Address for correspondence: Tomasz Szkudelski, Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland. email@example.com
Diabetes mellitus is a complex metabolic disease affecting about 5% of people all over the world. Data from the literature indicate that resveratrol is a compound exerting numerous beneficial effects in organisms. Rodent studies, for example, have demonstrated that resveratrol decreases blood glucose in animals with hyperglycemia. This effect seems to predominantly result from increased intracellular transport of glucose. Resveratrol was also demonstrated to induce effects that may contribute to the protection of β cells in diabetes. In experiments on pancreatic islets, the ability of resveratrol to reduce insulin secretion was demonstrated; this effect was confirmed in animals with hyperinsulinemia, in which resveratrol decreased blood insulin levels. Moreover, inhibition of cytokine action and attenuation of the oxidative damage of the pancreatic tissue by resveratrol were recently shown. Studies of animals with insulin resistance indicate that resveratrol may also improve insulin action. The mechanism through which resveratrol improves insulin action is complex and involves reduced adiposity, changes in gene expression, and changes in the activities of some enzymes. These data indicate that resveratrol may be useful in preventing and treating diabetes.
Diabetes mellitus is a complex metabolic disease and, according to the classification of the American Diabetes Association,1 is divided into different types: type 1 and type 2 diabetes are the most frequent. Type 1 diabetes accounts for less than 10% of all diabetic cases and results from the autoimmune destruction of β cells. Patients with type 1 diabetes are dependent on exogenous insulin. Type 2 diabetes affects about 90% of all people with diabetes and is characterized by defects in insulin secretion and action.
In the last few years, rodent studies and experiments in vitro provided evidence that resveratrol (3,5,4′-trihydroxystilbene)—a naturally occurring phytoalexin present in numerous plant species—exerts beneficial effects in the organism and may be helpful in preventing and treating some metabolic diseases, including diabetes.2,3 In general, the management of diabetes involves three main aspects: reduction of blood glucose, preservation of β cells, and, in the case of type 2 diabetes, improvement in insulin action. Data from the literature indicate that the beneficial effects of resveratrol in relation to diabetes comprise all these aspects (Fig. 1).
Reduction of blood glucose
The maintenance of blood glucose in the physiological range is pivotal in diabetes, since increased glycemia causes numerous diabetic complications.4 Therefore, different strategies, including treatment with hypoglycemic agents, are introduced in clinical practice to decrease blood glucose to physiological level. However, the prolonged administration of some agents reducing blood glucose (e.g., metformin or α-glucosidase inhibitors) induces unfavorable effects.5,6 In this context, a compound reducing blood glucose without any side effects, even if administered for a long period of time, would be very useful in both type 1 and type 2 diabetes.
Numerous studies on diabetic rats revealed the anti-hyperglycemic action of resveratrol. Among different beneficial effects of resveratrol found in diabetes, the ability of this compound to reduce hyperglycemia seems to be the best documented. The anti-hyperglycemic action of resveratrol was demonstrated in obese rodents7,8 and in two animal models of diabetes: in rats with streptozotocin- induced diabetes or with streptozotocin- nicotinamide-induced diabetes.9–15 Some studies also revealed that administration of resveratrol to diabetic rats resulted in diminished levels of glycosylated hemoglobin (HbA1C), which reflects the prolonged reduction of glycemia.10,15
The anti-hyperglycemic effect of resveratrol observed in diabetic animals is thought to result from its stimulatory action on intracellular glucose transport. Increased glucose uptake by different cells isolated from diabetic rats was found in the presence of resveratrol. Interestingly, in experiments on isolated cells, resveratrol was able to stimulate glucose uptake in the absence of insulin.9 The stimulation of glucose uptake induced by resveratrol seems to be due to increased action of glucose transporter in the plasma membrane. Studies on rats with experimentally induced diabetes demonstrated increased expression of the insulin-dependent glucose transporter, GLUT4, as a result of resveratrol ingestion, compared with diabetic animals not given resveratrol.14,16 It should be mentioned, however, that in some experiments on rats with streptozotocin-induced diabetes, resveratrol appeared to be ineffective and failed to decrease blood glucose.17,18
Preservation of β cells
Type 2 diabetes develops slowly, may be undetected for many years, and is usually accompanied by insulin resistance. Initially, blood glucose is maintained in the physiological range because of the compensatory increase in insulin secretion. This compensatory mechanism impedes and delays the diagnosis of diabetes. Moreover, chronic overstimulation of β cells causes their exhaustion and degradation, leading over time to insufficient secretion of insulin.19 According to this scenario, results of many studies demonstrate that in individuals with the chronic stimulation of β cells, temporary resting of these cells ameliorates their ability to secrete insulin and may delay the onset of the overt diabetes. These beneficial effects were observed in rodents and humans with type 1 diabetes and in humans with type 2 diabetes. A temporary inhibition of insulin secretion was also reported to delay the progress of type 2 diabetes.20 However, in clinical practice, only a few inhibitors of insulin secretion are used, and side effects appear during their prolonged administration. Therefore, numerous natural compounds are intensively studied in the context of their potential influence on insulin secretion.21,22
Rodent studies revealed that resveratrol may affect blood insulin concentrations. In animals with hyperinsulinemia, resveratrol was found to effectively reduce blood insulin. This effect was noticed in mice on a high-fat diet,23–26 in rats on a high-cholesterol-fructose diet,27 and in obese Zucker rats.28
According to some animal studies, experiments in vitro demonstrated the ability of resveratrol to reduce insulin secretion by freshly isolated rat pancreatic islets.29–31 The inhibition of insulin secretion caused by resveratrol was found to result from metabolic changes in β cells. Under physiological conditions, glucose-induced insulin secretion is preceded by a sequence of events involving intracellular transport of glucose and its oxidative metabolism, hyperpolarisation of the inner mitochondrial membrane, increased formation of ATP and an increase in the ATP/ADP ratio, closure of the ATP-sensitive potassium channels, depolarization of the plasma membrane, opening of voltage-sensitive calcium channels, and the rise in cytosolic Ca2+. The increase in cytosolic Ca2+ triggers secretion of insulin. Moreover, other signals in β cells are generated to maintain the sustained insulin-secretory response.32,33 In this sequence of events leading to increased secretion of insulin, resveratrol was demonstrated to act at the level of ATP formation. Pancreatic islets exposed to resveratrol released more lactate, and glucose oxidation was deeply decreased compared with control islets.30 Resveratrol was also reported to attenuate hyperpolarization of the inner mitochondrial membrane, indicating reduced activity of the mitochondrial respiratory chain. The metabolic changes induced by resveratrol resulted in decreased ATP levels in islet cells. Since the increase in ATP/ADP ratio is pivotal for insulin secretion, diminution of ATP formation in the presence of resveratrol resulted in attenuated secretion of the pancreatic hormone.30 Importantly, the inhibition of insulin secretion caused by resveratrol appeared to be reversible and was not due to permanent disturbances in β cells.29,30
Since chronic overstimulation of β cells is known to induce their degradation, inhibition of insulin secretion by resveratrol may attenuate these unfavorable effects. This assumption is, however, not proven in animal studies and requires further investigations.
The protective action of resveratrol on the endocrine pancreas may also involve other mechanisms. One of them is the inhibitory influence of resveratrol on cytokine action. Lee et al.34 recently reported that exposure of isolated rat pancreatic islets to cytokines resulted in numerous unfavorable effects, such as increased DNA binding of NF-κB, increased production of NO, and expression of iNOS. All these deleterious effects appeared to be suppressed by resveratrol. The protective action of resveratrol against cytokine-induced toxicity was additionally confirmed in experiments demonstrating increased viability of islets exposed to cytokines and resveratrol, compared with islets incubated with cytokines but without resveratrol. Importantly, resveratrol was also demonstrated to restore secretory function of β cells disrupted by cytokine action; the decrease in glucose-stimulated insulin secretion resulting from exposure to cytokines appeared to be fully restored when pancreatic islets were pretreated with resveratrol. This protective action of resveratrol against cytokine-induced dysfunction of β cells is thought to result from the ability of resveratrol to activate NAD+-dependent protein deacetylase Sirt1.34
Studies in vivo on animals with experimentally induced diabetes confirmed the important role of the inhibition of cytokine action in the mechanism thereby resveratrol protects pancreatic β cells. In streptozotocin-nicotinamide-induced diabetic rats, oral administration of resveratrol significantly reduced blood TNF-α, IL-1β, and IL-6 compared with diabetic rats non-treated with resveratrol.15
The other mechanism through which resveratrol exerts its protective action in diabetes is related to the anti-oxidant defense. It is known that the anti-oxidant defense in β cells is significantly lower compared with other kinds of cells, making them more susceptible to the oxidative damage.35 Palsamy and Subramanian15 recently reported that in streptozotocin-nicotinamide-induced diabetic rats, the levels of lipid peroxides, hydroperoxides, and protein carbonyls in the pancreatic tissue were significantly increased compared with non-diabetic animals, indicating oxidative damage. Simultaneously, the activities of enzymes participating in the anti-oxidant defense—such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase—in the pancreatic tissue of diabetic animals were deeply reduced. However, resveratrol administered to diabetic rats substantially ameliorated parameters of the oxidative damage and increased the activities of the above-mentioned enzymes.15 This effect of resveratrol seems to be very important, since oxidative stress is one of the factors leading to β cell failure in type 2 diabetes.36
These data indicate that resveratrol is able to attenuate cytokine-induced toxicity and effectively reduce oxidative damage of the pancreas, and thereby may ameliorate the endocrine function of this gland. This was confirmed by results demonstrating that in diabetic rats with hypoinsulinemia and with preserved ability of β cells to secrete insulin, administration of resveratrol resulted in the significant increase in blood insulin.11,15,16
Moreover, in streptozotocin-nicotinamide-induced diabetic rats ingesting resveratrol, degenerative changes of islets were less marked, and degranulation of β cells was lower. In addition, an increase in secretory granules and no vacuolarization were shown in islets of diabetic rats receiving resveratrol compared with cells of diabetic rats not treated with this compound.15 Although some studies demonstrated protective action of resveratrol on pancreas, experimental data on the beneficial influence of this compound on β cells in diabetes are still lacking, and thus further animal studies are required.
Improvement in insulin action
Type 2 diabetes is usually accompanied by insulin resistance, defined as the impaired action of insulin on target cells, mainly adipocytes, hepatocytes, and muscle cells. The insulin resistance develops mainly in overweight or obese individuals with type 2 diabetes.37 It is well documented that decreased adiposity improves insulin action.38 Moreover, a low-calorie diet and increased physical activity are known to improve metabolic control and insulin sensitivity in type 2 diabetes.
Animal studies provided evidence that resveratrol may be useful as a compound improving insulin action in type 2 diabetes. The ability of resveratrol to increase insulin sensitivity was studied in mice fed a high-fat diet and manifesting insulin resistance. The ingestion of resveratrol by these animals substantially improved action of insulin.23–25,39 Interestingly, a similar effect of resveratrol was also observed in obese Zucker rats.28 The improvement in insulin action in animals with genetic obesity-induced type 2 diabetes indicates that resveratrol is effective not only when insulin resistance is induced by a high-calorie diet.
The improvement in insulin action caused by resveratrol seems to result from different effects. One of them is reduced adiposity. Resveratrol-induced reduction in body fat content was demonstrated in mice and rats on a hypercaloric diet.24,39–43 Moreover, resveratrol ingestion was found to cause effects that are similar to those induced by calorie restriction.44,45
Consistent with animal studies, experiments in vitro revealed reduced ATP content46 and decreased accumulation of triglycerides in isolated rat adipocytes exposed to resveratrol.47 In these cells, resveratrol increased lipolytic response to epinephrine and decreased lipogenesis.47 Reduced accumulation of triglycerides in fat cells observed in the presence of resveratrol may contribute to decreased adiposity in the whole organism.
In another study performed on isolated human adipocytes, resveratrol effectively prevented insulin resistance induced by cell exposure to conjugated linoleic acid. In these experiments, insulin-stimulated glucose transport was significantly increased in adipocytes preincubated with conjugated linoleic acid and resveratrol, compared with cells exposed to conjugated linoleic acid alone. Moreover, resveratrol prevented inflammation induced by conjugated linoleic acid. The mechanism of this action is proposed to involve, among others, attenuation of cellular stress, prevention of activation of extracellular signal-related kinase, inhibition of inflammatory gene expression, and increase in peroxisome proliferator-activated receptor γ (PPAR-γ) activity.48
In resveratrol-induced improvement in insulin action a pivotal role is ascribed to the activation of Sirt1 and 5′-AMP-activated protein kinase (AMPK). Activation of these enzymes by resveratrol was demonstrated in numerous animal studies.23,24,34,40,41 The importance of AMPK in the mechanism of resveratrol action was additionally confirmed in experiments on AMPK-deficient mice. In AMPK-deficient mice fed a high-fat diet, resveratrol was ineffective and neither reduced body fat nor improved insulin action.39 However, in light of the most recent studies of Pacholec et al.,49 the role of Sirt1 in the mechanism of resveratrol action should be reconsidered, since these authors demonstrated that resveratrol is not a direct activator of Sirt1. Although the exact mechanism of resveratrol action is still poorly elucidated, there is no doubt that this compound is able to improve insulin action in different animal models of insulin resistance.
Data from the literature clearly demonstrate that resveratrol exerts pleiotropic action in organisms. The preventive and therapeutic action of this compound in relation to diabetes is complex and involves different effects. Elucidation of these beneficial properties of resveratrol is necessary to enable clinical human studies. Is seems quite possible that resveratrol, alone or in combination with current anti-diabetic therapies, will be used in preventing and treating diabetes.