about 1400 mg/kg body weight /day). GSE at all dose levels did not significantly affect clinical signs, hematology properties, organ weights, ophthalmology evaluates or histological findings. Bentivegna and Whitney (2002) calculated that the no-adverse-effect level (NOAEL) of GSE when orally administered to male and female rats over 90 days to be 2150 and 1780 mg/kg body weight/day, respectively.

Yamakoshi et al. (2002) examined the acute and chronic oral toxicity of 2 and 4 g/kg body weight/day of GSE using mutation, chromosomal aberration and micronucleus tests. No evidence of acute or chronic oral toxicity or mutagenerity was observed with any of the tests. The NOAEL for diets containing GSE was 1410 mg and 1501 mg/kg body weight/day for male and female rats, respectively. The corresponding NOAEL for a 80 kg human male or 60 kg female would be 112,800 and 97,565 mg/day of GSE, respectively, which are 282 and 243 times greater than the Health Canada recommended daily intake of 400 mg GSE per day.

Dubnick and Omaye (2001) reviewed 150 reports on the benefits of wine and grapes in individuals that ingested between 75 and 300 mg proanthocyanidins/day or 1-3 glasses of red wine. The authors concluded that proanthocyanidins not only had considerable health benefits but that side effects were rare and only occurred after the ingestion of pharmacological doses. Data in this review indicate that GSE, even when taken at doses several fold greater than the recommended level is safe and essentially causes no side effects.

Arora, P. et al. Bio-functional aspects of grape seeds – A Review. Intern J Phytomed 2:177-185, 2010.

Bagchi, D. et al. Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention. Toxicology 148(2-3):187-197, 2000.

Bagchi, R. S. et al. Acute and long-term safety evaluation of a novel IH636 grape seed proanthocyanidin extract. Res Commun Mol Pathol Pharmacol  109(3-4):165-97, 2001.

Bagchi, D. et al. Cellular protection with proanthocyanidins derived from grape seeds. Ann N Y Acad Sci 957:260-270. 2002.

Bagchi, D. et al. Smokeless tobacco, oxidative stress, apoptosis, and antioxidants in human oral keratinocytes. Free Radic Biol Med26(7-8):992-1000, 1999.

Bentivegna, S. S. and K. M. Whitney. Subchronic 3-month oral toxicity study of grape seed and grape skin extracts. Food Chem Toxicol 40(12):1731-43, 2002.

Brookmeyer, R. et al. Forecasting the global burden of Alzheimer’s disease.Alzheimer’s Dementia 3: 186-191, 2007.

Corder et al. Red wine procyanidins and vascular health. Nature 444(7119):566, 2006.

Dubnick, M. A. and S. T. Omaye. Evidence for grape, wine and tea polyphenols as modulators of atherosclerosis and ischemic heart disease in humans. J Nutr Func Med Foods 3:67-93, 2001.

Edirisinghe, I. et al. Mechanism of the endothelium-dependent relaxation evoked by a grape seed extract. Clin Sci (Lond). 114(4):331-337, 2008.

Hanahan, D. and R. Weinberg. The hallmarks of cancer. Cell 100 (1, 7):57-70, 2000.

Kar, P. et al. Effects of grape seed extract in Type 2 diabetic subjects at high cardiovascular risk: a double blind randomized placebo controlled trial examining metabolic markers, vascular tone, inflammation, oxidative stress and insulin sensitivity. Diab Med 26:526-531, 2009.

Kaur, M. et al. Anticancer and cancer chemopreventive potential of grape seed extract and other grape-based products. J Nutr 139(9):1806S-1812S, 2009.

Montagut, G. et al. Oligomers of grape-seed procyanidin extract activate the insulin receptor and key targets of the insulin signaling pathway differently from insulin. J Nutr Biochem 21(6):476-481, 2010.

Nassiri-Asl, M. and H. Hosseinzadeh. Review of the pharmacological effects of Vitis vinifera (Grape) and its bioactive compounds. Phytother Res. 23:1197-1204,2009.

Ray, S. et al.Acute and long-term safety evaluation of a novel IH636 grape seed proanthocyanidin extractRes Comm Mol Pathol Pharmacol 109(3-4):165-197, 2001.

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