ArticleLiterature Review

Szkudelski T, Szkudelska KAnti-diabetic effects of resveratrol. Ann N Y Acad Sci 1215:34-39

Wiley
Annals of the New York Academy of Sciences
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Abstract

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.

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... The mechanisms by which resveratrol can improve diabetes parameters are complex and are not yet fully understood. In glycemia, animal studies showed that resveratrol could have an anti-hyperglycemic effect that results from a stimulating activity in the intracellular glucose transport (Szkudelski and Szkudelska 2011). Also, experiments with rat cells showed that resveratrol could stimulate glucose uptake in the absence of insulin (Szkudelski and Szkudelska 2011). ...
... In glycemia, animal studies showed that resveratrol could have an anti-hyperglycemic effect that results from a stimulating activity in the intracellular glucose transport (Szkudelski and Szkudelska 2011). Also, experiments with rat cells showed that resveratrol could stimulate glucose uptake in the absence of insulin (Szkudelski and Szkudelska 2011). The increase in glucose uptake induced by resveratrol may be related to increased glucose transporter's action on the cytoplasmic membrane (Vallianou, Evangelopoulos, and Kazazis 2013). ...
... The increase in glucose uptake induced by resveratrol may be related to increased glucose transporter's action on the cytoplasmic membrane (Vallianou, Evangelopoulos, and Kazazis 2013). The mechanisms related to improving insulin action seem to be related to the reduction of adiposity, changes in the expression of genes, and changes in some enzymes' activity (Szkudelski and Szkudelska 2011). Resveratrol may also enhance adiponectin levels, being a potential mechanism for improving insulin sensitivity (Vallianou, Evangelopoulos, and Kazazis 2013). ...
Article
This study aimed to review the literature on studies that evaluated resveratrol's effects supplementation on parameters of diabetes in humans. We conducted an online search in the following databases: Pubmed, Lilacs, Scielo, Scopus, Web of Science, Embase, and Cochrane. It included experimental studies that investigated the effects of resveratrol supplementation for diabetes treatment or prevention and its relationship with fasting blood glucose, insulin resistance, and glycated hemoglobin. Observational, non-human studies and non-randomized clinical trials were excluded. We conducted a meta-analysis to evaluate the effects of resveratrol supplementation on fasting blood glucose, insulin resistance, and glycated hemoglobin. Thirty studies were included in the review. Almost 60% demonstrated at least one significant effect of the resveratrol supplementation related to diabetes. In the meta-analysis, there was a significant effect on the reduction of insulin resistance [SMD: −0.34; CI 95%: −0.64, −0.04; p = 0.01; I² = 70%] and glycated hemoglobin [SMD: −0.64; CI 95%: −1.22, −0.07; p = 0.01; I² = 90%]. For fasting blood glucose, the results were significant only for individuals with diabetes [SMD: −0.85; CI 95%: −1.49, −0.21; p = 0.01; I² = 90%]. This systematic review with meta-analysis demonstrated that resveratrol supplementation has protective effects on diabetes parameters.
... It is present in considerable amounts in peanuts, cherries, pistachios, and grapes, with the grape skin having the highest concentration; therefore, red wine is considered an important source of resveratrol [13]. Resveratrol is known for its anti-inflammatory [14], antidiabetic [15], anticancer [16], and cardioprotective properties [17]. It also has antiobesity effects by reducing lipogenesis, increasing lipolysis, and improving glucose homeostasis [18]. ...
... is may be contributed to the role of Res in protecting pancreatic β cells from free radical damage and deleterious cytokine [72]. Besides its vital role in decreasing adiposity [15], the ability of Res to improve insulin sensitivity was further confirmed in our study by upregulation of the expression of IRS-2 in our MS model, which was previously demonstrated in rats fed high-fructose corn syrup [73]. ...
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Metabolic syndrome (MS) is a serious health problem associated with an increase in risk factors for hepatic steatosis, which is the most common liver disease today. e goal of this study was to investigate the protective e ects of resveratrol against metabolic alterations associated with a high-fat high-fructose diet (HFFD). irty-two male rats were randomly divided into four equal groups: control (cont.), metabolic syndrome (MS), resveratrol (Res), and metabolic syndrome treated with resveratrol (MS + Res). Resveratrol was administrated orally at a dose of 30 mg/kg·bw, daily. After 10 weeks, body weight, serum biochemical parameters, hepatic oxidative stress, in ammatory markers, as well as mRNA levels of hepatic genes related to lipid metabolism and insulin signaling were measured. In addition, the liver was examined histopathologically to detect lipid deposition. Increased body weight, hepatic dysfunction, dyslipidemia, hepatic insulin resistance, hepatic oxidative and in ammatory stress conditions, upregulation of mRNA expression level of sterol regulatory element binding protein 1-c (SREBP1-c), and downregulation of mRNA expression levels of peroxisome proliferated activated receptor alpha (PPARα) and insulin receptor substrate-2 (IR-S2) were all observed in the MS rats. Hepatic steatosis was con rmed by hematoxylin and eosin and Oil Red O staining. Administration of resveratrol reduced liver steatosis, oxidative stress, and in ammatory state. Also, it improved lipid pro le as well as insulin sensitivity and reverted alterations in hepatic mRNA expression levels of the tested genes. Based on these ndings, resveratrol could be proposed as a therapeutic approach for MS prevention.
... Resveratrol was originally used in cancer treatment and has displayed beneficial effects on most degenerative and cardiovascular diseases, including atherosclerosis [26][27][28], hypertension [29], ischemic heart disease [30], diabetes [31], aging [32], and myocardial hypertrophy [33]. Among them, the beneficial effect of resveratrol on cardiac hypertrophy is not only achieved by lowering blood pressure, but also involves other factors besides the change in hemodynamic load. ...
... Importantly, AMPK can also inhibit cardiac remodeling by preventing myocardial fibrosis induced by angiotensin II [35]. Resveratrol was originally used in cancer treatment and has displayed beneficial effects on most degenerative and cardiovascular diseases, including atherosclerosis [26][27][28], hypertension [29], ischemic heart disease [30], diabetes [31], aging [32], and myocardial hypertrophy [33]. Among them, the beneficial effect of resveratrol on cardiac hypertrophy is not only achieved by lowering blood pressure, but also involves other factors besides the change in hemodynamic load. ...
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Cardiac fibrosis is a heterogeneous disease, which is characterized by abundant proliferation of interstitial collagen, disordered arrangement, collagen network reconstruction, increased cardiac stiffness, and decreased systolic and diastolic functions, consequently developing into cardiac insufficiency. With several factors participating in and regulating the occurrence and development of cardiac fibrosis, a complex molecular mechanism underlies the disease. Moreover, cardiac fibrosis is closely related to hypertension, myocardial infarction, viral myocarditis, atherosclerosis, and diabetes, which can lead to serious complications such as heart failure, arrhythmia, and sudden cardiac death, thus seriously threatening human life and health. Resveratrol, with the chemical name 3,5,4′-trihydroxy-trans-stilbene, is a polyphenol abundantly present in grapes and red wine. It is known to prevent the occurrence and development of cardiovascular diseases. In addition, it may resist cardiac fibrosis through a variety of growth factors, cytokines, and several cell signaling pathways, thus exerting a protective effect on the heart.
... The use of resveratrol, alone or in combination with modern antidiabetic therapies, may become the traditional E3S Web of Conferences 247, 01063 (2021) https://doi.org/10.1051/e3sconf/202124701063 ICEPP-2021 approach to effective treatment of diabetes mellitus or its complications [17,18]. ...
... The data are in good agreement with the results received by other researchers [17]. ...
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The current state of the agro-industrial complex and the food industry allows to satisfy the needs of various consumers groups. Among those needs, functional foods enriched with beneficial nutrients are becoming more and more popular. Polyphenols are sometimes used as such additives. The bioflavonoid resveratrol, among the group of polyphenols, has very promising antioxidant, therapeutic, antimicrobial properties. In this regard, studying the potential of its use in the food is highly relevant. Resveratrol is naturally present in the dark grapes. It is localized in the skin of the fruit and passes into the food substance during technological processing. This transition has its own patterns which are outlined in this article. Three varieties of grapes were chosen as the objects of the study: Cabernet Sauvignon, Merlot, Krasnostop. Clarified musts from these grape varieties, concentrated musts and wines were researched. High performance liquid chromatography (HPLC) was utilized as the research method. This method allows to separate liquids of complex composition into components with subsequent identification of the mixture composition. To calibrate the chromatograph, the standard “25 mg European Pharmacopoeia”, produced in France, was used as a standard for the pure substance of resveratrol. As the result of the study, it was found that resveratrol is present in the studied samples in various amounts from 4,4 to 7,0 mg / dm³ in the grape juice, from 6,9 to 12,6 mg/dm³ in the wine materials, from 12,4 to 21,3 mg / dm³ in the concentrated juice. These data help establishing the influence of the processing technology of wine and juice concentrates on the resveratrol content. The article also discusses the potential of using concentrated grape juice, rich in resveratrol, to obtain various food products.
... 219 Induces effects that might contribute to the protection of β cells in diabetes; it reduces insulin secretion in animals with hyperinsulinemia [120,121]. ...
... Carbohydrates and a cyclitol from Mexican plants with hypoglycemic activity.Among the flavonoids, the most abundant were flavonols(20,30,(45)(46)(47)62, 169), glycosides or not, and flavones(21)(22)(23)(24)32, 214-216, 229, 231), although a few dihydrochalcones(96,102,80,93,99,104), a biflavone (208), a flavanone(55), and three flavan-3-ols(2,113, 204) are included. The aromatic compounds comprise eight coumarins, one simple(7), and seven 4-phenylcoumarins(106-109, 116, 123 and 124); six hydroxycinnamic acids (3, 13, 27, 112, 217, 232); three chromenes(39)(40)(41); three depsides(120)(121)(122); two phthalides (171 and 172); two α-pyrone glycosides (9 and 10); one stilbene (219); and one hydroxybenzoic acid (1). The terpenoids included 11 sesquiterpenes(4-6, 25, 26, 42, 43, 175, 180, 182, 234), of which four were sesquiterpene lactones (25, 42, 43, 175) of the eudesmanolide, heliangolides, and melampolides types; the remaining were a nor-sesquiterpene (234); one acyclic diol (26), two eremophylanes (180, 182), and one bisabolene (4) and its rearranged products (5, 6). ...
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Like in many developing countries, in Mexico, the use of medicinal plants is a common practice. Based on our own field experience, there are at least 800 plants used for treating diabetes nowadays. Thus, their investigation is essential. In this context, this work aims to provide a comprehensive and critical review of the molecules isolated from Mexican hypoglycemic plants, including their source and target tested. In the last few years, some researchers have focused on the study of Mexican hypoglycemic plants. Most works describe the hypoglycemic effect or the mechanism of action of the whole extract, as well as the phytochemical profile of the tested extract. Herein, we analyzed 85 studies encompassing 40 hypoglycemic plants and 86 active compounds belonging to different classes of natural products: 28 flavonoids, 25 aromatic compounds, other than flavonoids, four steroids, 23 terpenoids, 4 oligosaccharides, and 1 polyalcohol. These compounds have shown to inhibit α-glucosidases, increase insulin secretion levels, increase insulin sensitivity, and block hepatic glucose output. Almost half of these molecules are not common metabolites, with a narrow taxonomic distribution, which makes them more interesting as lead molecules. Altogether, this analysis provides a necessary inventory useful for future testing of these active molecules against different hypoglycemic targets, to get a better insight into the already described mechanisms, and overall, to contribute to the knowledge of Mexican medicinal plants.
... RES may also be effective against diabetes [61,112,113]. One study found that RES reduced glycated hemoglobin (HbA1c), cholesterol, and systolic blood pressure levels, improving glycemic control [114]. ...
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Physical exercise is an essential component of human health. In recent years, scientific research has focused on identifying natural compounds and formulating new supplements aimed at enhancing athletic performance, accelerating muscle recovery, and minimizing the damage caused by physical exertion. The use of antioxidants to counteract the formation of reactive oxygen species (ROS) following physical activity (PA) is already a widely adopted practice. Resveratrol (RES), a polyphenol belonging to the stilbene class, is well known for its potent antioxidant activity and anti-inflammatory effects primarily attributed to the activation of sirtuins. RES possesses multiple nutraceutical properties used for the prevention and treatment of inflammatory, cardiovascular, neoplastic, and infectious diseases, thus attracting attention to study its use in combination with physical exercise to promote well-being. Animal trials combining RES and PA have mainly reported improvements in muscle, energy, and cardiovascular functions. The data presented and discussed in this narrative review are from Pubmed, Scopus, and the Human Gene Database (search limited to 2011 to 2025 with the keywords RES, sirtuins, and physical activity altogether or in combination with each other). This review gathers several studies on RES focusing on its nutraceutical properties, epigenetic activities via sirtuins, and the potential benefits of combining RES with PA in maintaining health and well-being based on trials performed first in animals and later in humans. Human studies have been conducted on various populations, including active adults, sedentary individuals, patients with diseases, and elderly individuals. Some studies have confirmed the benefits of RES observed in animal experiments. However, in some cases, no substantial differences were found between RES supplementation and the control group. In conclusion, the benefits of RES on PA reported in the literature are still not fully evident, given the contrasting studies and the still limited number of trials, but both RES and PA are successful tools for the maintenance of health and wellbeing.
... Resveratrol has several therapeutic benefits, including antioxidant [96][97][98], antiinflammatory [97][98][99], cardioprotective [96,97], and analgesic [100,101] effects, as well as an influence on obesity and diabetes [102][103][104]. Resveratrol has been researched further for its growing importance in a variety of neurological illnesses, including Alzheimer's disease [102,103], Parkinson's disease [105,106], and other neurodegenerative diseases [107,108], as well as brain tumors [109,110]. Furthermore, Resveratrol has shown anticancer action in a variety of additional cancer types, including breast, prostate, skin, lung, liver, and colorectal cancer [111][112][113]. ...
... It is known that hyperglycemia related to diabetes can induce high concentrations of reactive oxygen species (ROS) through various mechanisms, to which the retinal cells are the most exposed to suffer from oxidative stress and lipid peroxidation, thanks to the fact that they are extremely rich in polyunsaturated lipid membranes and exhibit high oxygen consumption [65][66][67]. Lately, considerable attention has been paid to the use of RSV to counteract the adverse effects produced by oxidative stress, angiogenesis, and inflammation in diabetic retinopathy due to various studies that have shown its ability to control glucose metabolism, decrease insulin resistance, and prevent lipoprotein oxidation, apoptosis, and the inhibition of platelet aggregation [44,[68][69][70]. It is necessary to study the mechanism of RSV in inflammation and angiogenesis, which are related to DR progression. ...
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Diabetic retinopathy (RD) is a microvascular disease that can cause the formation of fragile neovessels, increasing the risk of hemorrhages and leading to vision loss. Current therapies are based on the intravitreal injection of anti-VEGF (vascular endothelial growth factor), which is invasive and can cause secondary effects. The development of new treatments that complement the current therapies is necessary to improve the patient’s outcomes. Nanostructured formulations offer several advantages regarding drug delivery and penetration. In this research, a resveratrol nanosuspension (RSV-NS) was prepared and characterized using dynamic light scattering, field emission scanning electron microscopy, and infrared spectroscopy. The RSV-NS had an average particle size of 304.0 ± 81.21 nm with a PDI of 0.225 ± 0.036, and a spherical-like morphology and uniform particle distribution. Cell viability, proliferation, and migration were tested on endothelial cells (HMRECs). RSV-NS in a concentration of less than 18.75 µM did not have a cytotoxic effect on HMRECs. Likewise, proliferation and migration were significantly reduced compared to the unstimulated control at 37.5 µM. The RSV-NS did not present cytotoxic effects but decreased cell proliferation and migration, indicating that it could provide an important contribution to future medical implementations and could have a high potential to treat this disease.
... Hence, the search of plant-based natural antidiabetic drug candidates or drugs is an urgent need in modern research. Te natural compounds isolated from the plants such as apigenin, curcumin, naringenin, and resveratrol exhibit antihyperglycemic activities showing least side efects with high efcacy [5]. ...
Article
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The medicinal plant Chromolaena odorata is traditionally used by people living in different communities of Nepal and the globe against diabetes, soft tissue wounds, skin infections, diarrhea, malaria, and several other infectious diseases. The present study focuses on the qualitative and quantitative phytochemical analyses and antioxidant, antidiabetic, antibacterial, and toxicity of the plant for assessing its pharmacological potential. The extracts of flowers, leaves, and stems were prepared using methanol and distilled water as the extracting solvents. Total phenolic content (TPC) and total flavonoid content (TFC) were estimated by using the Folin–Ciocalteu phenol reagent method and the aluminum chloride colorimetric method. Antioxidant and antidiabetic activities were assessed using the DPPH assay and α-glucosidase inhibition assay. A brine shrimp assay was performed to study the toxicity, and the antibacterial activity test was performed by the agar well diffusion method. Phytochemical analysis revealed the presence of phenols, flavonoids, quinones, terpenoids, and coumarins as secondary metabolites. The methanol extract of leaves and flowers displayed the highest phenolic and flavonoid content with 182.26 ± 1.99 mg GAE/g, 128.57 ± 7.62 mg QE/g and 172.65 ± 0.48 mg GAE/g, 121.74 ± 7.06 mg QE/g, respectively. The crude extracts showed the highest DPPH free radical scavenging activity with half maximal inhibitory concentration (IC50) of 32.81 ± 5.26 µg/mL and 41.00 ± 1.10 µg/mL, respectively. The methanol extract of the leaves was found to be effective against bacterial strains such as K. pneumoniae (ZOI = 9.67 ± 0.32 mm), B. subtilis (ZOI = 15.00 ± 0 mm), and E. coli (7.3 ± 0.32 mm). The methanol extract of the flowers showed the most α-glucosidase inhibitory activity (IC50 227.63 ± 11.38 µg/mL), followed by the methanol extract of leaves (IC50 249.50 ± 0.97 µg/mL). The aqueous extract of the flowers showed the toxic effect with LC50 107.31 ± 49.04 µg/mL against the brine shrimp nauplii. In conclusion, C. odorata was found to be a rich source of plant secondary metabolites such as phenolics and flavonoids with potential effects against bacterial infection, diabetes, and oxidative stress in humans. The toxicity study showed that the aqueous extract of flowers possesses pharmacological activities. This study supports the traditional use of the plant against infectious diseases and diabetes and provides some scientific validation.
... RES has also demonstrated the attenuation of oxidative damage in pancreatic tissue and protection of β cells in diabetes. Therefore, RES may be useful in diabetes prevention and treatment (Szkudelski and Szkudelska 2011). Besides, the prenylated forms of trans-arachidin-1 (Ara-1) and transarachidin-3 (Ara-3) are the most significant stilbene compounds found in peanut sprout and peanut hairy root culture. ...
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Trans-resveratrol, trans-arachidin-1 (Ara-1), and trans-arachidin-3 (Ara-3) are major stilbene compounds found in elicited peanut hairy root culture and exert diverse potential biological and pharmaceutical activities. The aim of this study was to investigate the various approaches for enhancing the productivity of prenylated stilbene. The fast-growing peanut hairy root K2-K599-C line was elicited with chitosan (CHT), methyl jasmonate (MeJA), and cyclodextrin (CD) (CHT + MeJA + CD) as combined elicitors together with phenylalanine (Phe) as a precursor to feeding at 24, 48, and 72 h. The accumulation of stilbene compounds was investigated in this study as well as stilbene biosynthesis-related genes and plant defense gene expression. Upon an exogenous supply of Phe, elevated amounts of Ara-1 and Ara-3 were detected through the entire 72 h elicitation period while the non-Phe precursor feeding conditions exhibited an increasing amount of Ara-1 and Ara-3 up to 48 h, decreasing at 72 h. In addition, Phe precursor may serve as an early regulator of gene expression for the stilbene biosynthesis pathway, transcription factors, and pathogenesis-related proteins while a delayed response in transcriptional regulation was observed in the elicitation without Phe precursor feeding. Cellulase-assisted extraction was performed prior to solvent extraction of the culture medium. The results indicated a significant 1.73- and 1.57-fold increase in Ara-1 and Ara-3, respectively, compared to the non-cellulase-assisted process. To the best of our knowledge, this is the first study to propose an integrated approach to improving stilbene compound production in peanut hairy root culture.
... One of the best-studied naturally occurring non-flavonoid polyphenols from a group of stilbenes is resveratrol (3,5,4 -trihydroxystilbene; RSV) [129]. The positive effects of RSV in many diseases have been described as antidiabetic properties [130] and antimicrobial [131], antitumorigenic [132], antioxidant [133], neuroprotective [94,95] antiproliferative and anti-inflammatory action [134] via inhibition of prostaglandin synthesis and it also exhibits apoptosis. Resveratrol has structural and functional homology with estrogen and thus can bind to nuclear estrogen receptors (ER) and regulate their activity [135]. ...
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Oxidative stress (OS) has an important role in female reproduction, whether it is ovulation, endometrium decidualization, menstruation, oocyte fertilization, or development andimplantation of an embryo in the uterus. The menstrual cycle is regulated by the physiological concentration of reactive forms of oxygen and nitrogen as redox signal molecules, which trigger and regulate the length of individual phases of the menstrual cycle. It has been suggested that the decline in female fertility is modulated by pathological OS. The pathological excess of OS compared to antioxidants triggers many disorders of female reproduction which could lead to gynecological diseases and to infertility. Therefore, antioxidants are crucial for proper female reproductive function. They play a part in the metabolism of oocytes; in endometrium maturation via the activation of antioxidant signaling pathways Nrf2 and NF-κB; and in the hormonal regulation of vascular action. Antioxidants can directly scavenge radicals and act as a cofactor of highly valuable enzymes of cell differentiation and development, or enhance the activity of antioxidant enzymes. Compensation for low levels of antioxidants through their supplementation can improve fertility. This review considers the role of selected vitamins, flavonoids, peptides, and trace elements with antioxidant effects in female reproduction mechanisms.
... Resveratrol is one of the polyphenols that are present in large amounts in C. intybus [44]. Resveratrol is well-reported for its potent antidiabetic actions by reducing glucose levels, ameliorating the parameters of oxidative damage, and preserving β-cells [45]. A whole-cell voltage-clamp study on a mouse β-cell line revealed that resveratrol significantly inhibited the K ATP current at a concentration of 3 µmol/l and stimulated insulin secretion by causing membrane depolarization [46]. ...
Article
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Hyperglycemia, which is a chronic metabolic condition caused by either a defect in insulin secretion or insulin resistance, is a hallmark of diabetes mellitus (DM). Sustained hyperglycemia leads to the onset and development of many health complications. Despite the number of available antidiabetic medications on the market, there is still a need for novel treatment agents with increased efficacy and fewer adverse effects. Many medicinal plants offer a rich supply of bioactive compounds that have remarkable pharmacological effects with less toxicity and side effects. According to published evidence, natural antidiabetic substances influence pancreatic β-cell development and proliferation, inhibit pancreatic β-cell death, and directly increase insulin output. Pancreatic ATP-sensitive potassium channels play an essential role in coupling glucose metabolism to the secretion of insulin. Although much of the literature is available on the antidiabetic effects of medicinal plants, very limited studies discuss their direct action on pancreatic KATP. The aim of this review is to focus on the modulatory effects of antidiabetic medicinal plants and their active constituents on pancreatic KATP. The KATP channel should be regarded as a key therapeutic milestone in the treatment of diabetes. Therefore, continuous research into the interaction of medicinal plants with the KATP channel is crucial.
... The general conclusion of this meta-analysis is that resveratrol has a significant dose-response effect on glucose concentrations, HbA1c percentage and insulin levels in subjects with type 2 diabetes mellitus, aged 45-59 years. Among the mechanisms underlying the anti-diabetic effects of resveratrol, increased insulin sensitivity, activation of 5 -AMP-activated protein kinase (AMPK), epigenetic modifications of DNA sequence (including methylation and histone modifications) leading to changes in gene expression, and improvement of pancreatic β-cell functionality, due to the protection against oxidative damage, have been described (24)(25)(26)(27). In addition, several authors have proposed that changes induced by resveratrol in gut microbiota composition may well be involved on its anti-diabetic effect. ...
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Although a general healthy gut microbiota cannot be defined due to numerous internal and external individual factors, such as sex, age, ethnicity, genetics, environment, diet and drugs affect its composition, certain microbial species and gut microbiota compositions seem to be related to the progression of insulin resistance to type 2 diabetes, as well as the development of microvascular and macrovascular complications of diabetes. The present review aimed at gathering the reported information describing how resveratrol induced changes in microbiota composition can mediate the positive effects of this polyphenol on glucose homeostasis under type 2 diabetic conditions, both in animals and humans. Based on the fact that some changes observed in the gut microbiota of type 2 diabetic animals and patients are reversed by resveratrol treatment, and taking into account that some resveratrol mediated changes in gut microbiota composition are similar to those induced by anti-diabetic drugs such as metformin, it can be proposed that four genera, Alistipes, Allobaculum, Desulfovibrio and Blautia could be involved in the benefits of resveratrol on glycameic control. Nevertheless some limitations are observed in this research field: (a) the number of studies analyzing both the effects of resveratrol on glucose homeostasis and microbiota composition in the same cohort of animals, in order to know the potential involvement of microbiota in the anti-diabetic effects of this phenolic compound, are very scarce and practically inexistent in the case of humans., (b) the studies present inconsistencies concerning the effects of resveratrol on gut microbiota changes, (c) the experimental design used do not allow the researchers to establish a causal relationship between the changes in microbiota and the anti-diabetic effect, in the vast majority of the studies, (d) the knowledge about the role of each type of bacteria on glycaemic control is not sufficient so far.
... RSV has been shown to have an array of biological effects, including antioxidant [24], anti-inflammatory [25], neuroprotective [26], anti-diabetic [27], and anti-cancer properties [28][29][30][31]. The first study to examine the anticancer properties of RSV was published in 1997 by John Pezzuto's group [30]. ...
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Cervical cancer affects many women worldwide, with more than 500,000 cases diagnosed and approximately 300,000 deaths each year. Resveratrol is a natural substance of the class of phytoalexins with a basic structure of stilbenes and has recently drawn scientific attention due to its anticancer properties. The purpose of this review is to examine the effectiveness of resveratrol against cervical cancer. All available in vitro and in vivo studies on cervical cancer were critically reviewed. Many studies utilizing cervical cancer cells in culture reported a reduction in proliferation, cell cycle arrest, and induction of apoptosis. Apart from apoptosis, induction of autophagy was seen in some studies. Importantly, many studies have shown a reduction in the HPV oncoproteins E6 and E7 and increased levels of the tumor suppressor p53 with resveratrol treatment. A few studies examined the effects of resveratrol administration in mice ectopic-xenografted with cervical cancer cells showing reduced tumor volume and weight. Overall, the scientific data show that resveratrol has the ability to target/inhibit certain signaling molecules (EGFR, VEGFR, PKC, JNK, ERK, NF-kB, and STAT3) involved in cervical cancer cell proliferation and survival. Further in vivo experiments and clinical studies are required to better understand the potential of resveratrol against cervical cancer.
... After 30 min of incubation at 30°C of DPH with SMPs, different concentrations of pure resveratrol, resveratrol C-dots, or sucrose C-dots (0−200 μg/mL) were supplemented with SMPs, and the fluorescence anisotropy was measured at λ ex = 360 nm and λ em = 440 nm using a Fluorolog spectrofluorimeter (HORIBA, Japan). Anisotropy values were automatically calculated by the spectrofluorimeter software using eq 2: (2) in which I VV is with excitation and emission polarizers mounted vertically; I HH corresponds to the excitation and emission polarizers mounted horizontally; I HV is the excitation polarizer horizontal and the emission polarizer vertical; and I VH requires the excitation polarizer vertical and emission polarizer horizontal. 74 Each experiment was repeated at least three times. ...
Article
Resveratrol, a natural polyphenol, exhibits beneficial health properties and has been touted as a potential anti-tumor agent. Here, we demonstrate potent anti-cancer effects of carbon dots (C-dots) synthesized from resveratrol. The mild synthesis conditions retained resveratrol functional moieties upon the carbon dots' (C-dots) surface, an important requisite for achieving specificity toward cancer cells and biological activities. Indeed, the disruptive effects of the resveratrol-C-dot were more pronounced in several cancer cell types compared to normal cells, underscoring targeting capabilities of the C-dots, a pertinent issue for the development of cancer therapeutics. In particular, we observed impairment of mitochondrial functionalities, including intracellular calcium release, inhibition of cytochrome-C oxidase enzyme activity, and mitochondrial membrane perturbation. Furthermore, the resveratrol C-dots were more potent than either resveratrol molecules alone, known anti-cancer polyphenolic agents such as curcumin and triphenylphosphonium, or C-dots prepared from different carbonaceous precursors. This study suggests that resveratrol-synthesized C-dots may have promising therapeutic potential as anti-cancer agents.
... A positive association has also been ascribed to the consumption of Kimchi, which has been reported to result in better endurance and insulin sensitivity in experimental studies Islam and Choi 2009). Additionally, fermentable drinks rich in polyphenols, such as red wine, has been reported to have health beneficial effects in the context of T2D (Chiva-Blanch et al. 2013;Szkudelski and Szkudelska 2011). Other randomized controlled trials and results regarding the effects of fermentable foods on T2D are described in Table 4. ...
Article
Fermentation has been used since the Early Neolithic period to preserve foods. It has inherent organoleptic and nutritive properties that bestow health benefits, including reducing inflammation and oxidative stress, supporting the growth of salutogenic microbiota, enhancing intestinal mucosal protection and promoting beneficial immunometabolic health effects. The fermentation of food with specific microbiota increases the production salutogenic bioactive compounds that can activate Nrf2 mediated cytoprotective responses and mitigate the effects of the 'diseasome of aging' and its associated inflammageing, which presents as a prominent feature of obesity, type-2 diabetes, cardiovascular and chronic kidney disease. This review discusses the importance of fermented food in improving health span, with special reference to cardiometabolic diseases.
... The beneficial effects of resveratrol in metabolic disorders such as insulin resistance and T2DM have also been characterized. Data from the literature indicate that resveratrol ingestion is able to stimulate glucose uptake by increasing the translocation of GLUT4 (Szkudelski and Szkudelska, 2011). Moreover, resveratrol has been suggested to counteract the HFD-induced insulin resistance (Mendez-del Villar et al., 2014). ...
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Alzheimer’s disease (AD) is a chronic, complex neurodegenerative disorder mainly characterized by the irreversible loss of memory and cognitive functions. Different hypotheses have been proposed thus far to explain the etiology of this devastating disorder, including those centered on the Amyloid-β (Aβ) peptide aggregation, Tau hyperphosphorylation, neuroinflammation and oxidative stress. Nonetheless, the therapeutic strategies conceived thus far to treat AD neurodegeneration have proven unsuccessful, probably due to the use of single-target drugs unable to arrest the progressive deterioration of brain functions. For this reason, the theoretical description of the AD etiology has recently switched from over-emphasizing a single deleterious process to considering AD neurodegeneration as the result of different pathogenic mechanisms and their interplay. Moreover, much relevance has recently been conferred to several comorbidities inducing insulin resistance and brain energy hypometabolism, including diabetes and obesity. As consequence, much interest is currently accorded in AD treatment to a multi-target approach interfering with different pathways at the same time, and to life-style interventions aimed at preventing the modifiable risk-factors strictly associated with aging. In this context, phytochemical compounds are emerging as an enormous source to draw on in the search for multi-target agents completing or assisting the traditional pharmacological medicine. Intriguingly, many plant-derived compounds have proven their efficacy in counteracting several pathogenic processes such as the Aβ aggregation, neuroinflammation, oxidative stress and insulin resistance. Many strategies have also been conceived to overcome the limitations of some promising phytochemicals related to their poor pharmacokinetic profiles, including nanotechnology and synthetic routes. Considering the emerging therapeutic potential of natural medicine, the aim of the present review is therefore to highlight the most promising phytochemical compounds belonging to two major classes, polyphenols and monoterpenes, and to report the main findings about their mechanisms of action relating to the AD pathogenesis.
... For instance, the anticancer, antimicrobial(De Filippis et al., 2019;Tian and Liu, 2019), anti-osteoporosis(Tou, 2015), antidiabeticSasikumar et al., 2019;Szkudelski and Szkudelska, 2011), neuroprotective(De Filippis et al., 2019), antifatigue(Tian and Liu, 2019), anti-aging, cardioprotective(Hsieh and Wu, 2019), anti-obesity(Pan et al., 2018), antioxidant(Cavallini et al., 2016), anti-inflammatory(Cavallini et al., 2016), and anti-atherosclerosis (Bonnefont-Rousselot, 2016) activities of stilbenes are extensively reported ...
Article
Stilbenes are some of the important phenolic compounds originating from plant families like Vitaceae, Leguminaceae, Gnetaceae, and Dipterocarpaceae. Structurally, they have a C6–C2–C6 skeleton, usually with two isomeric forms. Stilbenes are biosynthesized due to biotic and abiotic stresses such as microbial infections, high temperatures, and oxidation. This review aims to provide a comprehensive overview of stilbenes’ botanical sources, chemistry, biosynthetic pathways, pharmacology, and clinical applications and challenges based on up-to-date data. All included studies were collected from PubMed, ScienceDirect, Google Scholar, and CNKI, and the presented data from these indexed studies were analyzed and summarized. A total of 459 natural stilbene compounds from 45 plant families and 196 plant species were identified. Pharmacological studies also show that stilbenes have various activities such as anticancer, antimicrobial, antioxidant, anti-inflammatory, anti-degenerative diseases, anti-diabetic, neuroprotective, anti-aging, and cardioprotective effects. Stilbene synthase (STS) is the key enzyme involved in stilbene biosynthetic pathways. Studies on the therapeutic application of stilbenes pinpoint that challenges such as low bioavailability and isomerization are the major bottlenecks for their development as therapeutic drugs. Although the medicinal uses of several stilbenes have been demonstrated in vivo and in vitro, studies on the development of stilbenes deserve more attention in the future.
... Interestingly, RES treatments antagonized all of the abovementioned effects and normalized the expression levels of both CPT-1 and UCP-2, suggesting a protective effect of RES on mitochondrial dysfunction, which could be basically mediated by inhibition of FA oxidation and their associated ROS generation. Such an effect could be related to the ability of RES to decrease the availability of FFAs by inhibiting hepatic lipogenesis as mentioned above and (or) due to inhibition of peripheral lipolysis by enhancing insulin action and decrease insulin resistance, as seen in this study and similar earlier studies (Lagouge et al. 2006;Szkudelski and Szkudelska 2011). Furthermore, even not investigated in our study, RES may favorably modulate the expression of fatty acid transporters (Ahn et al. 2008;Cho et al. 2012;Xin et al. 2013). ...
Article
Resveratrol (RES) has the ability to ameliorate nonalcoholic fatty liver disease (NAFLD) and the mechanism remains unclear. Hence, using high-fat diet (HFD) obese rat model, we investigated the effect of a low dose of RES (20 mg/kg) on the hepatic sterol regulatory element-binding protein (SREBPs)-lipogenesis pathway, enzymes involved in ␤-oxidation and activity of pancreatic lipase. Four groups of rats (n = 8) of control (12% of calories as fat) and HFD (40% of calories as fat) were administered orally with either normal saline as a vehicle or RES as a concomitant treatment for 8 weeks on a daily basis. Then, various biochemical, histological, and molecular experiments were carried out. RES prevented the development and progression of NAFLD and significantly improved insulin sensitivity through (1) inhibiting the proteolytic cleavage of SREBPs-1 and SREBPs-2 without affecting their precursor mRNA or protein levels, (2) inhibiting free fatty acid ␤-oxidation and generation of reactive oxygen species through significant inhibition of CPT-1 and UCP-2, and (3) decreasing activity of pancreatic lipase in vivo and in vitro. In conclusion, our findings are the first in the literature to show new mechanisms of the hepatoprotective effect of RES against HFD induced NAFLD in rats. Résumé : Avec le resvératrol (RES), il est possible d'atténuer la stéatose hépatique non alcoolique (SHNA), mais les modes d'action demeurent à éclaircir. Par conséquent, à l'aide d'un modèle de régime alimentaire à haute teneur en matières grasses (RHG) avec obésité chez le rat, nous avons étudié l'effet d'une faible dose de RES (20 mg/kg) sur la voie de signalisation de la lipogenèse hépatique par les protéines SREBP (« sterol regulatory element-binding proteins »), des enzymes jouant un rôle dans la ␤-oxydation et l'activité de la lipase pancréatique. Dans quatre groupes de rats (n = 8) témoins (12 % des calories sous forme de matières grasses) ou RHG (40 % des calories sous forme de matières grasses), nous avons administré une solution saline physiologique comme véhicule ou du RES comme traitement oral quotidien concomitant de 8 semaines. Puis, nous avons effectué diverses expériences biochimiques, histologiques et moléculaires. Le RES permettait de prévenir la survenue et l'évolution de la SHNA et d'améliorer nettement la sensibilité à l'insuline par les modes d'action suivants : (1) inhibition du clivage protéolytique des SREBP-1 et des SREBP-2 sans affecter les taux de leurs ARNm et protéines précurseurs, (2) inhibition de la ␤-oxydation des acides gras libres et de la production de dérivés réactifs de l'oxygène par l'inhibition marquée de CPT-1 et de UCP-2 et (3) diminution de l'activité de la lipase pancréatique in vivo et in vitro. En conclusion, ce sont les premiers résultats publiés à montrer de nouveaux modes d'action de l'effet hépatoprotecteur du RES contre la SHNA provoquée par le RHG chez le rat. [Traduit par la Rédaction] Mots-clés : resvératrol, résistance à l'insuline, stéatose hépatique, SREBP.
... The antihyperglycemic action of resveratrol was demonstrated in obese rodents and in two animal models of diabetes: in rats with streptozotocin induced diabetes or with streptozotocinnicotinamide-induced diabetes. Some studies also revealed that administration of resveratrol (1) to diabetic rats resulted in diminished levels of glycosylated hemoglobin (HbA1C), which reflects the prolonged reduction of glycaemia [96,97]. The anti-hyperglycemic effect of resveratrol observed in diabetic animals is thought to result from its stimulatory action on intracellular glucose transport through increased expression of the insulin-dependent glucose transporter GLUT4 [98]. ...
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Cyperaceae is a cosmopolitan plant family with approx. 5000 species distributed worldwide. Several members of this family are used in traditional medicines for the treatment of different diseases. In the last few decades, constituents with great chemical diversity were isolated from sedges, and a wide range of biological activities were detected either for crude extracts or for pure compounds. Among the isolated compounds, phenolic derivatives are the most important, especially stilbenoids, and flavonoids. To date, more than 60 stilbenoids were isolated from 28 Cyperaceae species. Pharmacological investigation of Cyperaceae stilbenoids revealed that several compounds possess promising activities; mainly antiproliferative, antibacterial, antioxidant and anthelmintic effects. Isolation, synthesis and pharmacological investigation of stilbenes are increasing constantly. As Cyperaceae species are very good sources of a wide variety of stilbenes, and several of them occur in large amount worldwide, they are worthy for phytochemical and pharmacological investigations. Moreover, stilbenes are important from chemotaxonomical point of view, and they play a key role in plant defense mechanisms as well. This review summarizes the stilbenoids isolated from sedges, and their biological activities.
... Sirt1 plays a critical role in metabolism and anti-aging effects [45]. The activation of Sirt1 has been shown to retard the aging process [46], as well as to attenuate neurodegeneration [47]. A wealth of data has shown that Sirt1 plays an important role in insulin resistance and type 2 diabetes [48]. ...
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Background: Insulin resistance has been reported to be closely correlated with the pathogenesis of MHE. The mechanism underlying the effects of thrombopoietin receptor agonist eltrombopag (ELT) on synaptic activity and formation involved in MHE pathogenesis remains unclear. Methods: The effect of ELT on neurodegeneration and insulin resistance was examined in the primary rat neurons and an MHE rat model. Results: We found that the level of thrombopoietin receptor c-MPL (MPL) expression was decreased in MHE brains, and ELT administration improved insulin resistance, alleviated the destruction of synaptic formation and enhanced learning and memory in the MHE rats, indicating the relationship between dowregulated ELT and insulin resistance. Then in vitro, ELT treatment ameliorated the impairment of glucose uptake, indicating the reduction of insulin resistance. High dose of glucose inhibited insulin-stimulated downregulation of Hypoxia-inducible factor-1α (HIF1α) expression, the inhibition of inflammatory response and upregulation of sirtuin-1 (Sirt1), destruction of synaptic formation and activity, which were all reversed by ELT treatment in insulin resistant neurons. Conclusions: These results indicate that ELT is a promising potential therapeutic agent for insulin resistance and defect in learning and memory.
... Quercetin (Q) is a naturally occurring flavonoid that is widely distributed in plants and natural foods and shows many beneficial effects such as anti-inflammatory, antioxidant, and antidiabetic activities [8]. Additionally, Q administration extended the lifespan of some experimental model organisms and minimized oxidative injury [9]. ...
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Medicinal uses and applications of metals and their complexes are of increasing clinical and commercial importance. The ligation behavior of quercetin (Q), which is a flavonoid, and its Zn (II) (Q/Zn) complex were studied and characterized based on elemental analysis, molar conductance, Fourier-transform infrared (FTIR) spectra, electronic spectra, proton nuclear magnetic resonance (¹H-NMR), thermogravimetric analysis, and transmission electron microscopy (TEM). FTIR spectral data revealed that Q acts as a bidentate ligand (chelating ligand) through carbonyl C(4) = O oxygen and phenolic C(3)–OH oxygen in conjugation with Zn. Electronic, FTIR, and ¹H-NMR spectral data revealed that the Q/Zn complex has a distorted octahedral geometry, with the following chemical formula: [Zn(Q)(NO3)(H2O)2].5H2O. Diabetes was induced by streptozotocin (STZ) injection. A total of 70 male albino rats were divided into seven groups: control, diabetic untreated group and diabetic groups treated with either MSCs and/or Q and/or Q/Zn or their combination. Serum insulin, glucose, C-peptide, glycosylated hemoglobin, lipid profile, and enzymatic and non-enzymatic antioxidant levels were determined. Pancreatic and lung histology and TEM for pancreatic tissues in addition to gene expression of both SOD and CAT in pulmonary tissues were evaluated. MSCs in combination with Q/Zn therapy exhibited potent protective effects against STZ induced hyperglycemia and suppressed oxidative stress, genotoxicity, glycometabolic disturbances, and structural alterations. Engrafted MSCs were found inside pancreatic tissue at the end of the experiment. In conclusion, Q/Zn with MSC therapy produced a synergistic effect against oxidative stress and genotoxicity and can be considered potential ameliorative therapy against diabetes with pulmonary dysfunction, which may benefit against COVID-19.
... Additionally, plasma insulin levels, hepatic glycogen synthesis, and glucokinase activity have been shown to increase significantly (p < 0.05), while blood glucose levels decreased significantly (p < 0.05) in response to polyphenol consumption in rodent models [26]. Polyphenols decreased blood glucose in animals with hyperglycemia, protected β-cells against oxidative stress, limited apoptosis, and improved insulin action via changes in adiposity, gene expression, and enzymatic activity [27]. They also inhibited the expression and action of endothelial nitric oxide synthase, thereby facilitating vasorelaxation and decreased LDL-c oxidation, thus offering cardio-and vasoprotection [28]. ...
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Food-based dietary management, enhanced with evidence-based commercial products, such as diabetes-specific nutrition formulas (DSNFs), can help control the development, progression, and severity of certain chronic diseases. In this review, evidence is detailed on the use of DSNFs in patients with or at risk for diabetes and cardiometabolic-based chronic disease. Many DSNF strategies target glycemic excursions and cardiovascular physiology, taking into account various elements of healthy eating patterns. Nevertheless, significant research, knowledge, and practice gaps remain. These gaps are actionable in terms of formulating and testing relevant and pragmatic research questions, developing an educational program for the uniform distribution of information, and collaboratively writing clinical practice guidelines that incorporate the evidence base for DSNF. In sum, the benefits of DNSF as part of validated clinical practice algorithms include mitigation of chronic disease progression, cost-savings for the healthcare system, and applicability on a global scale
... It also possesses antifungal activity in plants and has gained interest because of its multifaceted effect against diabetes and other life-threatening diseases. A number of diabetic models including streptozotocin (STZ), nicotinamides/STZ, and long term high-fat diets have been observed to study the beneficial effect of resveratrol (RES) [93][94][95]. Recently, the studies conducted on humans with RES supplementation have shown improvement in hypergly-cemic condition, sensitivity to insulin, and reduction in oxidative stress in patients with type 2 DM [96][97][98]. ...
Chapter
Due to depletion of non-renewable resources at an alarming rate, the need for utilization of renewable resources to make valuable chemicals is of profound importance.Though lignocellulose is most widely available renewable resource on earth, yet it is utilized much below its potential.The conversion of lignocellulose, especially from agricultural wastes and forest residues to vast array of fuels and polymeric precursors is of crucial relevance in the sustainability and development of energy and chemical industries. But, there are technical and economical hindrances to the development of a commercial processes utilizing lignocellulose. There are few promising technologies developed and many are being developed which will allow the conversion of lignocellulose commercially viable. The conversion of lignocellulose to simple sugars requires daunting biological processes which includes delignification and depolymerization. In the second step, the liberation of free sugar can be done by enzymes which can efficiently carry out the process. Hence, understanding the mechanisms, limitations and improvement of these key enzym
... Flavonoids are also useful for human health, working as cancer chemopreventive [41][42][43], antioxidant [44][45][46], anti-asthmatic [47][48][49], anti-inflammatory [50][51][52], anti-microbial [53][54][55] and anti-malarial [56][57][58] agents. Similarly, resveratrol, produced by the enzyme stilbene synthase, has proven to be a potent anti-angiogenic [59][60][61], anti-diabetic [62][63][64], anti-cancer [65][66][67], anti-viral [68][69][70], cardioprotective [71][72][73] and neuroprotective [74][75][76] compound, as well as a more powerful antioxidant and vasorelaxant than naringenin [77][78][79]. ...
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Marine microalgae are photosynthetic microorganisms at the base of the marine food webs. They are characterized by huge taxonomic and metabolic diversity and several species have been shown to have bioactivities useful for the treatment of human pathologies. However, the compounds and the metabolic pathways responsible for bioactive compound synthesis are often still unknown. In this study, we aimed at analysing the microalgal transcriptomes available in the Marine Microbial Eukaryotic Transcriptome Sequencing Project (MMETSP) database for an in silico search of polyketide synthase type III homologs and, in particular, chalcone synthase (CHS) and stilbene synthase (STS), which are often referred to as the CHS/STS family. These enzymes were selected because they are known to produce compounds with biological properties useful for human health, such as cancer chemopreventive, anti-inflammatory, antioxidant, anti-angiogenic, anti-viral and anti-diabetic. In addition, we also searched for 4-Coumarate: CoA ligase, an upstream enzyme in the synthesis of chalcones and stilbenes. This study reports for the first time the occurrence of these enzymes in specific microalgal taxa, confirming the importance for microalgae of these pathways and giving new insights into microalgal physiology and possible biotechnological applications for the production of bioactive compounds.
Chapter
Diabetes Mellitus (DM) receives significant attention from most scientists due to being a major global public health threat. Diabetes is considered one of the leading causes of death due to its micro and macrovascular complications. This insidious killer is estimated to reach a staggering number of 578 million (700 million by 2045) cases by 2030. In this book, utilizing the disciplines of clinical sciences, various contemporary topics related to diabetes are extensively discussed. These include the classification of diabetes, underlying causes, epidemiology, pathogenesis, impact on sexual functions, association with cancer, clinical manifestations, diagnostic methods, complications, and treatment options. Furthermore, intriguing and current subjects such as ""antidiabetic phytotherapy"" and ""the relationship between oral health and diabetes"" are also covered. By doing so, readers will acquire comprehensive and detailed knowledge about the clinical management of diabetes. Thus, this book not only serves those who seek to understand the scientific aspects of diabetes but also proves to be a valuable resource for healthcare professionals, researchers, and students in a clinical setting. We believe that this book will contribute to understanding the complexity of diabetes and provide beneficial solutions while shedding light on future studies.
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As hortaliças, de um modo geral, possuem uma grande importância na prática de uma alimentação adequada e balanceada, o que está diretamente relacionado com os princípios básicos da segurança alimentar e nutricional, principalmente no que diz respeito ao fornecimento de vitaminas, sais minerais e fibras. Algumas hortaliças podem ser ainda, excelentes fontes de carboidratos e proteínas. Por esta razão, o presente trabalho realizará uma avaliação dos compostos bioativos polifenóis, carotenoides e glucosinolatos de hortaliças e sua importância nutricional para prevenção de doenças. Possuindo por objetivo geral, analisar os benefícios dos compostos bioativos polifenóis, carotenoides e glucosinolatos das hortaliças e sua importância nutricional para prevenção de doenças, e objetivos específicos apresentar a definição de hortaliças, sua classificação e composição nutricional; definir os compostos bioativos, apresentando os principais tipos e; apresentar a ação dos compostos bioativos na prevenção de determinadas doenças. Para atingir tais objetivos, utilizou-se por metodologia uma revisão integrativa da literatura. Com a realização da mesma, foi possível constatar que são acumuladas evidências sobre os efeitos terapêuticos dos compostos bioativos, elevando desta maneira a importância do entendimento da biodisponibilidade destes compostos in vivo.
Chapter
Resveratrol, a compound in the class of polyphenol, is broadly recognized for its magnificent antioxidant, anti-inflammatory, anti-coagulation, and manipulation of apoptosis properties. Despite its potential, the low solubility, instability, and poor bioavailability limit the therapeutic effectiveness of this bioactive agent in treatments. Solid dispersion has been perceived as a significant accomplishment in addressing these challenges with several commercially successful products. Many studies, therefore, focused on this approach to enhance the physicochemical characteristics of resveratrol. This review provides a comprehensive view of resveratrol-loaded solid dispersion according to its four distinct generations that have been developed over the decades, their formulations, preparation methods and achievements. Besides, future perspectives and remarkable points are also discussed in the article.
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Diabetes mellitus is a common chronic metabolic disorder that is characterized by increased levels of glucose for prolonged periods of time. Incessant hyperglycemia leads to diabetic complications such as retinopathy, nephropathy, and neuropathy, and cardiovascular complications such as ischemic heart disease, peripheral vascular disease, diabetic cardiomyopathy, stroke, etc. There are many studies that suggest that various polyphenols affect glucose homeostasis and can help to attenuate the complications associated with diabetes. This review focuses on the possible role of various dietary polyphenols in palliating diabetes-induced cardiovascular complications. This review also aims to give an overview of the interrelationship among ROS production (due to diabetes), inflammation, glycoxidative stress, and cardiovascular complications as well as the anti-hyperglycemic effects of dietary polyphenols. Various scientific databases including Scopus, Web of Science, Google Scholar, PubMed, Science Direct, Springer Link, and Wiley Online Library were used for searching articles that complied with the inclusion and exclusion criteria. This review lists several polyphenols based on various pre-clinical and clinical studies that have anti-hyperglycemic potential as well as a protective function against cardiovascular complications. Several pre-clinical and clinical studies suggest that various dietary polyphenols can be a promising intervention for the attenuation of diabetes-associated cardiovascular complications.
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Diabetes mellitus is one of the major health problems in the world, the incidence and associated mortality are increasing. Inadequate regulation of the blood sugar imposes serious consequences for health. Conventional antidiabetic drugs are effective, however, also with unavoidable side effects. On the other hand, medicinal plants may act as an alternative source of antidiabetic agents. Examples of medicinal plants with antidiabetic potential are described, with focuses on preclinical and clinical studies. The beneficial potential of each plant matrix is given by the combined and concerted action of their profile of biologically active compounds.
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The World Health Organization aims to stop the rise of diabetes by 2025, and diet is one of the most efficient non-pharmacological strategies used to prevent it. Resveratrol (RSV) is a natural compound with anti-diabetic properties, and incorporating it into bread is a suitable way to make it more accessible to consumers as it can be included as part of their daily diet. This study aimed to evaluate the effect of RSV-enriched bread in preventing early type 2 diabetes cardiomyopathy in vivo. Male Sprague Dawley rats (3 weeks old) were divided into four groups: controls with plain bread (CB) and RSV bread (CBR), and diabetics with plain bread (DB) and RSV bread (DBR). Type 2 diabetes was induced by adding fructose to the drinking water for two weeks followed by an injection of streptozotocin (STZ) (40 mg/kg). Then, plain bread and RSV bread (10 mg RSV/kg body weight) were included in the rats’ diet for four weeks. Cardiac function, anthropometric, and systemic biochemical parameters were monitored, as well as the histology of the heart and molecular markers of regeneration, metabolism, and oxidative stress. Data showed that an RSV bread diet decreased the polydipsia and body weight loss observed in the early stages of the disease. At the cardiac level, an RSV bread diet diminished fibrosis but did not counteract the dysfunction and metabolic changes seen in fructose-fed STZ-injected rats.
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This study was conducted to evaluate the cymoxanil-mancozeb (CM) toxicity and investigate the ameliorative effect of resveratrol (Res) against cymoxanil-mancozeb toxicity. Forty rats were divided into four groups; the first group was used as a control group, the second group was exposed to Res only at a dose of 20 mg/kg body weight for 4 weeks, and the third group was administered CM only at a dose of 799 mg/kg body weight for 4 weeks, The fourth group was co-treated with Res+CM for 4 weeks. Blood samples were analyzed for hematological and biochemical parameters. The comet assay was done on liver and blood specimens and histopathological examinations of the liver and intestine. The results demonstrated that CM exposure caused a significant increase in WBCs, lymphocytes, granulocytes, monocytes ALT, AST, ALP, and GGT, and total cholesterol and triglycerides levels accompanied by a decrease in HGB, HCT, RBCs and MCV, MCH, MCHC, HDL and glucose levels with no significant DNA damage in liver and blood. CM mixture induced severe pathological changes in small intestine and liver. Co-treatment of Res with CM improved hematological picture, lipid and glucose profiles also liver enzymes and decreased changes in the architecture of the liver and intestine.
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There is a close relationship between Alzheimer's disease (AD) and diabetes mellitus (DM), and the link between the two is often referred to as type 3 diabetes mellitus (T3DM). Many natural bioactive compounds have shown the potential to treat AD and diabetes. We mainly review the polyphenols represented by resveratrol (RES) and proanthocyanidins (PCs) and alkaloids represented by berberine (BBR) and Dendrobium nobile Lindl. alkaloids (DNLA) from the perspective of T3DM to review the neuroprotective effects and molecular mechanisms of natural compounds in AD.
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The inflammasome is a protein complex composed of a variety of proteins in cells and which participates in the innate immune response of the body. It can be activated by upstream signal regulation and plays an important role in pyroptosis, apoptosis, inflammation, tumor regulation, etc. In recent years, the number of metabolic syndrome patients with insulin resistance (IR) has increased year by year, and the inflammasome is closely related to the occurrence and development of metabolic diseases. The inflammasome can directly or indirectly affect conduction of the insulin signaling pathway, involvement the occurrence of IR and type 2 diabetes mellitus (T2DM). Moreover, various therapeutic agents also work through the inflammasome to treat with diabetes. This review focuses on the role of inflammasome on IR and T2DM, pointing out the association and utility value. Briefly, we have discussed the main inflammasomes, including NLRP1, NLRP3, NLRC4, NLRP6 and AIM2, as well as their structure, activation and regulation in IR were described in detail. Finally, we discussed the current therapeutic options-associated with inflammasome for the treatment of T2DM. Specially, the NLRP3-related therapeutic agents and options are widely developed. In summary, this article reviews the role of and research progress on the inflammasome in IR and T2DM.
Chapter
Resveratrol is a stilbenoid polyphenolic molecule widely known for its biological properties, which is available in nature in various varieties of grapes, berries, and some plants. It has been shown to play an important role in the prevention and treatment of chronic diseases such as cancer, heart disease, metabolic, degenerative, autoimmune diseases, and even viral infections. One of the main mechanisms of action that it presents is linked to its antioxidant capacity as it is a strict polyphenol, which gives it the ability to stimulate an immune response in the host by regulating and differentiating immune cells, promoting the synthesis of specific proteins, activate apoptosis, stimulate the secretion of pro-inflammatory cytokines, and even modulate gene expression. These effects have favored the decrease in the progression of various inflammatory and degenerative diseases, thus demonstrating the immunomodulatory capacity of resveratrol on in vitro and in vivo models.
Chapter
Medicinal chemists around the world have been inspired by nature and have successfully extracted chemicals from plants. Research on enzymatic modifications of naturally occurring compounds has played a critical role in the search for biologically active molecules to treat diseases. This book explores compounds of interest to researchers and clinicians. It presents a comprehensive analysis about the medicinal chemistry (drug design, structure-activity relationships, permeability data, cytotoxicity, appropriate statistical procedures, and molecular modeling studies) of different compounds. Each chapter brings contributions from known scientists explaining experimental results which can be translated into clinical practice. Each chapter follows a specific format for a phytochemical agent with common chemical features: General background on the (phyto)chemistry of the scaffold General background on the pharmacological profile of the scaffold A Description of the proposed derivatives and their advantages with respect to the parent compounds (emphasizing the synthetic approaches and structure-activity relationships) In silico analysis of the crucial interactions with the biological target Clinical studies and patent survey (if available) on the new and proposed structures The objective of this book set is to fulfil gaps in currently acquired knowledge with information from the recent years. It serves as a guide for academic and professional researchers and clinicians.
Chapter
Full-text available
Medicinal chemists around the world have been inspired by nature and have successfully extracted chemicals from plants. Research on enzymatic modifications of naturally occurring compounds has played a critical role in the search for biologically active molecules to treat diseases. This book explores compounds of interest to researchers and clinicians. It presents a comprehensive analysis about the medicinal chemistry (drug design, structure-activity relationships, permeability data, cytotoxicity, appropriate statistical procedures, and molecular modeling studies) of different compounds. Each chapter brings contributions from known scientists explaining experimental results which can be translated into clinical practice. Each chapter follows a specific format for a phytochemical agent with common chemical features: General background on the (phyto)chemistry of the scaffold General background on the pharmacological profile of the scaffold A Description of the proposed derivatives and their advantages with respect to the parent compounds (emphasizing the synthetic approaches and structure-activity relationships) In silico analysis of the crucial interactions with the biological target Clinical studies and patent survey (if available) on the new and proposed structures The objective of this book set is to fulfil gaps in currently acquired knowledge with information from the recent years. It serves as a guide for academic and professional researchers and clinicians.
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The growing smooth talk in the field of natural compounds is due to the ancient and current interest in herbal medicine and their potentially positive effects on health. Dozens of antidiabetic natural compounds were reported and tested in vivo, in silico, and in vitro. The role of these natural compounds, their actions on the insulin signaling pathway, and the stimulation of the glucose transporter-4 (GLUT4) insulin-responsive translocation to the plasma membrane (PM) are all crucial in the treatment of diabetes and insulin resistance. In this review, we collected and summarized a group of available in vivo and in vitro studies which targeted isolated phytochemicals with possible antidiabetic activity. Moreover, the in silico docking of natural compounds with some of the insulin signaling cascade key proteins is also summarized based on the current literature. In this review, hundreds of recent studies on pure natural compounds that alleviate type II diabetes mellitus (type II DM) were revised. We focused on natural compounds that could potentially regulate blood glucose and stimulate GLUT4 translocation through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. On attempt to point out potential new natural antidiabetic compounds, this review also focuses on natural ingredients that were shown to interact with proteins in the insulin signaling pathway in silico, regardless of their in vitro/in vivo antidiabetic activity. We invite interested researchers to test these compounds as potential novel type II DM drugs and explore their therapeutic mechanisms.
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Polyphenolic compounds are thought to show considerable promise for the treatment of various metabolic disorders, including type 2 diabetes mellitus (T2DM). This review addresses evidence from in vitro, in vivo, and clinical studies for the antidiabetic effects of certain polyphenolic compounds. We focus on the role of cytotoxic human amylin (hA) aggregates in the pathogenesis of T2DM, and how polyphenols can ameliorate this process by suppressing or modifying their formation. Small, soluble amylin oligomers elicit cytotoxicity in pancreatic islet β-cells and may thus cause β-cell disruption in T2DM. Amylin oligomers may also contribute to oxidative stress and inflammation that lead to the triggering of β-cell apoptosis. Polyphenols may exert antidiabetic effects via their ability to inhibit hA aggregation, and to modulate oxidative stress, inflammation, and other pathways that are β-cell-protective or insulin-sensitizing. There is evidence that their ability to inhibit and destabilize self-assembly by hA requires aromatic molecular structures that bind to misfolding monomers or oligomers, coupled with adjacent hydroxyl groups present on single phenyl rings. Thus, these multifunctional compounds have the potential to be effective against the pleiotropic mechanisms of T2DM. However, substantial further research will be required before it can be determined whether a polyphenol-based molecular entity can be used as a therapeutic for type 2 diabetes.
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Purpose To investigate the adjunct efficacy and safety of vitamin supplements, including resveratrol, in patients with diabetic macular edema (DME) treated with intravitreal anti-vascular endothelial factor (anti-VEGF) agents. Methods Participants in this prospective study were 45 patients with DME, who were treated with either intravitreal anti-VEGF injections (n = 23, Group I) or with combination of intravitreal anti-VEGF injections and vitamin supplements, including resveratrol (n = 22, Group II). All patients underwent visual acuity measurement, slit-lamp examination and spectral domain-optical coherence tomography (SD-OCT) at baseline and monthly after the loading phase of three-monthly anti-VEGF injections, following a PRN protocol. Results There was a statistically significant improvement in visual acuity in both groups at month 12 compared to baseline, although the mean change in visual acuity did not differ between the two groups (p = 0.183). Accordingly, there was a statistically significant decrease in central retinal thickness in both groups at month 12 compared to baseline, while the mean difference in central retinal thickness was significantly greater in the “combination” group. The mean number of intravitreal anti-VEGF injection was less in Group II (6.45 ± 1.12 in Group II vs. 7.39 ± 1.31 in Group I, p = 0.018). Conclusions Vitamin supplements with resveratrol was found to be an effective adjunct to intravitreal anti-VEGF injections in patients with DME, offering better anatomic restoration with less injections at the 12-month follow-up.
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Chapter
Diabetes mellitus type 2 (type-2 diabetes) is a metabolic disorder characterized by the increased blood glucose concentration and insulin resistance in peripheral tissues (e.g., muscles and adipose tissue). The initiation of the pathological cascade of events that lead to type-2 diabetes has been subject of debate; however, it has been commonly accepted that the oversecretion of human islet amyloid polypeptide (hIAPP, a hormone co-secreted with insulin) by the pancreatic 𝛽-cells is the main trigger of type-2 diabetes. In fact, 90% of the type-2 diabetes patients present hIAPP deposits in the extracellular space of the 𝛽-cells. These hIAPP supramolecular arrangements (both fibrillar and oligomeric) have been reported to be the origin of cytotoxicity, which leads to 𝛽-cell dysfunction through a series of different mechanisms, including the interaction of hIAPP oligomers with the cell membrane that leads to the influx of Ca²⁺ and increase in the cellular oxidative stress, among others. This overview shows the importance of developing type-2 diabetes treatment strategies able to (1) remodel of the secondary structure of cytotoxic hIAPP oligomers entrapping them into off-pathway nontoxic species and (2) reestablish physiological levels of oxidative stress. Natural polyphenols are a class of antioxidant compounds that are able to perform both functions. Herein we review the published literature of the most studied polyphenols, in particular for their ability to remodel the hIAPP aggregation pathway, to rescue the in vitro pancreatic 𝛽-cell viability and function, as well as to perform under a complex biological environment, i.e., in vivo animal models and clinical trials. Overall, natural polyphenols are able to control the cytotoxic hIAPP aggregation and minimize hIAPP-mediated cellular dysfunction and can be considered as important lead compounds for the treatment of type-2 diabetes.
Chapter
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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. In this study we examined resveratrol (RSV)-mediated Glut-4 translocation in the streptozotocin (STZ)-induced diabetic myocardium. The rats were randomized into three groups: Control (Con), Diabetes Mellitus (DM) (STZ 65 mg/kg b.w., i.p.) & DM + RSV (2.5 mg/kg b.wt. for 2 weeks orally) (RSV). Isolated rat hearts were used as per the experimental model. RSV induced glucose uptake was observed in vitro with H9c2 cardiac myoblast cells. Decreased blood glucose level was observed after 30 days (375 mg/dl) in RSV-treated rats when compared to DM (587 mg/dl). Treatment with RSV demonstrated increased Adenosine Mono Phosphate Kinase (AMPK) phosphorylation compared to DM. Lipid raft fractions demonstrated decreased expression of Glut-4, Cav-3 (0.4, 0.6-fold) in DM which was increased to 0.75- and 1.1-fold on RSV treatment as compared to control. Increased Cav-1 expression (1.4-fold) in DM was reduced to 0.7-fold on RSV treatment. Increased phosphorylation of endothelial Nitric Oxide Synthase (eNOS) & Akt was also observed in RSV compared to DM (P < 0.05). Confocal microscopy and coimmunoprecipitation studies demonstrated decreased association of Glut-4/Cav-3 and increased association of Cav-1/eNOS in DM as compared to control and converse results were obtained on RSV treatment. Our results suggests that the effect of RSV is non-insulin dependent and triggers some of the similar intracellular insulin signalling components in myocardium such as eNOS, Akt through AMPK pathway and also by regulating the caveolin-1 and caveolin-3 status that might play an essential role in Glut-4 translocation and glucose uptake in STZ- induced type-1 diabetic myocardium.
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Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg(-1) day(-1)), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR.
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Resveratrol, a natural polyphenolic compound that is found in grapes and red wine, increases metabolic rate, insulin sensitivity, mitochondrial biogenesis, and physical endurance and reduces fat accumulation in mice. Although it is thought that resveratrol targets Sirt1, this is controversial because resveratrol also activates 5' AMP-activated protein kinase (AMPK), which also regulates insulin sensitivity and mitochondrial biogenesis. Here, we use mice deficient in AMPKalpha1 or -alpha2 to determine whether the metabolic effects of resveratrol are mediated by AMPK. Mice deficient in the catalytic subunit of AMPK (alpha1 or alpha2) and wild-type mice were fed a high-fat diet or high-fat diet supplemented with resveratrol for 13 weeks. Body weight was recorded biweekly and metabolic parameters were measured. We also used mouse embryonic fibroblasts deficient in AMPK to study the role of AMPK in resveratrol-mediated effects in vitro. Resveratrol increased the metabolic rate and reduced fat mass in wild-type mice but not in AMPKalpha1(-/-) mice. In the absence of either AMPKalpha1 or -alpha2, resveratrol failed to increase insulin sensitivity, glucose tolerance, mitochondrial biogenesis, and physical endurance. Consistent with this, the expression of genes important for mitochondrial biogenesis was not induced by resveratrol in AMPK-deficient mice. In addition, resveratrol increased the NAD-to-NADH ratio in an AMPK-dependent manner, which may explain how resveratrol may activate Sirt1 indirectly. We conclude that AMPK, which was thought to be an off-target hit of resveratrol, is the central target for the metabolic effects of resveratrol.
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Resveratrol is a natural polyphenolic compound that activates nicotinamide adenosine dinucleotide-dependent deacetylase SIRT1. Resveratrol has recently been shown to exert potent antidiabetic actions when orally delivered to animal models of type 2 diabetes. However, the tissue(s) mediating these beneficial effects is unknown. Because SIRT1 is expressed in central nervous system (CNS) neurons known to control glucose and insulin homeostasis, we hypothesized that resveratrol antidiabetic effects are mediated by the brain. Here, we report that long-term intracerebroventricular infusion of resveratrol normalizes hyperglycemia and greatly improves hyperinsulinemia in diet-induced obese and diabetic mice. It is noteworthy that these effects are independent of changes in body weight, food intake, and circulating leptin levels. In addition, CNS resveratrol delivery improves hypothalamic nuclear factor-kappaB inflammatory signaling by reducing acetylated-RelA/p65 and total RelA/p65 protein contents, and inhibitor of nuclear factor-kappaB alpha and IkappaB kinase beta mRNA levels. Furthermore, this treatment leads to reduced hepatic phosphoenolpyruvate carboxykinase 1 mRNA and protein levels and ameliorates pyruvate-induced hyperglycemia in this mouse model of type 2 diabetes. Collectively, our results unveiled a previously unrecognized key role for the CNS in mediating the antidiabetic actions of resveratrol.
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SIRT1, a class III histone/protein deacetylase, is known to interfere with the nuclear factor-kappaB (NF-kappaB) signaling pathway and thereby has an anti-inflammatory function. Because of the central role of NF-kappaB in cytokine-mediated pancreatic beta-cell damage, we postulated that SIRT1 might work in pancreatic beta-cell damage models. RINm5F (RIN) cells or isolated rat islets were treated with interleukin-1beta and interferon-gamma. SIRT1 was activated by resveratrol, a pharmacological activator, or ectopic overexpression. The underlying mechanisms of SIRT1 against cytokine toxicity were further explored. Treatment of RIN cells with cytokines induced cell damage, and this damage was well correlated with the expression of the inducible form of nitric oxide (NO) synthase (iNOS) and NO production. However, SIRT1 overexpression completely prevented cytokine-mediated cytotoxicity, NO production, and iNOS expression. The molecular mechanism by which SIRT1 inhibits iNOS expression appeared to involve the inhibition of the NF-kappaB signaling pathway through deacetylation of p65. In addition, SIRT1 activation by either resveratrol or adenoviral-directed overexpression of SIRT1 could prevent cytokine toxicity and maintain normal insulin-secreting responses to glucose in isolated rat islets. This study will provide valuable information not only into the mechanisms underlying beta-cell destruction but also into the regulation of SIRT1 as a possible target to attenuate cytokine-induced beta-cell damage.
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Inflammation plays a role in trans-10, cis-12 (10,12)-conjugated linoleic acid (CLA)-mediated delipidation and insulin resistance in adipocytes. Given the anti-inflammatory role of resveratrol (RSV), we hypothesized that RSV would attenuate inflammation and insulin resistance caused by 10,12 CLA in human adipocytes. RSV blocked 10,12 CLA induction of the inflammatory response by preventing activation of extracellular signal-related kinase and induction of inflammatory gene expression (i.e., IL-6, IL-8, IL-1beta) within 12 h. Similarly, RSV suppressed 10,12 CLA-mediated activation of the inflammatory prostaglandin pathway involving phospholipase A(2), cyclooxygenase-2, and PGF(2alpha). In addition, RSV attenuated 10,12 CLA increase of intracellular calcium and reactive oxygen species associated with cellular stress, and activation of stress-related proteins (i.e., activating transcription factor 3, JNK) within 12 h. 10,12 CLA-mediated insulin resistance and suppression of fatty acid uptake and triglyceride content were attenuated by RSV. Finally, 10,12 CLA-mediated decrease of peroxisome proliferator-activated receptor gamma (PPARgamma) protein levels and activation of a peroxisome proliferator response element (PPRE) reporter were prevented by RSV. RSV increased the basal activity of PPRE, suggesting that RSV increases PPARgamma activity. Collectively, these data demonstrate for the first time that RSV prevents 10,12 CLA-mediated insulin resistance and delipidation in human adipocytes by attenuating inflammation and cellular stress and increasing PPARgamma activity.
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Diabetes mellitus is a chronic disease that is growing in prevalence worldwide. Pharmacologic therapy is often necessary to achieve optimal glycemic control in the management of diabetes. Orally administered antihyperglycemic agents (OHAs) can be used either alone or in combination with other OHAs or insulin. The number of available OHAs has increased significantly in the last decade, which translates into more therapeutic options and complex decision-making for physicians. This review article is designed to help with these decisions. We review the mechanism of action, efficacy and side effects of the different classes of OHAs (alpha-glucosidase inhibitors, biguanides, insulin secretagogues, insulin sensitizers and intestinal lipase inhibitor) and discuss the current recommendations for their use.
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The resveratrol-induced cardiac protection was studied in Zucker obese rats. Rats were divided into five groups: group 1, lean control; group 2, obese control (OC); group 3, obese rats treated orally with 5 mg kg(-1) day(-1) of resveratrol (OR) for 2 wk; group 4, obese rats received 10% glucose solution ad libitum for 3 wk (OG); and group 5, obese rats received 10% glucose for 3 wk and resveratrol (OGR) during the 2nd and 3rd wk. Body weight, serum glucose, and insulin were measured, and then hearts were isolated and subjected to 30 min of ischemia followed by 120 min of reperfusion. Heart rate, coronary flow, aortic flow, developed pressure, the incidence of reperfusion-induced ventricular fibrillation, and infarct size were measured. Resveratrol reduced body weight and serum glucose in the OR compared with the OC values (414 +/- 10 g and 7.08 +/- 0.41 mmol/l, respectively, to 378 +/- 12 g and 6.11 +/- 0.44 mmol/l), but insulin levels were unchanged. The same results were obtained for the OG vs. OGR group. Resveratrol improved postischemic cardiac function in the presence or absence of glucose intake compared with the resveratrol-free group. The incidence of ventricular fibrillation and infarct size was reduced by 83 and 20% in the OR group, and 67 and 16% in the OGR group, compared with the OC and OG groups, respectively. Resveratrol increased GLUT-4 expression and reduced endothelin expression and cardiac apoptosis in ischemic-reperfused hearts in the presence or absence of glucose intake. Thus the protective effect of resveratrol could be related to its direct effects on the heart.
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  Flavonoids are usually found in fruits and other plant organs and therefore widely consumed. They are antioxidants, anti-inflammatory, anticarcinogenic, and protective against coronary disease and metabolic disorders. These beneficial effects make them good candidates for the development of new functional foods with potential protective/preventive properties against several diseases. We must consider that this fact could lead to a higher intake of some of these flavonoids. Most of the studies concerning their beneficial effects showed peripheral activity of these molecules, but there is no clear information about their central effects on a key organ on metabolic control: the endocrine pancreas. The pancreas has an endocrine function of major importance to regulate nutrient metabolism, such as control of glucose homeostasis via insulin and glucagon secretion. Its importance in whole body nutrient equilibrium is highlighted by the fact that several pathologies, such as type 1 and/or 2 diabetes, are related at some point to a pancreatic cell deregulation. In this review, we compile the most relevant results concerning the effects of flavonoids on several aspects of pancreatic functionality. Studies using animals with drug-induced diabetes support the hypothesis that flavonoids can ameliorate this pathogenesis. The great diversity of flavonoid structures makes it difficult to establish common effects in the pancreas. Published data suggest that there might be direct effects of flavonoids on insulin secretion, as well as on prevention of beta-cell apoptosis, and they could even act via modulation of proliferation. The mechanisms of action involve mainly their antioxidant properties, but other pathways might also take place.
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Resveratrol is a polyphenolic phytoalexin produced in appreciable amounts as a secondary metabolite in grapevines in response to fungal infections. Based on the present knowledge, it appears to be a promising bioactive natural molecule with potential applications in phytotherapy or pharmacology. The present study was aimed to evaluate the antidiabetic properties of resveratrol in streptozotocin-nicotinamide induced experimental diabetes in rats. The diabetic rats orally treated with resveratrol (5 mg kg(-)(1)b.w d(-)(1)) for 30 days resulted in significant (p<0.05) decrease in the levels of blood glucose, glycosylated hemoglobin, blood urea, serum uric acid, serum creatinine and diminished activities of pathophysiological enzymes such as aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP). The antihyperglycemic nature of resveratrol is also evidenced from the improvement in the levels of plasma insulin and hemoglobin. Further, the results are comparable with glyclazide, an oral standard drug. Thus, the present findings suggest that resveratrol may be considered as an effective therapeutic agent for the treatment of diabetes mellitus.
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Resveratrol and genistein are plant-derived compounds known to exert pleiotropic effects in many cell types, including adipocytes. However, the effects of these compounds on the energetic status of fat cells are unknown. The present study aimed to determine whether resveratrol and genistein influence adenosine triphosphate (ATP) levels in freshly isolated rat adipocytes. To determine the effects of resveratrol and genistein on adipocyte ATP content, cells were exposed to insulin and glucose or insulin and alanine without tested compounds or with 6.25 to 50 μmol/L resveratrol or genistein. Resveratrol substantially reduced glucose- and alanine-derived ATP in adipocytes. This was not due to the inhibition of glucose transport because the influence of the test compound on insulin-stimulated glucose uptake by adipocytes appeared to be stimulatory. Moreover, resveratrol reduced both alanine oxidation and mitochondrial membrane hyperpolarization. It was also demonstrated that preincubation of cells with resveratrol slightly diminished ATP levels despite the withdrawal of the tested compound from the buffer. The genistein effect was accompanied by attenuation of the mitochondrial membrane hyperpolarization. The compound failed to significantly affect insulin-stimulated glucose uptake by fat cells. Similarly to resveratrol, preincubation of adipocytes with genistein slightly reduced ATP in cells exposed to glucose and insulin. Results of the present study revealed the potent ability of resveratrol to reduce ATP in rat adipocytes, whereas genistein appeared to be less effective. It is suggested that both tested compounds diminish adipocyte ATP via attenuation of the metabolic activity of mitochondria. Because numerous cellular events are strongly ATP dependent, the ATP-depleting effects of resveratrol and genistein may have pleiotropic consequences for adipocyte functions.
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In the present study, resveratrol, a polyphenolic SIRT1 activator was evaluated for its SIRT1 activation in an in vitro fluorescent based assay (EC(50) : 7 μM). The efficacy of resveratrol was also evaluated in ob/ob mice for its antidiabetic and associated metabolic effects. Mice aged 5-8 weeks were included in four groups; control and resveratrol at 5, 15, 50 mg/kg, b.i.d. and were dosed orally. After 4 weeks of drug treatment, body weights were noted and random blood glucose and insulin was estimated for the antidiabetic effect. Animals were also subjected to the oral glucose tolerance test to observe any improvement in the glucose excursion. Triglycerides, total cholesterol, adiponectin and free fatty acid levels were also estimated. The results showed that resveratrol exhibited significant antihyperglycemic activity with an improvement in the insulin levels compared with the control mice. There was also a significant improvement observed in the glucose excursion in the oral glucose tolerance test performed for 120 min; although an insignificant improvement in the triglycerides, total cholesterol, adiponectin and free fatty acid levels was observed at different doses of resveratrol tested. The present findings suggest that resveratrol is an antihyperglycemic agent and drugs similar to resveratrol can be considered as an effective therapeutic adjuvant for the current treatment of diabetes mellitus.
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Recently resveratrol, a compound naturally occurring in various plants, has been proposed as a potential anti-obesity compound. The aim of the present work was to analyse the effects of different doses of resveratrol on body fat and serum parameters in rats. Thirty-two male Sprague-Dawley rats were randomly divided into four groups and fed on a hypercaloric diet for 6 weeks. The doses oftrans-resveratrol used were 6, 30 and 60 mg/kg body weight/d in RSV1, RSV2 and RSV3 groups respectively. The stability of resveratrol when added to the diet was evaluated. Blood samples were collected, and white adipose tissue from different anatomical locations, interscapular brown adipose tissue, gastrocnemious muscles and liver were weighed. Commercial kits were used to measure serum cholesterol, glucose, triacylglycerols and non-esterified fatty acids. While the lowest dose did not have a body fat reducing effect, the intermediate dose reduced all the white adipose depots. The highest dose significantly reduced mesenteric and subcutaneous depots but not epididymal and perirenal tissues. Although the reduction in all the anatomical locations analysed was 19% in the RSV3 group, in the RSV2 group it was 24%. No significant differences among the experimental groups were found in brown adipose tissue, gastrocnemious muscle or liver weights. Serum parameters were not affected by resveratrol intake because no differences among the experimental groups were observed. These results suggest that resveratrol is a molecule with potential anti-obesity effect. The most effective of the three experimental doses was 30 mg/kg body weight/d.
Article
Chronic exposure of pancreatic beta-cells to supraphysiologic glucose causes adverse beta-cell dysfunction. Thus, the present study was aimed to investigate the hypothesis that oral administration of resveratrol attenuates hyperglycemia, proinflammatory cytokines and antioxidant competence and protects beta-cell ultrastructure in streptozotocin-nicotinamide-induced diabetic rats. Oral administration of resveratrol (5 mg/kg body weight) to diabetic rats for 30 days showed a significant decline in the levels of blood glucose, glycosylated hemoglobin (HbA1c), TNF-alpha, IL-1beta, IL-6, NF-kappaB p65 unit and nitric oxide (NO) with concomitant elevation in plasma insulin. Further, resveratrol treated diabetic rats elicited a notable attenuation in the levels of lipid peroxides, hydroperoxides and protein carbonyls in both plasma and pancreatic tissues. The diminished activities of pancreatic superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione-S-transferase (GST) as well as the decreased levels of plasma ceruloplasmin, vitamin C, vitamin E and reduced glutathione (GSH) in diabetic rats were reverted to near normalcy by resveratrol administration. Based on histological and ultrastructural observations, it is first-time reported that the oral administration of resveratrol may effectively rescue beta-cells from oxidative damage without affecting their function and structural integrity. The results of the present investigation demonstrated that resveratrol exhibits significant antidiabetic potential by attenuating hyperglycemia, enhancing insulin secretion and antioxidant competence in pancreatic beta-cells of diabetic rats.
Article
Resveratrol belongs to the large group of biologically active substances found in plants. This compound is classified as phytoestrogen because of its ability to interact with estrogen receptor. Numerous beneficial effects of resveratrol described in the literature involve cardioprotective, anti-cancer, anti-inflammatory and antioxidant action. Recently, this broad spectrum of effects is enlarged by new data demonstrating a great potency of this compound in relation to obesity and diabetes. It is well established that resveratrol exerts beneficial effects in rodents fed a high-calorie diet. In some studies, resveratrol was reported to reduce body weight and adiposity in obese animals. The action of this compound involves favourable changes in gene expressions and in enzyme activities. The accumulating evidence also indicates the benefits of resveratrol in diabetes and diabetic complications. It is known that resveratrol affects insulin secretion and blood insulin concentration. In animals with hyperinsulinemia, resveratrol was found to reduce blood insulin. Moreover, numerous data indicate that in diabetic rats, resveratrol is able to reduce hyperglycemia. The mechanism of resveratrol's action is complex and is demonstrated to involve both insulin-dependent and insulin-independent effects. These data point to the potential possibility of use of resveratrol in preventing and/or treating both obesity and diabetes.
Article
Resveratrol, a polyphenol found in several vegetal sources, has been shown to possess lifespan-promoting properties in yeast and metazoans, including small mammals. While in yeast and low metazoans resveratrol acts mainly by activating the histone deacetylase Sir2, in mammals it appears to target - besides the Sir2 homolog SIRT1 - several crucial pathways for the control of metabolism, including the AMPK and the insulin-IGF1 receptors axis. The action of resveratrol on these pathways has been linked to its capability to i) prolong lifespan following chronic administration to mice and ii) protect from the development of diet-induced obesity and obesity-dependent metabolic disorders. Here we summarise the current understanding on how resveratrol displays its remarkable properties by acting on the control of insulin secretion and by modulation of insulin action in pheripheral insulin-responsive tissues. Since resveratrol has the potential for pharmacological exploitation to prevent the establishment of insulin-resistance and thus postpone - or even prevent - the onset of type 2 diabetes, toxicologic and pharmacodynamics studies in humans have been initiated. These studies show that resveratrol is non-toxic and easily absorbed by humans. As a drawback, its bioavailability is very limited due to the fast metabolic alterations to which it is subjected in the plasma. Therefore, we also review here the efforts that have been made - in the drug discovery field - to identify new molecules endowed with resveratrol-like pharmacological properties but with better bioavailability, which could prove to possess therapeutic potential.
Article
The aim of the present study was to investigate the effects of resveratrol (RV), an important neuroprotective compound on NTPDase, 5'-nucleotidase and acetylcholinesterase (AChE) activities in cerebral cortex synaptosomes of streptozotocin (STZ)-induced diabetic rats. The animals were divided into six groups (n=8): control/saline; control/RV 10mg/kg; control/RV 20mg/kg; diabetic/saline; diabetic/RV 10mg/kg; diabetic/RV 20mg/kg. After 30 days of treatment with resveratrol the animals were sacrificed and the cerebral cortex was removed for synaptosomes preparation and enzymatic assays. The results demonstrated that NTPDase and 5'-nucleotidase activities were significantly increased in the diabetic/saline group (p<0.05) compared to control/saline group. Treatment with resveratrol significantly increased NTPDase, 5'-nucleotidase activities in the diabetic/RV10 and diabetic/RV20 groups (p<0.05) compared to diabetic/saline group. When resveratrol was administered per se there was also an increase in the activities of these enzymes in the control/RV10 and control/RV20 groups (p<0.05) compared to control/saline group. AChE activity was significantly increased in the diabetic/saline group (p<0.05) compared to control/saline group. The treatment with resveratrol prevented this increase in the diabetic/RV10 and diabetic/RV20 groups. In conclusion, this study demonstrated that the resveratrol interfere with the purinergic and cholinergic neurotransmission by altering NTPDase, 5'-nucleotidase and AChE activities in cerebral cortex synaptosomes of diabetic rats. In this context, we can suggest that resveratrol should be considered potential therapeutics and scientific tools to be investigated in brain disorders associated with the diabetes.
Article
The estrogen receptor ERalpha is emerging as a key molecule involved in glucose and lipid metabolism. The main functions of pancreatic beta-cells are the biosynthesis and release of insulin, the only hormone that can directly decrease blood glucose levels. Estrogen receptors ERalpha and ERbeta exist in beta-cells. The role of ERbeta is still unknown, yet ERalpha plays an important role in the regulation of insulin biosynthesis, insulin secretion and beta-cell survival. Activation of ERalpha by 17beta-estradiol (E2) and the environmental estrogen bisphenol-A (BPA) promotes an increase of insulin biosynthesis through a non-classical estrogen-activated pathway that involves phosphorylation of ERK1/2. The activation of ERalpha by physiological concentrations of E2 may play an important role in the adaptation of the endocrine pancreas to pregnancy. However, if ERalpha is over stimulated by an excess of E2 or the action of an environmental estrogen such as BPA, it will produce an excessive insulin signaling. This may provoke insulin resistance in the liver and muscle, as well as beta-cell exhaustion and therefore, it may contribute to the development of type II diabetes.
Article
The beneficial action of moderate wine consumption is increasingly being attributed to resveratrol (trans-3,4',5-trihydroxystilbene). To test the safety of resveratrol use as a dietary supplement, 24 male Wistar rats were initially divided into three groups: (C, n=6) was given standard chow and water; (R, n=6) received standard chow and 6 mg/l resveratrol in its drinking water (1mg/kg/day), and (HFD, n=12) received high-fat diet and water. In order to more appropriately study the effects of resveratrol on high-fat diet, after 30 days of treatments, HFD-rats were divided into two subgroups (n=6/group):(HFD) remained receiving high-fat diet and water; (HFD-R) given high-fat diet and 6 mg/l resveratrol in its drinking water (1mg/kg/day). The total experimental period was 45 days. The resveratrol dose took into account its average concentration in wine, the time variability of wine ingestion, and so of resveratrol consumption in humans. HFD-rats had hyperglycaemia, dyslipidemia, increased serum oxidized-LDL (ox-LDL) and hepatic oxidative stress. Comparing HFD-R and HFD-rats, resveratrol improved lipid profile and glucose level, enhanced superoxide dismutase, thus reducing ox-LDL and hepatic oxidative stress. Resveratrol, in standard-fed-rats reduced glutathione-antioxidant defense system and enhanced hepatic lipid hydroperoxide. In conclusion, based on the results of this single dose preliminary study with resveratrol in the drinking water of male Wistar rats for 30 days, it may be concluded that resveratrol may have beneficial effects in high-fat diets (e.g. ox-LDL, decreased serum and hepatic oxidativestress), but not in standard-fed diets (effects produced include enhanced hepatic oxidative stress). Further studies are indicated.
Article
Diabetes mellitus is associated with platelet alterations that may contribute to the development of cardiovascular complications. The present study investigates the effects of resveratrol (RSV), an important compound with cardioprotective activities, on NTPDase, ecto-nucleotide pyrophosphatase/phosphodiesterase (E-NPP), 5'-nucleotidase and adenosine deaminase (ADA) activities in platelets from streptozotocin (STZ)-induced diabetic rats. The animals were divided into six groups (n=8): control/saline; control/RSV 10 mg/kg; control/RSV 20 mg/kg; diabetic/saline; diabetic/RSV 10 mg/kg; diabetic/RSV 20 mg/kg. RSV was administered during 30 days and after this period the blood was collected for enzymatic assay. The results demonstrated that NTPDase, E-NPP and 5'-nucleotidase activities were significantly higher in the diabetic/saline group (P<0.05) compared to control/saline group. Treatment with RSV significantly increased NTPDase, 5'-nucleotidase and E-NPP activities in the diabetic/RSV10 and diabetic/RSV20 groups (P<0.05) compared to diabetic/saline group. When RSV was administered per se there was also an increase in the activities of these enzymes in the control/RSV10 and control/RSV20 groups (P<0.05) compared to control/saline group. ADA activity was significantly increased in the diabetic/saline group (P<0.05) compared to control/saline group. The treatment with RSV prevented this increase in the diabetic/RSV10 and diabetic/RSV20 groups. No significant differences in ADA activity were observed in the control/RSV10 and control/RSV20 compared to control/saline group. The present findings demonstrate alterations in nucleotide hydrolysis in platelets of STZ-induced diabetic rats and treatment with RSV was able to modulate adenine nucleotide hydrolysis, which may be important in the control of the platelet coagulant status in diabetes.
Article
Resveratrol is a natural polyphenolic stilbene derivative found in several human diet components that possess important and wide-ranging effects in biological systems including anticancer, anti-inflammatory, antioxidant, cardio-protective, and anti-ageing actions and beneficial properties against metabolic diseases. This study addresses the effects of long-term administration of resveratrol on several functional alterations arising from the metabolic syndrome experimental model of obese Zucker rats, and the possible mechanisms involved. The high plasma concentrations of triglycerides, total cholesterol, free fatty acids, insulin and leptin found in obese Zucker rats were reduced in obese rats that received resveratrol. Furthermore, the elevated hepatic lipid content was significantly lower in obese rats treated with resveratrol, an effect which was related to the increased phosphorylation of 5'-AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in the liver of these animals. Resveratrol treatment also improved the inflammatory status peculiar to this model, as it increased the concentration of adiponectin and lowered tumor necrosis factor-alpha production in the visceral adipose tissue (VAT) of obese Zucker rats. Moreover, chronic intake of resveratrol enhanced VAT eNOS expression among obese Zucker rats. These effects parallel the activation of AMPK and inhibition by phosphorylation of ACC in this tissue. The raised systolic blood pressure and reduced aortic eNOS expression found in obese Zucker rats were significantly improved in the resveratrol-treated obese rats. In conclusion, resveratrol improved dyslipidemia, hyperinsulinemia, hyperleptinemia and hypertension in obese Zucker rats, and produced anti-inflammatory effects in VAT, effects that seem to be mediated by AMPK activation.
Article
Resveratrol, a ubiquitous stress-induced phytoalexin, has demonstrated a wide variety of biological activities which make it a good candidate for the treatment of diabetes mellitus. The present study was aimed to evaluate its therapeutic potential by assaying the activities of key enzymes of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats. The daily oral treatment of resveratrol (5 mg/kg body weight) to diabetic rats for 30 days demonstrated a significant (p<0.05) decline in blood glucose and glycosylated hemoglobin levels and a significant (p<0.05) increase in plasma insulin level. The altered activities of the key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in liver and kidney tissues of diabetic rats were significantly (p<0.05) reverted to near normal levels by the administration of resveratrol. Further, resveratrol administration to diabetic rats improved hepatic glycogen content suggesting the antihyperglycemic potential of resveratrol in diabetic rats. The obtained results were compared with glyclazide, a standard oral hypoglycemic drug. Thus, the modulatory effects of resveratrol on attenuating these enzymes activities afford a promise for widespread use for treatment of diabetes in the future.
Article
Resveratrol is a naturally occurring diphenolic compound exerting numerous beneficial effects in the organism. The present study demonstrated its short-term, direct influence on lipogenesis, lipolysis and the antilipolytic action of insulin in freshly isolated rat adipocytes. In fat cells incubated for 90 min with 125 and 250 μM resveratrol (but not with 62.5 μM resveratrol), basal and insulin-induced lipogenesis from glucose was significantly reduced. The antilipogenic effect was accompanied by a significant diminution of CO2 release and enhanced production of lactate. The inhibition of glucose conversion to lipids found in the presence of resveratrol was not attenuated by activator of protein kinase C. However, acetate conversion to lipids appeared to be insensitive to resveratrol.
Article
To study the effect of resveratrol on the nonalcoholic fatty liver (NAFL). Thirty Wistar rats were allocated into three groups (10 for each): a normal control group (NC, fed with standard chow), a high fat feeding group (HF, fed with a high fat diet) and a resveratrol treated group (RT). The RT rats were fed a high fat diet all the time (as the HF) and received resveratrol administration (100 mg . kg-1. d-1) started on the 6th week of the experiment. The experiment lasted for 16 weeks. Then all the rats were sacrificed and hyperinsulinemic-euglycemic clamp was performed to evaluate insulin sensitivity. Liver histology was studied by HE stained microscopic preparations of the livers. Phosphorylation of AMP-activated protein kinase (AMPK) levels were determined by Western blot. Compared to the NC, visceral fat index and liver mass index was lower and fasting serum insulin (FINS) was higher and glucose infusion rate (GIR) was lower in the HF (t=10.554, P less than 0.01). Severe liver steatosis was observed microscopically in the HF. In addition, phosphorylation of AMPK levels in the HF was 45.8% lower than that of the NC (t=8.384, P less than 0.01). Compared with the HF, the visceral fat index, liver mass index, FINS and GIR were all much lower, and the liver steatosis was milder than those in the RT. Further phosphorylation of AMPK seen was 70.2% higher in RT compared with that in the NC (t=3.816, P less than 0.01). Resveratrol administration improved high-fat feeding induced insulin resistance and fatty liver by activating AMPK.
Article
The association of obesity with type 2 diabetes has been recognized for decades, and the major basis for this link is the ability of obesity to engender insulin resistance. Insulin resistance is a fundamental aspect of the etiology of type 2 diabetes and is also linked to a wide array of other pathophysiologic sequelae including hypertension, hyperlipidemia, atherosclerosis (i.e., the metabolic syndrome, or syndrome X), and polycystic ovarian disease (1). Although many details of the mechanisms by which the enlarged adipose tissue mass that defines obesity causes systemic insulin resistance remain unknown, the past several years have witnessed an explosive increase in our understanding of what may now be referred to as the adipo-insulin axis. There are also grounds for considering the related possibility that insulin resistance and hyperinsulinemia, in addition to being caused by obesity, can contribute to the development of obesity. In this Perspective, we will review recent progress, highlight areas of controversy or uncertainty, and suggest approaches to clarifying the unresolved issues.
Article
Glucose stimulates insulin secretion by generating triggering and amplifying signals in beta-cells. The triggering pathway is well characterized. It involves the following sequence of events: entry of glucose by facilitated diffusion, metabolism of glucose by oxidative glycolysis, rise in the ATP-to-ADP ratio, closure of ATP-sensitive K+ (KATP) channels, membrane depolarization, opening of voltage-operated Ca2+ channels, Ca2+ influx, rise in cytoplasmic free Ca2+ concentration ([Ca2+]i), and activation of the exocytotic machinery. The amplifying pathway can be studied when beta-cell [Ca2+]i is elevated and clamped by a depolarization with either a high concentration of sulfonylurea or a high concentration of K+ in the presence of diazoxide (K(ATP) channels are then respectively blocked or held open). Under these conditions, glucose still increases insulin secretion in a concentration-dependent manner. This increase in secretion is highly sensitive to glucose (produced by as little as 1-6 mmol/l glucose), requires glucose metabolism, is independent of activation of protein kinases A and C, and does not seem to implicate long-chain acyl-CoAs. Changes in adenine nucleotides may be involved. The amplification consists of an increase in efficacy of Ca2+ on exocytosis of insulin granules. There exists a clear hierarchy between both pathways. The triggering pathway predominates over the amplifying pathway, which remains functionally silent as long as [Ca2+]i has not been raised by the first pathway; i.e., as long as glucose has not reached its threshold concentration. The alteration of this hierarchy by long-acting sulfonylureas or genetic inactivation of K(ATP) channels may lead to inappropriate insulin secretion at low glucose. The amplifying pathway serves to optimize the secretory response not only to glucose but also to nonglucose stimuli. It is impaired in beta-cells of animal models of type 2 diabetes, and indirect evidence suggests that it is altered in beta-cells of type 2 diabetic patients. Besides the available drugs that act on K(ATP) channels and increase the triggering signal, novel drugs that correct a deficient amplifying pathway would be useful to restore adequate insulin secretion in type 2 diabetic patients.
Article
Type 2 diabetes mellitus is a heterogeneous disorder characterized by 2 pathogenic defects, impaired insulin secretion and insulin resistance. The resultant hyperglycemia causes microvascular and macrovascular complications that increase morbidity and mortality in patients with diabetes mellitus. Optimum glycemic control in patients with type 1 and type 2 diabetes mellitus prevents the development of microvascular disease and, to a lesser extent, macrovascular disease. Prandial hyperglycemia may be an independent risk factor for the development of diabetic complications. This article reviews the pathophysiologic mechanisms of glucose metabolism and describes the results of epidemiological and interventional studies that have demonstrated the association of acute and chronic hyperglycemia with the development of diabetic complications. The American Diabetes Association has defined diagnostic and treatment goals for diabetes mellitus, striving to achieve near-normal glycemic control to delay or prevent the development of diabetic complications. A number of oral antidiabetic agents and insulins are currently available for the treatment of type 2 diabetes mellitus in the United States. These agents target fasting and postmeal plasma glucose levels to improve glycemic control. Alone or in combination, these agents have enhanced the clinical approaches to treating diabetes mellitus.
Article
Mitochondrial metabolism is crucial for the coupling of glucose recognition to the exocytosis of the insulin granules. This is illustrated by in vitro and in vivo observations discussed in the present review. Mitochondria generate ATP, which is the main coupling messenger in insulin secretion. However, the subsequent Ca2+ signal in the cytosol is necessary but not sufficient for full development of sustained insulin secretion. Hence, mitochondria generate ATP and other coupling factors serving as fuel sensors for the control of the exocytotic process. Numerous studies have sought to identify the factors that mediate the amplifying pathway over the Ca2+ signal in glucose-stimulated insulin secretion. Predominantly, these factors are nucleotides (GTP, ATP, cAMP, NADPH), although metabolites have also been proposed, such as long-chain acyl-CoA derivatives and glutamate. Hence, the classical neurotransmitter glutamate receives a novel role, that of an intracellular messenger or co-factor in insulin secretion. This scenario further highlights the importance of glutamate dehydrogenase, a mitochondrial enzyme well recognized to play a key role in the control of insulin secretion. Therefore, additional putative messengers of mitochondrial origin are likely to participate in insulin secretion.
Article
The pattern of insulin release is crucial for regulation of glucose and lipid haemostasis. Deficient insulin release causes hyperglycemia and diabetes, whereas excessive insulin release can give rise to serious metabolic disorders, such as nesidioblastosis (Persistent Hyperinsulinemic Hypoglycemia of Infancy, PHHI) and might also be closely associated with development of type 2 diabetes and obesity. Type 2 diabetes is characterized by fasting hyperinsulinemia, insulin resistance and impaired insulin release, i.e. reduced first phase insulin release and decreased insulin pulse mass. The beta cell function of patients with type 2 diabetes slowly declines and will ultimately result in beta cell failure and increasing degrees of hyperglycemia. Type 2 diabetes, in combination with obesity and cardiovascular disorders, forms the metabolic syndrome. It has been possible to improve beta cell function and viability in preclinical models of type 1 and type 2 diabetes by reducing insulin secretion to induce beta cell rest. Clinical studies have furthermore indicated that inhibitors of insulin release will be of benefit in treatment or prevention of diabetes and obesity. Pancreatic beta cells secrete insulin in response to increased metabolism and by stimulation of different receptors. The energy status of the beta cell controls insulin release via regulation of open probability of the ATP sensitive potassium (K(ATP)) channels to affect membrane potential and the intracellular calcium concentration [Ca(2+)](i). Other membrane bound receptors and ion channels and intracellular targets that modulate [Ca(2+)](i)will affect insulin release. Thus, insulin release is regulated by e.g. somatostatin receptors, GLP-1 receptors, muscarinic receptors, cholecystokinin receptors and adrenergic receptors. Although the relationship between hyperinsulinemia and certain metabolic diseases has been known for decades, only a few inhibitors of insulin release have been characterized in vitro and in vivo. These include the K(ATP) channel openers diazoxide and NN414 and the somatostatin receptor agonist octreotide.
Article
Aberrant energy metabolism is one characteristic of diabetes mellitus (DM). Two types of DM have been identified, type 1 and type 2. Most of type 2 DM patients eventually become insulin dependent because insulin secretion by the islets of Langerhans becomes exhausted. In the present study, we show that resveratrol (3,5,4'-trihydroxylstilbene) possesses hypoglycemic and hypolipidemic effects in streptozotocin-induced DM (STZ-DM) rats. In resveratrol-treated STZ-DM rats, the plasma glucose concentration on day 14 was reduced by 25.3 +/- 4.2%, and the triglyceride concentration was reduced by 50.2 +/- 3.2% compared with the vehicle-treated rats. In STZ-nicotinamide DM rats, the plasma glucose concentration on day 14 was reduced by 20.3 +/- 4.2%, and the triglyceride concentration was reduced by 33.3 +/- 2.2% compared with the vehicle-treated rats. Resveratrol administration ameliorates common DM symptoms, such as body weight loss, polyphagia, and polydipsia. In STZ-nicotinamide DM rats, resveratrol administration significantly decreased insulin secretion and delayed the onset of insulin resistance. Further studies showed that glucose uptake by hepatocytes, adipocytes, and skeletal muscle and hepatic glycogen synthesis were all stimulated by resveratrol treatment. Because the stimulation of glucose uptake was not attenuated in the presence of an optimal amount of insulin in insulin-responsive cells, the antihyperglycemic effect of resveratrol appeared to act through a mechanism(s) different from that of insulin.
Article
Molecular mechanisms involving oxidative stress have been increasingly implicated in the pathogenesis of type 2 diabetes. These implications have arisen from reports that glucolipotoxicity of the pancreatic islet and non-islet tissues can lead to deterioration of islet function and insulin sensitivity, as well as structural abnormalities in tissues adversely affected by diabetes. Co-incident with these changes are profound alterations in insulin gene expression, which involve greatly diminished levels of two transcription factors, MafA and Pdx-1.
Article
Resveratrol is a naturally occurring phytoalexin exerting cardioprotective, anticancer and antioxidant action. The most recent investigations have demonstrated that this compound plays a beneficial role alleviating some diabetic complications. However, resveratrols' influence on the endocrine function of the pancreas is unknown. The objective of the present study was to determine whether resveratrol affects insulin secretion from freshly isolated rat pancreatic islets. Incubations of pancreatic islets with resveratrol (1-100 microM, 90 min) revealed that the release of insulin induced by 6.6 and 16.6 mM glucose was substantially restricted by this compound in a concentration-dependent manner. This effect was not permanent and disappeared after resveratrol withdrawal from the buffer. However, the proper hormone secretion was not restored when glucose was replaced by other secretagogues - leucine with glutamine - indicating that disturbances other than the inhibition of glucose transport and glycolysis were responsible for the resveratrol-evoked reduction in insulin secretion. Glucose-induced insulin release tested in the presence of the sulfonylurea glibenclamide was also found to be reduced by resveratrol. Moreover, the activation of adenylyl cyclase by forskolin did not restrict the inhibitory effect of resveratrol on glucose-induced insulin release. In contrast, phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, suppressed completely the inhibitory effect of 1 and 10 microM resveratrol on insulin release. However, this compound at the highest concentration tested diminished its secretion even in the presence of PMA. The perifusion studies revealed that the depression of insulin release caused by resveratrol began a few minutes after its addition to the medium. Results obtained in the present investigations demonstrate that resveratrol is a compound exerting a clear-cut, but reversible inhibitory effect on insulin secretion from isolated pancreatic islets.
Article
Resveratrol, a polyphenolic substance found in grape skin, is proposed to account in part for the protective effect of red wine in the cardiovascular system. The aim of the present study is to investigate the action and possible mechanisms of resveratrol-produced regulation of plasma glucose in normal and diabetic rats including the animal model of streptozotocin (STZ)-induced and nicotinamide-STZ-induced (NA-STZ), and insulin-resistant diabetic rats. Resveratrol (p.o.) produced a hypoglycemic effect in a dose-dependent manner in normal and diabetic rats, and the insulin level was increased following resveratrol treatment in normal and NA-STZ diabetic rats. In insulin-deficient STZ-diabetic rats, resveratrol significantly lowered the plasma glucose 90 min after oral treatment, and the hypoglycemic effect was abolished by phosphatidyl-3-kinase (PI3K) inhibitors (LY294002 and wortmannin) which also inhibited resveratrol-induced Akt phosphorylation in soleus muscle of STZ-diabetic rats. The change in the protein expression level of glucose transporter subtype 4 (GLUT4) in the soleus muscle and phosphoenolpyruvate carboxykinase (PEPCK) in the liver of STZ-diabetic rats treated with resveratrol (3 mg/kg, p.o.) for 7 days was examined. Resveratrol normalized hepatic PEPCK expression and increased GLUT4 expression in the soleus muscle of STZ-diabetic rats. The results indicate that the mechanisms contributing to the hypoglycemic effect of resveratrol include insulin-dependent and insulin-independent pathway, and PI3K-Akt-signaling was involved in the latter mechanism to enhance glucose uptake in skeletal muscle.
Article
Resveratrol is a stilbene present in different plant species and exerting numerous beneficial effects, including prevention of diabetes and attenuation of some diabetic complications. Its inhibitory effect on insulin secretion was recently documented, but the exact mechanism underlying this action remains unknown. Experiments employing diazoxide and a high concentration of K(+) revealed that, in depolarized pancreatic islets incubated for 90 min with resveratrol (1, 10, and 100 microM), insulin secretion stimulated by glucose and leucine was impaired. The attenuation of the insulin secretory response to 6.7 mM glucose was not abrogated by blockade of intracellular estrogen receptors and was found to be accompanied by diminished islet glucose oxidation, enhanced lactate production, and reduced ATP levels. Glucose-induced hyperpolarization of the mitochondrial membrane was also reduced in the presence of resveratrol. Moreover, in depolarized islets incubated with 2.8 mM glucose, activation of protein kinase C or protein kinase A potentiated insulin release; however, under these conditions, resveratrol was ineffective. Further studies also revealed that, under conditions of blocked voltage-dependent calcium channels, the stilbene reduced insulin secretion induced by a combination of glucose with forskolin. These data demonstrate that resveratrol 1) inhibits the amplifying pathway of insulin secretion, 2) exerts an insulin-suppressive effect independently of its estrogenic/anti-estrogenic activity, 3) shifts islet glucose metabolism from mitochondrial oxidation to anaerobic,4) fails to abrogate insulin release promoted without metabolic events, and 5) does not suppress hormone secretion as a result of the direct inhibition of Ca(2+) influx through voltage-dependent calcium channels.
Article
Excessive oxidative stress has been implicated in the pathology and complications of diabetes, which leads to myocardial ischemia reperfusion injury. The present study was designed to examine whether resveratrol (trans-3,5,4'-trihydroxystilbene), a polyphenolic compound present in red wine has a direct cardioprotective effect on diabetic myocardium. Resveratrol (2.5 mg/kg body wt/day) and L-NAME (25 mg/kg body wt/day) were administered orally for 15 days to streptozotocin (65 mg/kg)-induced diabetic rats. Sprague Dawley rats were divided into 5 groups: (i) control, (ii) diabetic, (iii) diabetic+resveratrol, (iv) diabetic+resveratrol+L-NAME (nitric oxide synthase inhibitor), and (v) diabetic+L-NAME. In our present study resveratrol demonstrated significant reduction in glucose level in diabetic rats. After the treatment, the hearts were excised and subjected to 30 min of global ischemia followed by 2 h of reperfusion. Resveratrol-treated diabetic rats demonstrated significant reduction in glucose levels as compared to the nontreated diabetic animals, and improved left ventricular function throughout reperfusion compared to the diabetic or L-NAME-treated animals (dp/dt(max) 1457+/-51 vs 999+/-44 mm Hg/s at 120 min reperfusion). Cardioprotection from ischemic injury in resveratrol-treated diabetic rats showed decreased infarct size (42% vs 51%) and cardiomyocyte apoptosis (35% vs 40%) as compared with diabetic animals. Resveratrol produced significant induction of p-AKT, p-eNOS, Trx-1, HO-1, and VEGF in addition to increased activation of MnSOD activity in diabetic animals compared to nondiabetic animals. However treatment with L-NAME in resveratrol-treated and nontreated diabetic animals demonstrated significant downregulation of the above-noted protein expression profile and MnSOD activity. In the present study we found that the mechanism(s) responsible for the cardioprotective effect of resveratrol in the diabetic myocardium include upregulation of Trx-1, NO/HO-1, and VEGF in addition to increased MnSOD activity and reduced blood glucose level. Thus this study shows a novel mechanism of pharmacological preconditioning with resveratrol in the diabetic myocardium.
Article
Insulin resistance is often characterized as the most critical factor contributing to the development of type 2 diabetes. SIRT1 has been reported to be involved in the processes of glucose metabolism and insulin secretion. However, whether SIRT1 is directly involved in insulin sensitivity is still largely unknown. Here we show that SIRT1 is downregulated in insulin-resistant cells and tissues and that knockdown or inhibition of SIRT1 induces insulin resistance. Furthermore, increased expression of SIRT1 improved insulin sensitivity, especially under insulin-resistant conditions. Similarly, resveratrol, a SIRT1 activator, enhanced insulin sensitivity in vitro in a SIRT1-dependent manner and attenuated high-fat-diet-induced insulin resistance in vivo at a dose of 2.5 mg/kg/day. Further studies demonstrated that the effect of SIRT1 on insulin resistance is mediated by repressing PTP1B transcription at the chromatin level. Taken together, the finding that SIRT1 improves insulin sensitivity has implications toward resolving insulin resistance and type 2 diabetes.
Article
Resveratrol, a naturally occurring phytoalexin, is known to exert numerous beneficial effects in the organism. Literature data indicate that this compound may, among other effects, play a role in prevention of diabetes and diabetic complications. Resveratrol was recently found to affect insulin secretion in vitro and to change blood insulin concentrations. These effects are, however, not fully elucidated. In the present study, 1, 10 and 100microM resveratrol incubated for 90min with pancreatic islets isolated from normal rats failed to affect basal insulin release, but substantially impaired the secretory response to physiological and maximally effective glucose. In depolarized islets exposed to resveratrol, succinate-induced insulin secretion was also diminished. The blockade of somatostatin receptors substantially enhanced insulin secretion induced by 6.7mM glucose and simultaneously suppressed the inhibitory effect of 1microM resveratrol, but at 10 and 100microM, resveratrol was still able to attenuate hormone secretion. Acetylcholine clearly increased the insulin-secretory response to 6.7mM glucose and canceled the inhibitory effect of 1microM resveratrol. However, resveratrol at concentrations 10 and 100microM strongly decreased insulin secretion. The direct activation of protein kinase C totally suppressed the inhibitory influence of 1 and 10microM resveratrol on hormone secretion. However, activation of this enzyme appeared to be insufficient to cancel the insulin-suppressive effect of 100microM resveratrol. These data indicate that resveratrol-induced inhibition of insulin secretion may be partially mitigated by suppression of somatostatin action, activation of protein kinase C or the presence of acetylcholine. The in vivo experiment revealed that resveratrol, administered to normal rats at the dose 50mg/kg body weight, diminished blood insulin concentrations at 30min, without concomitant changes in glycemia. These observations point to the direct insulin-suppressive action of resveratrol in the rat.
Article
The concept of ‘β-cell rest’, or suppression of insulin release from β-cells, was originally developed in the context of type 1 diabetes mellitus. Clinicians noted that the initiation of insulin therapy in newly diagnosed patients often led to partial remission, the so-called ‘honeymoon period’, which is characterized by increased endogenous insulin secretion and reduced exogenous insulin requirements. This was first formally documented by Jackson et al. in 1940, who reported ‘a regimen of control designed to approximate normal conditions of metabolism’, which markedly decreased insulin requirements in children with type 1 diabetes (1). The first controlled clinical trial of β-cell rest was performed in the 1970’s, when Mirouze et al. reported increased ‘remission’ rates in patients treated with intensive vs. conventional insulin therapy (2). These and other observations generated the hypothesis that decreased demand on β-cells can improve insulin secretion and β-cell viability. This concept was subsequently expanded into the field of type 2 diabetes (3). In the context of this review, we use the term β-cell rest ‘inclusively’, meaning that the agents used to induce β-cell rest may have many additional beneficial effects on glucose metabolism beyond their direct action on β-cells. Most obvious is the case of exogenous insulin, which ameliorates glucotoxicity and simultaneously reduces endogenous insulin secretion – effects that are difficult to tease apart, especially in the clinical setting. Another important distinction is difficult or impossible to make in the clinical arena: whether improved β-cell function is observed because of more work performed by existing β-cells or by a greater number including new β-cells.
Article
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. In this study we examined resveratrol (RSV)-mediated Glut-4 translocation in the streptozotocin (STZ)-induced diabetic myocardium. The rats were randomized into three groups: Control (Con), Diabetes Mellitus (DM) (STZ 65 mg/kg b.w., i.p.) & DM+RSV (2.5 mg/kg b.wt. for 2 weeks orally) (RSV). Isolated rat hearts were used as per the experimental model. RSV induced glucose uptake was observed in vitro with H9c2 cardiac myoblast cells. Decreased blood glucose level was observed after 30 days (375 mg/dl) in RSV-treated rats when compared to DM (587 mg/dl). Treatment with RSV demonstrated increased Adenosine Mono Phosphate Kinase (AMPK) phosphorylation compared to DM. Lipid raft fractions demonstrated decreased expression of Glut-4, Cav-3 (0.4, 0.6-fold) in DM which was increased to 0.75- and 1.1-fold on RSV treatment as compared to control. Increased Cav-1 expression (1.4-fold) in DM was reduced to 0.7-fold on RSV treatment. Increased phosphorylation of endothelial Nitric Oxide Synthase (eNOS) & Akt was also observed in RSV compared to DM (P<0.05). Confocal microscopy and coimmunoprecipitation studies demonstrated decreased association of Glut-4/Cav-3 and increased association of Cav-1/eNOS in DM as compared to control and converse results were obtained on RSV treatment. Our results suggests that the effect of RSV is non-insulin dependent and triggers some of the similar intracellular insulin signalling components in myocardium such as eNOS, Akt through AMPK pathway and also by regulating the caveolin-1 and caveolin-3 status that might play an essential role in Glut-4 translocation and glucose uptake in STZ- induced type-1 diabetic myocardium.