Nutraceutical prospective: The synergetic mechanism of action of inositols and resveratrol on metabolic syndrome

Open access

Abstract

It has been known that inositols function as insulin second messengers and mediate different insulin-dependent processes and are a valid natural, non-pharmaceutical alternative to contrast insulin-resistance as well as associated metabolic syndrome in women with Polycystic ovarian disease (PCOS). Several studies also have shown positive effects of resveratrol in reducing glucose and lipid concentrations in patients. Recently, clinical evidence has proven that an D-chiro-inositol/resveratrol combination has a potential role to play in maintaining metabolic and endocrine health, however no large clinical trials have demonstrated the medical effectiveness of the combination, and the combined mode of action remains poorly discussed. Herein, we address the hypothesis of a synergistic mechanism adopted by D-chiro-inositol and resveratrol in reducing insulin resistance and hyperlipidemia and thus showing a greater therapeutic potential compared to treatment with inositol’s alone.

Introduction

Metabolic Syndrome (MetS) is a series of symptoms and signs, that recur with singular characteristics (diabetes, obesity, hypertension, ovarian polycytosis, cardiovascular disease)(1, 2). When in MetS, type 2 diabetes predominates, prevalent therapy for glucose intolerance and diabetes is required (3). MetS may occur in pregnancy with prevalence of alterations in glucose metabolism and require proper treatment. Clinical aspects and health benefits of functional foods and nutraceuticals on several metabolic factors have been suggested, however, limited evidence does not allow to draw final conclusions on preventive health strategies and nutritional guidelines that should be encouraged during pregnancy (4). Several studies have shown the positive effects of inositols, D-chiro-inositol (DCI) and Myo-inositol (MI) in reducing glucose and lipid concentrations. In particular studies have demonstrated these effects in prediabetic and diabetic patients in late pregnancy (5, 6, 7, 8, 9). Recent research data also suggests the preventive effect of resveratrol supplementation for the prevention of diabetic embryopathologies (10). Other studies have reported that resveratrol in addition to the combination of inositols (DCI + MI) reduce extracellular glucose levels and extra and intra cellular lipid levels in obese pregnant women (11). Thus, the supplementation with resveratrol could be considered a valid treatment in patients with prediabetic and diabetic glucose intolerance (11, 12).

The central role of insulin resistance in the metabolic syndrome

Insulin resistance (IR) is a pathological condition in which cells, tissues or a whole organism fail to respond normally to the hormone insulin. Consequently, beta cells in the pancreas increase the production of insulin thus leading to excess levels of insulin circulating in the blood. “Compensatory hyperinsulinemia”, is the organism’s response to low cellular glucose, a condition that occurs even if the blood glucose levels remain in the normal range. IR plays a central role in 70–80% of obese women and in 15-30% of lean women diagnosed with PCOS, and portrays the pathogenic link between metabolic and reproductive disorders present in this syndrome (13). Clinical manifestations commonly associated with IR and present in PCOS are hyperandrogenism, menstrual irregularities, and other metabolic manifestations (14). Hyperandrogenism, is a condition in which IR increases the production of gonadotropins, especially luteinizing hormone (15). The elevated levels of circulating insulin in women with PCOS, together with high levels of LH, could determine follicular growth arrest. Follicular development and oocyte growth are indicative of oocyte immaturity, which contribute to the onset of an anovulatory phase (16), and poor oocyte quality (17). The compensatory hyperinsulinemia also leads to altered secretion of gonadotropin-releasing hormone (GnRH) and the inhibition of hepatic production of sex hormone-binding globulin (SHBG). This consecutively leads to an increased concentration of circulating free androgens (18). Consistent with these metabolic and hormonal findings associated with the complex metabolic disorders in PCOS, natural insulin-sensitising molecules, such as inositols could possess great therapeutic potential. These molecules could provide benefit by ameliorating reproductive and metabolic outcomes for women with PCOS.

Inositols in metabolic syndrome

Inositols are a stereoisomeric family, comprised of 9 isomers, myo-, cis-, allo-, epi-, muco-, neo, scylloand, D and L chiro-inositols. Myo-inositol (MI) is found in nature, while D-chiro-inositol (DCI) is a product obtained through the epimerizing hydroxyl of myo-inositol (19). MI and DCI function as insulin second messengers. Thus, inositols can mediate insulin in various insulin-dependent processes (20). MI is converted to an inositolphosphoglycan (IPG) insulin second messenger (MI-IPG) involved in several cellular functions that control the glucose metabolism, such as glucose uptake. DCI is also converted to an IPG insulin second messenger (DCI-IPG), participates in the insulin signaling cascade and is involved in glycogen synthesis (21). Insulin-resistance also increases plasma concentrations of free fatty acid (FFA). The increased levels of FFA is due to increased production from liver and increased mobilization from adipose tissue. Excess of FFA or the reduction of glucose transport activity leads inactivation of pyruvate dehydrogenase (PDH) and other key enzymes. These effects may be a consequence of altered insulin signaling through decreased insulin receptor substrate-1 (IRS-1) associated PI3 kinase activity (22). In fact, restoring inositols levels, with oral supplementations of MI and DCI has been demonstrated to ameliorates insulin-resistance, hyperandrogenism, regularity of menstrual cycles, and oocyte quality in patients with PCOS (23, 24).

Resveratrol in metabolic syndrome

Resveratrol (3, 5, 4 trihydroxystilbene) a natural polyphenolic compound is found in and produced by several plants. The richest source of natural resveratrol is a plant known from traditional Chinese and Japanese medicine called Polygonum cuspidatum, (25). Lower quantities of resveratrol can be found in peanuts, grapes, red wine and mulberries (26). Resveratrol has emerged in recent years as a molecule conferring strong protection against metabolic, cardiovascular and other age-related complications, such as neurodegenerative disorders. Given its potential as a novel molecule for the development of drugs that treat metabolic disorders, understanding the molecular mechanisms underlying resveratrol’s metabolic modulations is imperative. Resveratrol indirectly activates hepatocellular AMP-activated protein kinase (AMPK). AMPK is the central target for the metabolic effects dependent on resveratrol (27). The crucial mediator of cellular metabolism, AMPK is stimulated by conditions that increase AMP/ATP and ADP/ATP ratios such as physical exercise, is-chemia, and glucose deprivation. AMPK is also involved in feeding behavior and entrains circadian rhythms of metabolism (28). Studies have demonstrated the activation of AMPK is depended upon the specific inhibition phosphodiesterase IV (29). In human HepG2 hepatocytes, polyphenols, including molecules such as resveratrol increased phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), its downstream target. This particular activation has been demonstrated to lead to an amplified activity of AMPK with the effectiveness 200 times that of metformin. Metformin, in fact is a first-line medication for the treatment of type 2 diabetes and also a known activator of AMPK. Treatment with metformin improves lipids and macrovascular disease in diabetes (30). This indirectly points out to a novel mechanism of action of resveratrol towards lowering lipids through the activation of AMPK, and thus benefits hyperlipidemia and atherosclerosis specifically in diabetes via AMPK activation (30). It has been reported that resveratrol administration to DOCA-salt hypertensive rats decreased oxidative stress and lipid peroxidation. These effects determined the improvement of the cardiovascular function (31). Furthermore, hyperglycaemia in microvascular endothelial cells leads to mitochondrial dysfunction. Thus, resveratrol-mediated mitochondrial protection could be used to prevent long-term diabetic cardiovascular complications (32). Indeed, resveratrol’s effect on metabolic health has received considerable attention in the last decade. Pre-clinical and clinical studies have acknowledged promising results regarding beneficial effects. Some of which have also focused on the capability of resveratrol in preventing and reducing obesity-induced metabolic disturbances. However, future research should focus on dose, efficacy and bioavailability of the molecule in order to guarantee and determine the therapeutic potential is still a necessity.

The proposed synergetic mechanism of a nutraceutical association- Inositols/Resveratrol

Inositol’s mediate different actions of insulin and act to partially restore insulin sensitivity and enhancing glucose availability (21) thus are considered a valid nutraceutical formulation to contrast insulin-resistance as well as associated metabolic syndrome in women with Polycystic ovarian disease (PCOS). DCI is involved insulin signal transduction pathway and in the stimulation of key enzymes that are sequentially involved in the regulation of glucose metabolism (20). Recently, clinical evidence has proven that an D-chiro-inositol/resveratrol combination has a potential role to play in maintaining metabolic and endocrine health (11). Specifically nutraceutical combination based on Inositols (DCI+ MI) and trans-resveratrol (RSV) was more effective than Inositols alone in reducing total cholesterol, HDL, LDL, triglycerides and glucose blood levels (11). Under these circumstances and given the significant amelioration of serum glucose levels with the association of resveratrol it appeared clear that both DCI and RSV acted upon related metabolic pathways and that the consequences would benefit diabetes and be useful to the patients with risk factors for metabolic syndrome. Herein, we propose a synergistic mechanism adopted by D-chiro-inositol and resveratrol in reducing insulin resistance and hyperlipidemia. Thus showing a greater therapeutic potential compared to treatment with inositols alone. This mechanism amplifies glucose uptake and its metabolism as well as inhibiting fatty acid synthesis and promoting mitochondrial β-oxidation. RSV could facilitate glucose uptake by the translocation of Glucose transporter type 4 (GLUT4) and glycolysis, both mechanisms dependent upon the activation and metabolic activity of AMPK (33). The activation of AMPK also inactivates ACC (acetyl-CoA carboxylase), leading to the inhibition of fatty acid synthesis and the promotion of mitochondrial β-oxida-tion (34) (Fig. 1). Thus, the final result would be less extracellular glucose concentration and fat and on the contrary increased intracellular glucose and metabolized fat in the respiratory chain. The association of inositols with resveratrol, represents a valid, alternative therapeutic approach for the treatment of insulin resistance. Given the central role of IR in the pathogenesis and related metabolic disorders in PCOS a therapy based on inositols and resveratrol could presently as discussed herein provide further benefit.

Figure 1
Figure 1

The proposed synergetic mechanism of a nutraceutical association- Inositols/Resveratrol.

Citation: The EuroBiotech Journal 2, 1; 10.2478/ebtj-2018-0006

AbbreviationsIR-

Insulin Resistance

RSV-

Resveratrol

DCI-

D-Chiro-Inositol

MI –

Myo-Inositol

PCO-

Polycystic Ovarian Disease

AMPK-

AMP-activated protein kinase

GLUT4-

Glucose transporter type 4

Conflict of interestConflict of interest statement The authors declare that they have no conflicts of interest for the publication of this article.

References

  • 1

    Iqbal J Al Qarni A. Metabolic syndrome dyslipidemia and regulation of lipoprotein metabolism. Curr Diabetes Rev. 2017 Jul 5.

  • 2

    Chen C Jing G. Insulin resistance and polycystic ovary syndrome in a chinese population. Endocr Pract. 2017 Jul 6.

  • 3

    Leite PB Dâmaso AR. Long-term interdisciplinary therapy decreases symptoms of binge eating disorder and prevalence of metabolic syndrome in adults with obesity. Nutr Res. 2017 Apr;40:57-64.

    • Crossref
    • PubMed
    • Export Citation
  • 4

    Al-Dughaishi T Nikolic D. Nutraceuticals as Lipid-Lowering Treatment in Pregnancy and Their Effects on the Metabolic Syndrome. Curr Pharm Biotechnol. 2016;17(7):614-23.

    • Crossref
    • PubMed
    • Export Citation
  • 5

    Dong D Reece EA. New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects. Am J Obstet Gynecol. 2016 Feb;214(2):192-202.

    • Crossref
    • PubMed
    • Export Citation
  • 6

    Greene ND Leung KY Copp AJ. Inositol neural tube closure and the prevention of neural tube defects. Birth Defects Res. 2017 Jan 30;109(2):68-80.

    • Crossref
    • PubMed
    • Export Citation
  • 7

    Farren M Daly N. The Prevention of Gestational Diabetes Mellitus With Antenatal Oral Inositol Supplementation: A Randomized Controlled Trial. Diabetes Care. 2017 Jun;40(6):759-763.

    • Crossref
    • PubMed
    • Export Citation
  • 8

    Brown J Crawford TJ. Dietary supplementation with myo-inositol in women during pregnancy for treating gestational diabetes. Cochrane Database Syst Rev. 2016 Sep 7;9:CD012048.

    • PubMed
    • Export Citation
  • 9

    Malvasi A Casciaro F. Myo-inositol D-chiro-inositol folic acid and manganese in second trimester of pregnancy: a preliminary investigation. Eur Rev Med Pharmacol Sci. 2014;18(2):270-4

    • PubMed
    • Export Citation
  • 10

    Singh CK Kumar A. Diabetic complications in pregnancy: is resveratrol a solution? Exp Biol Med (Maywood). 2013 May;238(5):482-90.

    • Crossref
    • PubMed
    • Export Citation
  • 11

    Malvasi A Kosmas I. Can trans resveratrol plus d-chiro-inositol and myo-inositol improve maternal metabolic profile in overweight pregnant patients? Clin Ter. 2017 Jul-Aug;168(4):e240-e247.

    • PubMed
    • Export Citation
  • 12

    Timmers S Konings E. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011 Nov 2;14(5):612-22.

    • Crossref
    • PubMed
    • Export Citation
  • 13

    Fauser BC Tarlatzis BC Rebar RW Legro RS Balen AH Lobo R Carmina E Chang J Yildiz BO Laven JS Boivin J Petraglia F Wijeyeratne CN Norman RJ Dunaif A Franks S Wild RA Dumesic D Barnhart K. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop GroupFertil Steril. 2012 Jan;97(1):28-38.e25.

  • 14

    Baillargeon JP Iuorno MJ Nestler JE. Insulin sensitizers for polycystic ovary syndrome. Clin Obstet Gynecol. 2003 Jun;46(2):325-40. Review.

    • Crossref
    • PubMed
    • Export Citation
  • 15

    Højlund K. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance. Dan Med J. 2014 Jul;61(7):B4890. Review.

    • PubMed
    • Export Citation
  • 16

    De Leo V Musacchio MC Cappelli V Massaro MG Morgante G Petraglia F. Genetic hormonal and metabolic aspects of PCOS: an update.. Reprod Biol Endocrinol. 2016 Jul 16;14(1):38

    • Crossref
    • PubMed
    • Export Citation
  • 17

    Qiao J Feng HL. Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence. Hum Reprod Update. 2011;17:17-33.

    • Crossref
    • PubMed
    • Export Citation
  • 18

    Toprak S Yönem A Cakir B Güler S Azal O Ozata M Corakçi A. Insulin resistance in nonobese patients with polycystic ovary syndrome. Horm Res. 2001;55(2):65-70.

    • PubMed
    • Export Citation
  • 19

    Larner J. D-chiro-inositol-its functional role in insulin action and its deficit in insulin resistance. Int J Exp Diabetes Res 2002; 3: 47-60.

    • Crossref
    • PubMed
    • Export Citation
  • 20

    Nestler J Unfer V. Reflections on inositol(s) for PCOS therapy: steps toward success. Gynecol Endocrinol 2015; 31: 501-505.

    • Crossref
    • PubMed
    • Export Citation
  • 21

    Larner J Huang LC Tang G Suzuki S Sch wartz CF Romero G Roulidis Z Zeller K Shen TY Oswald AS. Insulin mediators: structure and formation. Cold Spring Harb Symp Quant Biol 1988; 53: 965-97.

    • Crossref
    • PubMed
    • Export Citation
  • 22

    Dresner A. Laurent D. Marcucci M. et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. Journal of Clinical Investigation. 1999;103(2):253-259.

    • Crossref
    • Export Citation
  • 23

    Laganà AS Rossetti P Buscema M La Vignera S Condorelli RA Gullo G Granese R Triolo O.Metabolism and Ovarian Function in PCOS Women: A Therapeutic Approach with Inositols. Int J Endocrinol. 2016;2016:6306410.

    • PubMed
    • Export Citation
  • 24

    Pizzo A Lagan`a AS and Barbaro A Comparison betweeneffects ofmyo-inositol and d-chiro-inositol on ovarian function and metabolic factors in women with PCOS Gynecological Endocrinology 2014; 30 (3) 205-208.

    • Crossref
    • Export Citation
  • 25

    Nonomura S Kanagawa H Makimoto A. Chemical constituents of polygonaceous plants. I. Studies on the components of Ko-J O-Kon. Polygonum cuspidatum Sieb Et Zucc Yakugaku Zasshi 1963; 83 988-990.

  • 26

    Howitz KT Bitterman KJ Cohen HY Lamming DW. Lavu S Wood JG Zipkin RE Chung P Kisielewski A Zhang LL et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan Nature 2003; 425 191-196.

    • Crossref
    • PubMed
    • Export Citation
  • 27

    Um JH Park SJ Kang H Yang S Foretz M McBurney MW Kim MK Viollet B Chung JH. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes. 2010 Mar;59(3):554-63.

    • Crossref
    • PubMed
    • Export Citation
  • 28

    Hardie DG. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13 251-262.

    • Crossref
    • PubMed
    • Export Citation
  • 29

    Chung JH Manganiello V Dyck JR. Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol. 2012; 22(10):546-54.

    • Crossref
    • PubMed
    • Export Citation
  • 30

    Zang M. Polyphenols stimulate AMP-activated protein kinase lower lipids and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55 2180-2191.

    • Crossref
    • PubMed
    • Export Citation
  • 31

    Chan V Fenning A Iyer A Hoey A Brown L. Resveratrol improves cardiovascular function in DOCA-salt hypertensive rats. Current Pharmaceutical Biotechnology. 2011;12(3):429-436.

    • Crossref
    • PubMed
    • Export Citation
  • 32

    Joshi MS Williams D Horlock D Samarasinghe T Andrews KL Jefferis AM Berger PJ Chin-Dusting JP Kaye DM. Role of mitochondrial dysfunction in hyperglycaemia-induced coronary microvascular dysfunction: Protective role of resveratrol. Diab Vasc Dis Res. 2015 May;12(3):208-16.

    • Crossref
    • PubMed
    • Export Citation
  • 33

    Zhu KN Jiang CH. Two triterpeniods from Cyclocarya paliurus (Batal) Iljinsk (Juglandaceae) promote glucose uptake in 3T3-L1 adipocytes: The relationship to AMPK activation. Phytomedicine. 2015 Aug 15;22(9):837-46.

    • Crossref
    • PubMed
    • Export Citation
  • 34

    Wang S Song P Zou MH. AMP-activated protein kinase stress responses and cardiovascular diseases. Clin Sci (Lond). 2012 Jun;122(12):555-73.

    • Crossref
    • PubMed
    • Export Citation

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  • 1

    Iqbal J Al Qarni A. Metabolic syndrome dyslipidemia and regulation of lipoprotein metabolism. Curr Diabetes Rev. 2017 Jul 5.

  • 2

    Chen C Jing G. Insulin resistance and polycystic ovary syndrome in a chinese population. Endocr Pract. 2017 Jul 6.

  • 3

    Leite PB Dâmaso AR. Long-term interdisciplinary therapy decreases symptoms of binge eating disorder and prevalence of metabolic syndrome in adults with obesity. Nutr Res. 2017 Apr;40:57-64.

    • Crossref
    • PubMed
    • Export Citation
  • 4

    Al-Dughaishi T Nikolic D. Nutraceuticals as Lipid-Lowering Treatment in Pregnancy and Their Effects on the Metabolic Syndrome. Curr Pharm Biotechnol. 2016;17(7):614-23.

    • Crossref
    • PubMed
    • Export Citation
  • 5

    Dong D Reece EA. New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects. Am J Obstet Gynecol. 2016 Feb;214(2):192-202.

    • Crossref
    • PubMed
    • Export Citation
  • 6

    Greene ND Leung KY Copp AJ. Inositol neural tube closure and the prevention of neural tube defects. Birth Defects Res. 2017 Jan 30;109(2):68-80.

    • Crossref
    • PubMed
    • Export Citation
  • 7

    Farren M Daly N. The Prevention of Gestational Diabetes Mellitus With Antenatal Oral Inositol Supplementation: A Randomized Controlled Trial. Diabetes Care. 2017 Jun;40(6):759-763.

    • Crossref
    • PubMed
    • Export Citation
  • 8

    Brown J Crawford TJ. Dietary supplementation with myo-inositol in women during pregnancy for treating gestational diabetes. Cochrane Database Syst Rev. 2016 Sep 7;9:CD012048.

    • PubMed
    • Export Citation
  • 9

    Malvasi A Casciaro F. Myo-inositol D-chiro-inositol folic acid and manganese in second trimester of pregnancy: a preliminary investigation. Eur Rev Med Pharmacol Sci. 2014;18(2):270-4

    • PubMed
    • Export Citation
  • 10

    Singh CK Kumar A. Diabetic complications in pregnancy: is resveratrol a solution? Exp Biol Med (Maywood). 2013 May;238(5):482-90.

    • Crossref
    • PubMed
    • Export Citation
  • 11

    Malvasi A Kosmas I. Can trans resveratrol plus d-chiro-inositol and myo-inositol improve maternal metabolic profile in overweight pregnant patients? Clin Ter. 2017 Jul-Aug;168(4):e240-e247.

    • PubMed
    • Export Citation
  • 12

    Timmers S Konings E. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011 Nov 2;14(5):612-22.

    • Crossref
    • PubMed
    • Export Citation
  • 13

    Fauser BC Tarlatzis BC Rebar RW Legro RS Balen AH Lobo R Carmina E Chang J Yildiz BO Laven JS Boivin J Petraglia F Wijeyeratne CN Norman RJ Dunaif A Franks S Wild RA Dumesic D Barnhart K. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop GroupFertil Steril. 2012 Jan;97(1):28-38.e25.

  • 14

    Baillargeon JP Iuorno MJ Nestler JE. Insulin sensitizers for polycystic ovary syndrome. Clin Obstet Gynecol. 2003 Jun;46(2):325-40. Review.

    • Crossref
    • PubMed
    • Export Citation
  • 15

    Højlund K. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance. Dan Med J. 2014 Jul;61(7):B4890. Review.

    • PubMed
    • Export Citation
  • 16

    De Leo V Musacchio MC Cappelli V Massaro MG Morgante G Petraglia F. Genetic hormonal and metabolic aspects of PCOS: an update.. Reprod Biol Endocrinol. 2016 Jul 16;14(1):38

    • Crossref
    • PubMed
    • Export Citation
  • 17

    Qiao J Feng HL. Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence. Hum Reprod Update. 2011;17:17-33.

    • Crossref
    • PubMed
    • Export Citation
  • 18

    Toprak S Yönem A Cakir B Güler S Azal O Ozata M Corakçi A. Insulin resistance in nonobese patients with polycystic ovary syndrome. Horm Res. 2001;55(2):65-70.

    • PubMed
    • Export Citation
  • 19

    Larner J. D-chiro-inositol-its functional role in insulin action and its deficit in insulin resistance. Int J Exp Diabetes Res 2002; 3: 47-60.

    • Crossref
    • PubMed
    • Export Citation
  • 20

    Nestler J Unfer V. Reflections on inositol(s) for PCOS therapy: steps toward success. Gynecol Endocrinol 2015; 31: 501-505.

    • Crossref
    • PubMed
    • Export Citation
  • 21

    Larner J Huang LC Tang G Suzuki S Sch wartz CF Romero G Roulidis Z Zeller K Shen TY Oswald AS. Insulin mediators: structure and formation. Cold Spring Harb Symp Quant Biol 1988; 53: 965-97.

    • Crossref
    • PubMed
    • Export Citation
  • 22

    Dresner A. Laurent D. Marcucci M. et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. Journal of Clinical Investigation. 1999;103(2):253-259.

    • Crossref
    • Export Citation
  • 23

    Laganà AS Rossetti P Buscema M La Vignera S Condorelli RA Gullo G Granese R Triolo O.Metabolism and Ovarian Function in PCOS Women: A Therapeutic Approach with Inositols. Int J Endocrinol. 2016;2016:6306410.

    • PubMed
    • Export Citation
  • 24

    Pizzo A Lagan`a AS and Barbaro A Comparison betweeneffects ofmyo-inositol and d-chiro-inositol on ovarian function and metabolic factors in women with PCOS Gynecological Endocrinology 2014; 30 (3) 205-208.

    • Crossref
    • Export Citation
  • 25

    Nonomura S Kanagawa H Makimoto A. Chemical constituents of polygonaceous plants. I. Studies on the components of Ko-J O-Kon. Polygonum cuspidatum Sieb Et Zucc Yakugaku Zasshi 1963; 83 988-990.

  • 26

    Howitz KT Bitterman KJ Cohen HY Lamming DW. Lavu S Wood JG Zipkin RE Chung P Kisielewski A Zhang LL et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan Nature 2003; 425 191-196.

    • Crossref
    • PubMed
    • Export Citation
  • 27

    Um JH Park SJ Kang H Yang S Foretz M McBurney MW Kim MK Viollet B Chung JH. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes. 2010 Mar;59(3):554-63.

    • Crossref
    • PubMed
    • Export Citation
  • 28

    Hardie DG. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13 251-262.

    • Crossref
    • PubMed
    • Export Citation
  • 29

    Chung JH Manganiello V Dyck JR. Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol. 2012; 22(10):546-54.

    • Crossref
    • PubMed
    • Export Citation
  • 30

    Zang M. Polyphenols stimulate AMP-activated protein kinase lower lipids and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55 2180-2191.

    • Crossref
    • PubMed
    • Export Citation
  • 31

    Chan V Fenning A Iyer A Hoey A Brown L. Resveratrol improves cardiovascular function in DOCA-salt hypertensive rats. Current Pharmaceutical Biotechnology. 2011;12(3):429-436.

    • Crossref
    • PubMed
    • Export Citation
  • 32

    Joshi MS Williams D Horlock D Samarasinghe T Andrews KL Jefferis AM Berger PJ Chin-Dusting JP Kaye DM. Role of mitochondrial dysfunction in hyperglycaemia-induced coronary microvascular dysfunction: Protective role of resveratrol. Diab Vasc Dis Res. 2015 May;12(3):208-16.

    • Crossref
    • PubMed
    • Export Citation
  • 33

    Zhu KN Jiang CH. Two triterpeniods from Cyclocarya paliurus (Batal) Iljinsk (Juglandaceae) promote glucose uptake in 3T3-L1 adipocytes: The relationship to AMPK activation. Phytomedicine. 2015 Aug 15;22(9):837-46.

    • Crossref
    • PubMed
    • Export Citation
  • 34

    Wang S Song P Zou MH. AMP-activated protein kinase stress responses and cardiovascular diseases. Clin Sci (Lond). 2012 Jun;122(12):555-73.

    • Crossref
    • PubMed
    • Export Citation
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    The proposed synergetic mechanism of a nutraceutical association- Inositols/Resveratrol.

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