Resveratrol is a stilbene compound, and a phytoalexin,

synthesized by plants in response to stressful stimuli, usually caused by infection. It is abundantly present in red wine, ports and sherries, red grapes, blueberries, peanuts, itadori tea, as well as hops, pistachios, and in grape and cranberry juices. The anti-hyperglycemic effects of resveratrol seem to be the result of an increased action of the glucose transporter in the cytoplasmic membrane. Studies on rats with streptozotocin-induced diabetes have demonstrated that the expression of the insulin-dependent glucose transporter, GLUT4, is increased after resveratrol ingestion. Also, resveratrol enhances adiponectin levels, which could be one of the potential mechanisms by which it improves insulin sensitivity. Another important observation is that resveratrol induces the secretion of the gut incretin hormone, glucagon-like peptide-1. Resveratrol is also reported to activate Sir2 (silent information regulatory 2), a SIRT1 homolog, thus mimicking the benefits of calorie restriction. It produces a wide variety of effects in mammalian cells, including activation of AMP-activated protein kinase, which is involved in some of the same metabolic pathways as SIRT1, which may influence other mechanisms via the involvement of nuclear factor kappa B (NF-κB). In the near future, resveratrol-based therapies with either resveratrol or its analogs that have better bioavailability could be useful in the treatment of diabetes and its complications, either alone or in combination with other anti-diabetic drugs.

Abbreviations:

AMP - adenosine monophosphate; AMPK - adenosine-monophosphate-activated protein kinase; cAMP - cyclic adenosine monophosphate; COX - cyclooxygenase; CR - calorie restriction; DN - diabetic nephropathy; DNA - deoxyribonucleic acid; DsbA-L - disulfide-bond A oxidoreductase-like protein; FOXO1 - forkhead box protein O1; GLUT4 - glucose transporter 4; GSTM - glutathione-S-transferases Mu; HbA1c - glycosylated hemoglobin; HDL - high-density lipoprotein; LDL - low-density lipoprotein; mRNA - messenger ribonucleic acid; NAD+ - nicotinamide adenine dinucleotide; NADPH - nicotinamide adenine dinucleotide phosphate; NF-κB - nuclear factor kappa B; NO - nitric oxide; Nrf2 - nuclear factor erythroid 2-related factor 2; PPARγ - peroxisome peroxide proliferator activator receptor γ; ROS - reactive oxygen species; RSV - resveratrol; SIRT1 - sirtuin 1; SIR2 - silent information regulator 2; TNFα - tumor necrose factor α

Introduction

Resveratrol (RSV), or 3,5,4-trihydroxystilbene, is a stilbene compound, and a phytoalexin, synthesized by plants in response to stressful stimuli, usually to infection. In addition to its presence in red wine, ports, and sherries, it is also found in red grapes, blueberries, peanuts, itadori tea, hops, pistachios, and in grape and cranberry juices. RSV exerts beneficial effects in humans and may be helpful in preventing and treating metabolic diseases such as obesity and diabetes mellitus.

Anti-hyperglycemic action of RSV

RSV has anti-hyperglycemic effects in diabetic animals, which is associated with its stimulatory action on intracellular glucose transport. In the presence of RSV, glucose uptake is increased by different cells isolated from diabetic rats. Interestingly, in experiments on isolated cells, RSV has been able to stimulate glucose uptake in the absence of insulin. The stimulation of glucose uptake induced by RSV seems to be the result of an increased action of the glucose transporter in the cytoplasmic membrane. Studies in rats with streptozotocin-induced diabetes have demonstrated that the expression of the insulin-dependent glucose transporter, GLUT4, after resveratrol ingestion is increased, compared with diabetic animals which were not given RSV. It should be mentioned, however, that in some experiments in rats with streptozotocin-induced diabetes, RSV appeared to be ineffective and failed to decrease blood glucose.

It has been shown that RSV has anti-diabetic properties in vitro and in vivo by improving mitochondrial function and energy expenditure. Several studies have demonstrated that RSV enhances adiponectin levels, which could be one of the potential mechanisms by which RSV improves insulin sensitivity. RSV also promotes adiponectin expression and improves insulin sensitivity in adipocytes, an effect which is mediated by inhibition of inflammation. Recently, it has been demonstrated that RSV enhances adiponectin cellular levels and multimerization by upregulation of DsbA-L, which in turn is mediated by the FOXO1 and AMPK signaling pathways. Consistent with this finding is that both FOXO1 expression and adiponectin mRNA expression are upregulated by RSV treatment in human visceral adipocytes. However, while RSV treatment has been shown to significantly enhance the expression levels of DsbA-L, it has had little effects on the mRNA levels of adiponectin .The exact reason for this discrepancy remains unknown, but FOXO1 has been found to suppress PPARγ gene expression.

It is widely known that PPARγ positively regulates adiponectin gene expression and secretion. In another study performed on isolated human adipocytes, RSV has effectively prevented insulin resistance induced by cell exposure to conjugated linoleic acid. In these experiments, insulin-stimulated glucose transport is elevated in adipocytes incubated with conjugated linoleic acid and RSV, compared with cells exposed to conjugated linoleic acid alone. This effect may be partially explained by an increase in PPARγ activity. Apart from this effect, RSV has recently been suggested to induce the secretion of the gut incretin hormone glucagon-like peptide-1. A four week supplementation with 150 mg daily of RSV in obese patients, has not affected fasting or postprandial plasma levels of incretin hormone, but suppressed postprandial glucagon responses.

Resveratrol as a caloric restriction mimetic - the role of AMPK and SIRT1

RSV is the most studied caloric restriction mimetic. As one of the molecules through which calorie restriction improves lifespan extension or delays age-related diseases, initial studies of aging in yeast have identified silent information regulator 2 (Sir2), which is a NAD⁺-dependent deacetylase. Homologues of Sir2 in higher eukaryotic organisms are referred to as sirtuins. SIRT1, the sirtuin that is most closely related to Sir2, is one of seven sirtuins in mammals. The beneficial effects of calorie restriction involve the function of SIRT1, which is induced by calorie restriction in various tissues. The significance of SIRT1 on the effects of calorie restriction has been demonstrated using genetically altered mice. Bordone et al. have reported that Sirt1 transgenic mice exhibited a calorie restriction-like phenotype, with reduced levels of blood cholesterol, adipokines, insulin, and fasting glucose and greater glucose tolerance than control mice.

RSV is reported to activate Sir2 (silent information regulatory 2), a SIRT1 homolog, thus mimicking the benefits of calorie restriction (without really restricting calorie intake) such as increasing lifespan in yeast, worms, flies, and fish. Recently, the assumption that activation of Sir2, by direct binding with RSV, is responsible for extended lifespan has been challenged in experiments in multiple organisms. For example, RSV is known to produce a wide variety of effects in mammalian cells, including activation of AMP-activated protein kinase (AMPK), which is involved in some of the same metabolic pathways as SIRT1, and which directly phosphorylates PGC-1α. SIRT1 may activate the kinase upstream of AMPK, but this pathway does not appear to be necessary for AMPK stimulation by RSV. Recently, it has been reported that SIRT1 is essential for moderate doses of RSV to stimulate AMPK and improve mitochondrial function in vitro and in vivo.

In RSV-induced improvement of insulin's action, a key role is attributed to the activation of SIRT1 and AMPK. Activation of these enzymes by RSV has been demonstrated in numerous animal studies. The importance of AMPK in RSV action has been additionally demonstrated in experiments on AMPK-deficient mice. In AMPK-deficient mice fed with a high-fat diet, RSV has been ineffective and has not reduced body fat nor has it improved insulin action. However, more recent studies on the role of SIRT1 in the mechanism of RSV action suggest that its action should be reconsidered, since they have shown that RSV is not a direct activator of Sirt1. Although the exact mechanisms of RSV action are still unclear, there is no doubt that this compound is able to improve insulin action in different animal models of insulin resistance.

RSV is not a SIRT1-specific activator, and the mechanism by which it activates SIRT1 remains largely unclear. Although RSV may directly activate SIRT1 allosterically, AMPK is required upstream for the activation of SIRT1 by RSV. In addition, Park et al. have reported that RSV activates SIRT1 through the activation of AMPK, via the inhibition of phosphodiesterase 4 and the elevation of cAMP in cells, thereby providing a novel mechanism which explains the RSV-induced activation of SIRT1. A recent study reported by Price et al. have demonstrated a direct link between SIRT1 and the metabolic benefits of RSV. These authors reported that a moderate dose of RSV first has activated SIRT1 and then induced the de-acetylation of liver kinase B 1 and AMPK activation, leading to increased mitochondrial biogenesis and function. Moreover, a high dose of RSV may directly activate AMPK, independently of SIRT1.

RSV has also been documented to restore secretory function of β-cells disrupted by cytokine action; the decrease in glucose-stimulated insulin secretion resulting from exposure to cytokines has been found to be fully restored when pancreatic islets were pretreated with RSV. This protective action of resveratrol against cytokine-induced dysfunction of β-cells is suggested to result from the ability of RSV to activate NAD⁺-dependent protein deacetylase Sirt1.

Resveratrol and COX-1 inhibition

There have been several reports on RSV, including a study of RSV as an inhibitor of arachidonate metabolism via interactions with 5-lipoxygenase and cyclooxygenase (COX) pathways in leukocytes. These reports have attributed the effects of RSV to the inhibition of prostaglandins synthesis via the inhibition of COX-1. They have shown that RSV can discriminate between COX-1 and COX-2, suggesting that it could result in the elimination of prostaglandin synthesis via COX-1.