In a recent study, researchers randomly assigned 66 participants with diabetes to receive one gram of resveratrol or placebo daily for 45 days.

Factors such as age, gender, bodyweight and blood pressure were similar for participants in both groups. Various outcome measures, including body weight, fasting blood glucose, insulin resistance, blood pressure, and cholesterol levels were evaluated before and after the 45 days of supplementation.

The researchers found that the participants in the resveratrol group had significantly lower blood pressure, blood glucose and insulin resistance when compared to their levels at the beginning of the study.

Additionally, high-density lipoprotein HDL, or "good" cholesterol significantly increased. Conversely, participants in the placebo group had moderately, but significantly, increased blood glucose and low-density lipoprotein LDL, or "bad" cholesterol levels when compared to the beginning of the study.

Changes in insulin resistance in the placebo group were lacking. Effects on body weight and body mass index in both groups were lacking. The authors concluded that resveratrol may have beneficially antidiabetic effects in people with diabetes. Additional well-designed clinical trials are necessary to further evaluate these findings.

Attention was first drawn to resveratrol in when it was mentioned as a constituent of red wine. Humans have been consuming wine for approximately 7, years. The regulation of glucose uptake and its subsequent utilization is critical for the maintenance of glucose homeostasis.

Homeostasis of blood glucose by insulin involves stimulation of glucose uptake by translocation of glucose transporter Glut-4 from intracellular pool to the caveolar membrane system. Resveratrol increases the expression of this glucose transporter Glu-4 and excites the glucose uptake.

Skeletal muscle is the largest organ in the body and contributes to immeasurable features of organismal biology, and its dysfunction stimulates numerous diseases, including diabetes. Skeletal muscle is the main site of glucose disposal after glucose ingestion. Insulin resistance in skeletal muscle is thus the main driver of postprandial hyperglycemia.

The transcriptional coactivator PGC-1α has emerged as a key driver of metabolic programming in skeletal muscle, both in muscle health and disease.

PGC-1α has different roles in different tissues, but in nearly every context, PGC-1α stimulates the transcriptional program of mitochondrial biogenesis. PGC-1α dysfunction, and thus mitochondrial insufficiency, contributes to insulin resistance in skeletal muscle.

Resveratrol also has proven to enhance the PGC-1α—skeletal muscle protein levels. Further resveratrol also activates Akt expression, a modulator of insulin-signaling pathway. Akt is the major effector of the IR-IRSPI3K pathway and is activated by phosphorylation. Resveratrol treatment increases the phosphorylation level of Akt, particularly of its Thr and Ser residues which is essential for its basal and full activation.

Several studies have found that resveratrol has positive effects on inhibiting the insulin secretion from pancreatic β-cells and prevents it from chronic overstimulation, decreases the plasm insulin concentration, and increases the insulin sensitivity.

Possible explanations include resveratrol-mediated suppression of cytokine action through decreased DNA binding of nuclear transcription factor κB, production of nitric oxide, and expression of inducible nitric oxide synthesis [ 14 ].

The advancement in the knowledge of potent antioxidants has uncovered the way for greater insight in the treatment of diabetic complications. The antioxidant activity of resveratrol is well proven, and there is a good accordance between antioxidant and antidiabetic activity of resveratrol.

Resveratrol maintains the concentration of intracellular antioxidants in biological systems by dual methods, that is, by acting as scavenger of free radicals and by increasing the activity of antioxidant enzymes such as catalase, glutathione peroxidase, glutathione S-transferase, and glutathione reductase [ 14 ].

In a study on isolated liver mitochondria, addition of resveratrol to the incubation medium significantly increased the activity of manganese-containing superoxide dismutase and diminishes ROS generation. It has been shown that resveratrol significantly reduced the oxidation of thiol groups in proteins of human platelets [ 15 ].

α-Amylase and α-glucosidase are key enzymes involved in carbohydrate digestion. α-Amylase hydrolyzes starch and glycogen into maltose and ultimately increases the blood sugar.

α-Glucosidase hydrolyzes oligosaccharides and disaccharides into glucose, which is absorbed through the gut wall to become blood glucose. Thus, inhibition of the activity of these enzymes is viewed as one of the most effective therapeutic approaches in the reduction of glucose levels in plasma, as a consequence, the suppression of postprandial hyperglycemia.

Various plant extracts containing resveratrol have been evaluated for α-amylase inhibitory activity and have shown beneficial effects in bringing down the pace of digestion and assimilation of sugars and thereby leading to the effective management of type 2 diabetes by decreasing the postprandial hyperglycemia, some of which are highlighted below.

Antioxidant and α-glucosidase inhibitory potential of reservatrol isolated from Rumex bucephalophorus have been reported, which revealed that reservatrol was at least five times more potent α-glucosidase inhibitory activity as compared to standard drug acarbose [ 16 ].

A study on peanut extracts correlated the reservatrol content with the α-amylase and α-glucosidase inhibitory activity. The standard resveratrol sample showed α-amylase and α-glucosidase inhibitory activity 5. In another study, resveratrol had shown potent α-glucosidase inhibitory activity against both yeast and mammal α-glucosidase with IC 50 , 0.

Piceatannol, with an additional OH group as compared to resveratrol, showed higher α-glucosidase inhibitory activity as compared to resveratrol [ 18 ]. The structure activity relationship of polyphenols isolated from other plant sources has been extensively reviewed as inhibitors of α-amylase and α-glucosidase.

Detailed SAR has revealed that both α-amylase and α-glucosidase share the same properties in terms of structural requirements for inhibition [ 19 ]. Studies reveal that inhibitory activity is influenced by a number of hydroxyl groups and their positions, methylation, methoxylation, glycosylation, etc.

Broadly, it is considered that hydroxylation of phenols increases the α-amylase inhibitory activity and methoxylation, which blocks the free hydroxyl groups and reduces the inhibitory activity [ 19 ]. Apparently, the activity is increased by more phenolic substitutions. Piceatannol with four OH groups showed higher activity than resveratrol with three free hydroxyl groups as for the study of Zhang et al.

This is further evident by the study of Lam et al. Pentahydroxystilbene 5 OH groups showed higher inhibitory activity IC 50 Molecular docking studies have revealed that, overall, the inhibitory activity of phenols depends on two parameters: i hydrogen bonding capacity of the OH groups of the phenols with the side chains of amino acids such as Asp and Glu, and ii planarity of aromatic rings to form an efficient conjugated π-π system with the indole Trp59 of the active site [ 20 ].

and Vateria indica Linn. The compounds showed a concentration-dependent inhibition of both α-glucosidase and α-amylase enzymes.

Further, the study also indicated the positive effect of hopeaphenols as antiglycating agents, with IC 50 values of The results indicated that the hopeaphenols can be a promising natural compound in diabetic management [ 21 ]. Few reports exist on the in-vivo studies of stilbenoids other than resveratrol.

Among them is the effect of pterostilbene, which improves glycemic control in insulin-resistant obese rats by increasing hepatic glucokinase activity and increasing skeletal muscle glucose uptake [ 22 ]. In vitro studies also indicate that pterostilbene protected pancreatic beta cells against oxidative stress and apoptosis [ 23 ].

Antihyperglycemic properties of pterostilbene along with other phenolic constituents of Pterocarpus marsupium have been reported [ 24 , 25 ], whereas pterostilbene has been shown to be beneficial in animal models of diabetes and metabolic disorders.

Further, the study by Lam et al. Although numerous data exist on the beneficial outcomes of resveratrol in diabetic animals and in vitro , there are limited studies that have specifically investigated the antidiabetic effects of resveratrol in humans. Further, because of not only a limited number of clinical surveys, but also limited sample size and conflicting data, the use of resveratrol as an effective antidiabetic agent has been delayed [ 27 ].

Few of the reported clinical trial data are discussed below. Glycated hemoglobin HbA1c levels reflect glycemic control and can, consequently, be employed as a predictor of the microvascular and macrovascular complications associated with type 2 diabetes. HbA1c levels seem to be determined by postprandial hyperglycemia.

The study reported improvement in HbA1c, systolic blood pressure, and total cholesterol in patients with type 2 DM treated with resveratrol combined with the oral hypoglycemic agents.

The study showed that resveratrol did not cause any changes in a glucose-dependent insulinotropic polypeptide GIP and glucagon-like peptide 1 GLP-1 levels in diabetes patients.

However, they did show that resveratrol significantly decreased insulin resistance and blood glucose and delayed glucose peaks after meals.

In the study, resveratrol treatment was shown to significantly decrease HbA1c, systolic blood pressure, and total cholesterol. A decrease in oxidative stress assessed by measuring urinary ortho-tyrosine excretion, a bio marker of oxidative stress, was also reported. Nevertheless, the authors found no evidence that resveratrol influenced homeostasis model of assessment of β-cell function HOMA-β and therefore suggested that the mechanism of antidiabetic effects might be referable to a reduction in oxidative stress and a more-efficient insulin signaling.

Resveratrol activated the Akt insulin signaling pathway by increasing the phosphoAkt:Akt ratio in platelets. Most significant notice from the above two studies is the extra security of resveratrol as compared to available standard antidiabetic medication [ 31 ]. In contrast, in a randomized control trial by Thazhath et al.

The study revealed no significant improvement in glycemic control [ 32 ]. They studied two incretin hormones that affect postprandial hyperglycemia: glucose-dependent insulinotropic polypeptide GIP and glucagon-like peptide 1 GLP-1 from the bowel.

In healthy people, both hormones stimulate insulin, but in type 2 patients, only GLP-1 can act to stimulate insulin. GLP-1 can also suppress glucagon secretion and energy intake and slow gastric emptying, thereby targeting postprandial hyperglycemia. In rodent models, resveratrol has been shown to upregulate GLP-1 and lower glycemia, but Thazhath et al.

found that in human patients, there was no difference between the GLP-1 secretion, fasting glucose level, postprandial glucose level, HbA1c, gastric emptying, body weight, or energy intake in the resveratrol-treated versus the placebo group.

Similarly, resveratrol treatment for 6 months did not improve metabolic parameters in type 2 diabetic patients [ 33 ]. Crandall et al. studied older adults with impaired glucose tolerance IGT , a major risk factor for diabetes as well as cardiovascular disease.

They establish that although fasting plasma glucose was unchanged with low dose of resveratrol treatment, peak postmeal glucose and 3-h glucose declined.

Further postmeal insulin decreased and insulin sensitivity imporved. Thus, established resveratrol as a promising therapy for insulin resistance [ 34 ]. A meta-analysis was carried out by Liu et al. in [ 35 ] and more recently by Zhu et al. in [ 36 ] with the aim of qualitatively comparing the published data on effect of resveratrol on plasma glucose levels, glycated hemoglobin HbA1c , and insulin sensitivity.

A fixed-effect model analysis was carried out to pool the data, nine studies with participants in case by study of Zhu et al. and participants of 11 eligible studies in case of Liu et al.

Resveratrol was unable to reduce the plasma glucose levels at low concentrations. These studies also revealed that compared to placebo group, the patients who received resveratrol supplement also showed low insulin levels. Further resveratrol was also effective in reducing the systolic and diastolic blood pressures.

However, no significant difference was observed in LDL and HDL levels. On the other hand, effect of pterostilbene on human type 2 diabetes is yet to be researched. Administration of blueberry Vaccinium myrtillus and sea buckthorn Hippophae rhamnoides extract for children with type 1 diabetes for 2 months elicited a reduction in HBA1c levels and an increase in SOD and glutathione peroxidase levels [ 37 ].

Since pterostilbene has been isolated from Vaccinium myrtillus [ 38 ], this effect may be ascribable to the presence of pterostilbene alongside other bioactive compounds in the excerpt.

Some beneficial effects have also been reported in resveratrol treatment in nondiabetic humans. In obese subjects, Timmers and colleagues [ 39 ] reported significant improvement in the metabolic profile and general health after resveratrol supplementation for 30 days, thereby describing resveratrol as a calorie restriction mimetic.

Resveratrol showed beneficial effects on glucose homeostasis and insulin sensitivity, reduced intrahepatic lipid IHL content and expression of inflammatory genes and improved mitochondrial efficiency.

These effects may be linked with the activation of AMPK and increased SIRT1 and PGC-1α protein content in the muscle [ 39 ]. One of the major challenges surrounding the clinical utility of resveratrol is achieving its stability and adequate bioavailability at tolerable doses—a common issue in translating promising findings from cell culture and animal models into clinical efficacious drugs.

However, the data on toxicity of resveratrol in long-term experiments are scarce. Its reported oral bioavailability values range from 20 to After intravenous administration, resveratrol exhibited a very short half-life of 14 min due to rapid metabolism. This poor bioavailability can be ascribed to the rapid conjugation of trans-resveratrol to glucuronic acid and sulfates, producing glucuronides and sulfate conjugates that accumulate in plasma and urine.

In detail, resveratrol is absorbed in a relatively high rate through the small intestine either via passive diffusion due to its nonpolar character or through active diffusion across the intestinal epithelium via cell ATP-dependent binding cassette transporters.

Inside the enterocytes of the small intestine and hepatocytes of the liver, the glucuronide and sulfate conjugation of trans-resveratrol to the major metabolites are extensive.

The extensive metabolism to glucuronide and sulfate conjugates during absorption is well described and decreases circulating levels of free trans-resveratrol.

Thus, metabolism of resveratrol ultimately results in relatively small amounts of free trans-resveratrol in the plasma to be delivered to other tissues. Strategies to increase bioavailability from oral delivery of resveratrol are generally focused on increasing the rate of resveratrol absorption into the enterocytes and decreasing intracellular metabolism [ 40 ].

Further, the photostability of the resveratrol itself must also be considered when developing formulations, as resveratrol is sensitive to both heat and UV light.

New approaches to increase the bioavailability of resveratrol can help to actualize its potentials as a therapeutic agent in DM and related complications. Different approaches have been utilized by various researchers to increase the stability and bioavailability, some of which are discussed below.

One simple approach to enhance bioavailability has been the consumption of resveratrol in combination with other phenolic compounds that play as the substrate for enzymes involved in resveratrol metabolism; such compounds which have demonstrated the positive effects are piperine, quercetin, etc.

Combined effect of resveratrol along with curcumins was evaluated by Rouse et al. on animal models and human islet cell lines. Beneficial effects were demonstrated on insulin secretion by these naturally occurring polyphenols.

However, the study revealed that the combination of resveratrol along with curcuminoids either did not yield any additional benefits or reduced the beneficial effects observed with the individual treatments. It would be noteworthy to test the combined effect of these two well-studied compounds on human models along with cinnamon and another known natural compound effective for diabetics.

Further, clinical data are available on co-administration of resveratrol with various food and beverage, which contain subsequent amounts of other polyphenols such as grape juice, etc. Due to 3-hydroxyl groups, resveratrol rapidly undergoes glucuronidation or sulphation.

The presence of two methoxy groups in the pterostilbene structure makes it more lipophilic and thus more bioavailable and also more metabolically stable because it has only one free hydroxyl group available for glucuronidation or sulphation.

However, the data also reveal that more the free hydrozyl groups, it shows better activity in in-vitro assays.

Furthermore, administration of pterostilbene in a clinical trial at a dose of mg twice daily for 6—8 weeks was found to be safe and did not evoke any remarkable adverse reactions.

Still, there are no clinical studies on the antidiabetic effect of pterostilbene on diabetic patients and its co-treatment with resveratrol.

Another approach to increase the absorption of resveratrol in the gastrointestinal tract is improving the material properties of resveratrol used in the oral dosage, given the rapid metabolism of resveratrol. This is the basis for SRT, the patented formulation of micronized oral version of resveratrol that may have higher bioavailability.

The small particle size with the emulsifiers in solution theoretically increases surface area for intestinal absorption while also improving suspension properties [ 42 ]. Another approach to maximize the bioavailability of free trans-resveratrol is to develop resveratrol prodrugs, which could be used to improve the anti-diabetic efficacy of resveratrol.

Assuming that maximizing free trans-resveratrol is the primary goal, resveratrol prodrug generates in vivo resveratrol through enzymatic reactions. Some of these technologies have been investigated in animal studies with no report in humans. Metabolism of prodrugs into resveratrol in tissues of interest can maximize tissue concentration and can be beneficial in the treatment of tissue specific complications in diabetic patients.

Targeted delivery of resveratrol prodrugs into tissues of interest via delivery systems such as liposome-mediated delivery or nanotechnological approaches may result in the improved therapeutic effect. Also, intravenous injection as an option to the traditional oral route of administration of resveratrol may bypass gastrointestinal absorption, conjugation, and hepatic metabolism, therefore resulting in increased bioavailability and improved results in diabetic patients.

A routine of recent surveys have concentrated on applying nanotechnology to improve the bioavailability of resveratrol and have generally demonstrated improved stability and bioavailability with minimal side effects compared to oral dosing.

The nanoencapsulation methods include polylactic coglycolic acid nanoparticles [ 43 , 44 ], carboxymethyl chitosan nanoparticles [ 45 ], solid lipid nanoparticles [ 46 ], and cyclodextrin nanoparticles [ 47 ]. Studies revealed sustained release profiles, which enhanced plasma bioavailability compared to free resveratrol.

Nanoencapsulation was also effective in improving the solubility and stability of resveratrol. Read more: Alternative treatments for diabetes ». The standard method for measuring aortic stiffness is a test called the carotid-femoral pulse wave velocity CFPWV test.

In the new study, researchers used a CFPWV test to determine aortic stiffness in 57 patients with type 2 diabetes. On average, participants were 56 years of age and were considered obese according to standard body mass index BMI calculations.

In the beginning, the patients were administered daily doses of milligrams of resveratrol for two weeks. This was then increased to milligrams per day for a further two weeks. The patients were also administered a matched, polyphenol-free placebo treatment for a total of four weeks, with a washout period of two weeks between treatments.

In the overall study group, no statistically significant changes were detected after administering resveratrol. However, in a subgroup of 23 patients who experienced high arterial stiffness at study baseline, a milligram per day dose of resveratrol seemed to decrease aortic stiffness by 9 percent.

Additionally, this effect correlated proportionally with the dosage: a milligram daily intake of resveratrol reduced aortic stiffness by a smaller 4. By contrast, aortic stiffness increased when the patients took the placebo treatment. However, Hamburg — who is also chief of the vascular biology section at the Boston University School of Medicine in Massachusetts — cautions that resveratrol may not be as beneficial to people who do not have diabetes.

Studies with longer treatment are needed to test the effects of a daily resveratrol supplement on vascular function. Resveratrol is a plant compound found in red wine.

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