Mediterranean Diet Nutrients to Turn the Tide against Insulin Resistance and Related Diseases

Maria Mirabelli, Eusebio Chiefari, Biagio Arcidiacono, Domenica Maria Corigliano, Francesco Saverio Brunetti, Valentina Maggisano, Diego Russo, Daniela Patrizia Foti, Antonio Brunetti, Maria Mirabelli, Eusebio Chiefari, Biagio Arcidiacono, Domenica Maria Corigliano, Francesco Saverio Brunetti, Valentina Maggisano, Diego Russo, Daniela Patrizia Foti, Antonio Brunetti

Abstract

Insulin resistance (IR), defined as an attenuated biological response to circulating insulin, is a fundamental defect in obesity and type 2 diabetes (T2D), and is also linked to a wide spectrum of pathological conditions, such as non-alcoholic fatty liver disease (NAFLD), cognitive impairment, endothelial dysfunction, chronic kidney disease (CKD), polycystic ovary syndrome (PCOS), and some endocrine tumors, including breast cancer. In obesity, the unbalanced production of pro- and anti-inflammatory adipocytokines can lead to the development of IR and its related metabolic complications, which are potentially reversible through weight-loss programs. The Mediterranean diet (MedDiet), characterized by high consumption of extra-virgin olive oil (EVOO), nuts, red wine, vegetables and other polyphenol-rich elements, has proved to be associated with greater improvement of IR in obese individuals, when compared to other nutritional interventions. Also, recent studies in either experimental animal models or in humans, have shown encouraging results for insulin-sensitizing nutritional supplements derived from MedDiet food sources in the modulation of pathognomonic traits of certain IR-related conditions, including polyunsaturated fatty acids from olive oil and seeds, anthocyanins from purple vegetables and fruits, resveratrol from grapes, and the EVOO-derived, oleacein. Although the pharmacological properties and clinical uses of these functional nutrients are still under investigation, the molecular mechanism(s) underlying the metabolic benefits appear to be compound-specific and, in some cases, point to a role in gene expression through an involvement of the nuclear high-mobility group A1 (HMGA1) protein.

Keywords: HMGA1; Mediterranean diet; extra-virgin olive oil; insulin resistance; nutraceuticals.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Polyunsaturated fatty acids (PUFAs) from olive oil, nuts, and seeds and the amelioration of glycemic escursions. GLP-1, glucagon-like peptide 1.
Figure 2
Figure 2
Anthocyanins from purple-colored vegetables and fruits and the mechanisms for neuroprotection. PPARγ, peroxisome proliferator-activated receptor γ; FFA, free fatty acids.
Figure 3
Figure 3
Resveratrol from grapes, berries and wine and the amelioration of hyperandrogenism in polycystic ovary syndrome (PCOS). SIRT1, sirtuin 1; AMPK, AMP-activated protein kinase.
Figure 4
Figure 4
Dietary modulation of HMGA1 functions in the maintenance of glycemic homeostasis, tumorigenesis and atherosclerosis. EVOO, extra virgin olive oil; SFAs, saturated fatty acids; AGO2, argonaute RISC catalytic component 2; CREBBP, CREB (cAMP response element binding protein) binding protein; PKCε, protein kinase C isoform ε; HMGA1, high-mobility group A1 protein.
Figure 5
Figure 5
Beneficial effects of the MedDiet on IR-related traits: summary. NAFLD, non-alcoholic fatty liver disease; CKD, chronic kidney disease; PCOS, polycystic ovary syndrome.

References

    1. Brunetti A., Chiefari E., Foti D. Recent advances in the molecular genetics of type 2 diabetes mellitus. World J. Diabetes. 2014;5:128–140. doi: 10.4239/wjd.v5.i2.128.
    1. Kelly G.S. Insulin resistance: Lifestyle and nutritional interventions. Altern Med. Rev. 2000;5:109–132.
    1. Czech M.P. Insulin action and resistance in obesity and type 2 diabetes. Nat. Med. 2017;23:804–814. doi: 10.1038/nm.4350.
    1. Brunetti A., Foti D., Goldfine I.D. Identification of unique nuclear regulatory proteins for the insulin receptor gene, which appear during myocyte and adipocyte differentiation. J. Clin. Invest. 1993;92:1288–1295. doi: 10.1172/JCI116702.
    1. Hong S.H., Choi K.M. Sarcopenic Obesity, Insulin Resistance, and Their Implications in Cardiovascular and Metabolic Consequences. Int. J. Mol. Sci. 2020;21:494. doi: 10.3390/ijms21020494.
    1. De Rosa S., Arcidiacono B., Chiefari E., Brunetti A., Indolfi C., Foti D.P. Type 2 diabetes mellitus and cardiovascular disease: Genetic and epigenetic links. Front. Endocrinol. 2018;9:2. doi: 10.3389/fendo.2018.00002.
    1. Arcidiacono B., Iiritano S., Nocera A., Possidente K., Nevolo M.T., Ventura V., Foti D., Chiefari E., Brunetti A. Insulin resistance and cancer risk: An overview of the pathogenetic mechanisms. Exp. Diabetes Res. 2012;2012:789174. doi: 10.1155/2012/789174.
    1. Torchen L.C. Cardiometabolic Risk in PCOS: More than a Reproductive Disorder. Curr. Diab. Rep. 2017;17:137. doi: 10.1007/s11892-017-0956-2.
    1. Della Pepa G., Vetrani C., Lombardi G., Bozzetto L., Annuzzi G., Rivellese A.A. Isocaloric Dietary Changes and Non-Alcoholic Fatty Liver Disease in High Cardiometabolic Risk Individuals. Nutrients. 2017;9:1065. doi: 10.3390/nu9101065.
    1. Chiefari E., Tanyolaç S., Iiritano S., Sciacqua A., Capula C., Arcidiacono B., Nocera A., Possidente K., Baudi F., Ventura V., et al. A polymorphism of HMGA1 is associated with increased risk of metabolic syndrome and related components. Sci. Rep. 2013;3:1491. doi: 10.1038/srep01491.
    1. Arnold S.E., Arvanitakis Z., Macauley-Rambach S.L., Koenig A.M., Wang H.Y., Ahima R.S., Craft S., Gandy S., Buettner C., Stoeckel L.E., et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums. Nat. Rev. Neurol. 2018;14:168–181. doi: 10.1038/nrneurol.2017.185.
    1. Jakobsen G.S., Smastuen M.C., Sandbu R., Nordstrand N., Hofsø D., Lindberg M., Hertel J.K., Hjelmesæth J. Association of Bariatric Surgery vs Medical Obesity Treatment with Long-term Medical Complications and Obesity-Related Comorbidities. JAMA. 2018;319:291–301. doi: 10.1001/jama.2017.21055.
    1. Rueda-Clausen C.F., Ogunleye A.A., Sharma A.M. Health Benefits of Long-Term Weight-Loss Maintenance. Annu. Rev. Nutr. 2015;35:475–516. doi: 10.1146/annurev-nutr-071714-034434.
    1. Heggen E., Klemsdal T.O., Haugen F., Holme I., Tonstad S. Effect of a low-fat versus a low-gycemic-load diet on inflammatory biomarker and adipokine concentrations. Metab. Syndr. Relat. Disord. 2012;10:437–442. doi: 10.1089/met.2012.0012.
    1. Chen L., Chen R., Wang H., Liang F. Mechanisms Linking Inflammation to Insulin Resistance. Int. J. Endocrinol. 2015;2015:508409. doi: 10.1155/2015/508409.
    1. Accattato F., Greco M., Pullano S.A., Carè I., Fiorillo A.S., Pujia A., Montalcini T., Foti D.P., Brunetti A., Gulletta E. Effects of acute physical exercise on oxidative stress and inflammatory status in young, sedentary obese subjects. PLoS ONE. 2017;12:e0178900. doi: 10.1371/journal.pone.0178900.
    1. Shai I., Schwarzfuchs D., Henkin Y., Shahar D.R., Witkow S., Greenberg I., Golan R., Fraser D., Bolotin A., Vardi H., et al. Dietary Intervention Randomized Controlled Trial (DIRECT) Group. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N. Engl. J. Med. 2008;359:229–241. doi: 10.1056/NEJMoa0708681.
    1. Greco M., Chiefari E., Montalcini T., Accattato F., Costanzo F.S., Pujia A., Foti D., Brunetti A., Gulletta E. Early effects of a hypocaloric, Mediterranean diet on laboratory parameters in obese individuals. Mediat. Inflamm. 2014;2014:750860. doi: 10.1155/2014/750860.
    1. Menotti A., Puddu P.E. How the Seven Countries Study contributed to the definition and development of the Mediterranean diet concept: A 50-year journey. Nutr. Metab. Cardiovasc. Dis. 2015;25:245–252. doi: 10.1016/j.numecd.2014.12.001.
    1. Davis C., Bryan J., Hodgson J., Murphy K. Definition of the Mediterranean Diet; a Literature Review. Nutrients. 2015;7:9139–9153. doi: 10.3390/nu7115459.
    1. Diolintzi A., Panagiotakos D., Sidossis L. From Mediterranean diet to Mediterranean lifestyle: A narrative review. Public Health Nutr. 2019;22:2703–2713. doi: 10.1017/S1368980019000612.
    1. Hussain T., Tan B., Yin Y., Blachier F., Tossou M.C., Rahu N. Oxidative Stress and Inflammation: What Polyphenols Can Do for us? Oxid. Med. Cell Longev. 2016;2016:7432797. doi: 10.1155/2016/7432797.
    1. Galan-Lopez P., Sanchez-Oliver A.J., Pihu M., Gisladottir T., Dominguez R., Ries F. Association between Adherence to the Mediterranean Diet and Physical Fitness with Body Composition Parameters in 1717 European Adolescents: The AdolesHealth Study. Nutrients. 2019;12:77. doi: 10.3390/nu12010077.
    1. Archero F., Ricotti R., Solito A., Carrera D., Civello F., Di Bella R., Bellone S., Prodam F. Adherence to the Mediterranean Diet among School Children and Adolescents Living in Northern Italy and Unhealthy Food Behaviors Associated to Overweight. Nutrients. 2018;10:1322. doi: 10.3390/nu10091322.
    1. Thorpe K.E., Florence C.S., Howard D.H., Joski P. The impact of obesity on rising medical spending. Health Aff. (Millwood) 2004 doi: 10.1377/hlthaff.W4.480.
    1. Zheng Y., Ley S.H., Hu F.B. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat. Rev. Endocrinol. 2018;14:88–98. doi: 10.1038/nrendo.2017.151.
    1. American Diabetes Association Economic Costs of Diabetes in the U.S. in 2017. Diabetes Care. 2018;41:917–928. doi: 10.2337/dci18-0007.
    1. Ye J. Mechanisms of insulin resistance in obesity. Front. Med. 2013;7:14–24. doi: 10.1007/s11684-013-0262-6.
    1. Leahy J.L. Pathogenesis of type 2 diabetes mellitus. Arch. Med. Res. 2005;36:197–209. doi: 10.1016/j.arcmed.2005.01.003.
    1. Arcidiacono B., Iiritano S., Chiefari E., Brunetti F.S., Gu G., Foti D.P., Brunetti A. Cooperation between HMGA1, PDX-1, and MafA is essential for glucose- induced insulin transcription in pancreatic beta cells. Front. Endocrinol. 2015;5:237. doi: 10.3389/fendo.2014.00237.
    1. Knowler W.C., Barrett-Connor E., Fowler S.E., Hamman R.F., Lachin J.M., Walker E.A., Nathan D.M., Diabetes Prevention Program Research Group Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 2002;346:393–403.
    1. American Diabetes Association 5. Lifestyle Management: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl. 1):S46–S60. doi: 10.2337/dc19-S005.
    1. Esposito K., Maiorino M.I., Ciotola M., Di Palo C., Scognamiglio P., Gicchino M., Petrizzo M., Saccomanno F., Beneduce F., Ceriello A., et al. Effects of a Mediterranean-style diet on the need for antihyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes: A randomized trial. Ann. Intern. Med. 2009;151:306–314. doi: 10.7326/0003-4819-151-5-200909010-00004.
    1. Boucher J.L. Mediterranean eating pattern. Diabetes Spectr. 2017;30:72–76. doi: 10.2337/ds16-0074.
    1. Rinaldi S., Campbell E.E., Fournier J., O’Connor C., Madill J. A comprehensive review of the literature supporting recommendations from the Canadian Diabetes Association for the use of a plant-based diet for management of type 2 diabetes. Can. J. Diabetes. 2016;40:471–477. doi: 10.1016/j.jcjd.2016.02.011.
    1. Pawlak R. Vegetarian diets in the prevention and management of diabetes and its complications. Diabetes Spectr. 2017;30:82–88. doi: 10.2337/ds16-0057.
    1. Trichopoulou A., Bamia C., Trichopoulos D. Mediterranean diet and survival among patients with coronary heart disease in Greece. Arch. Intern. Med. 2005;165:929–935. doi: 10.1001/archinte.165.8.929.
    1. Trichopoulou A., Costacou T., Bamia C., Trichopoulos D. Adherence to a Mediterranean diet and survival in a Greek population. N. Engl. J. Med. 2003;348:2599–2608. doi: 10.1056/NEJMoa025039.
    1. Jennings A., Berendsen A.M., de Groot L.C.P.G.M., Feskens E.J.M., Brzozowska A., Sicinska E., Pietruszka B., Meunier N., Caumon E., Malpuech-Brugère C., et al. Mediterranean-Style Diet Improves Systolic Blood Pressure and Arterial Stiffness in Older Adults. Hypertension. 2019;73:578–586. doi: 10.1161/HYPERTENSIONAHA.118.12259.
    1. Guasch-Ferré M., Li J., Hu F.B., Salas-Salvadó J., Tobias D.K. Effects of walnut consumption on blood lipids and other cardiovascular risk factors: An updated meta-analysis and systematic review of controlled trials. Am. J. Clin. Nutr. 2018;108:174–187. doi: 10.1093/ajcn/nqy091.
    1. Estruch R., Ros E., Salas-Salvadó J., Covas M.I., Corella D., Arós F., Gómez-Gracia E., Ruiz-Gutiérrez V., Fiol M., Lapetra J., et al. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. N. Engl. J. Med. 2018;378:e34. doi: 10.1056/NEJMoa1800389.
    1. Kim H., Caulfield L.E., Garcia-Larsen V., Steffen L.M., Coresh J., Rebholz C.M. Plant-Based Diets Are Associated with a Lower Risk of Incident Cardiovascular Disease, Cardiovascular Disease Mortality, and All-Cause Mortality in a General Population of Middle-Aged Adults. J. Am. Heart Assoc. 2019;8:e012865. doi: 10.1161/JAHA.119.012865.
    1. Qian F., Korat A.A., Malik V., Hu F.B. Metabolic Effects of Monounsaturated Fatty Acid-Enriched Diets Compared with Carbohydrate or Polyunsaturated Fatty Acid-Enriched Diets in Patients with Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Diabetes Care. 2016;39:1448–1457. doi: 10.2337/dc16-0513.
    1. Martínez-González M.A., de la Fuente-Arrillaga C., Nunez-Cordoba J.M., Basterra-Gortari F.J., Beunza J.J., Vazquez Z., Benito S., Tortosa A., Bes-Rastrollo M. Adherence to Mediterranean diet and risk of developing diabetes: Prospective cohort study. BMJ. 2008;336:1348–1351. doi: 10.1136/.
    1. Salas-Salvadó J., Bulló M., Babio N., Martínez-González M.Á., Ibarrola-Jurado N., Basora J., Estruch R., Covas M.I., Corella D., Arós F., et al. PREDIMED Study Investigators. Reduction in the incidence of type 2 diabetes with the Mediterranean diet: Results of the PREDIMED-Reus nutrition intervention randomized trial. Diabetes Care. 2011;34:14–19. doi: 10.2337/dc10-1288.
    1. Lamping K.G., Nuno D.W., Coppey L.J., Holmes A.J., Hu S., Oltman C.L., Norris A.W., Yorek M.A. Modification of high saturated fat diet with n-3 polyunsaturated fat improves glucose intolerance and vascular dysfunction. Diabetes Obes. Metab. 2013;15:144–152. doi: 10.1111/dom.12004.
    1. Matravadia S., Herbst E.A., Jain S.S., Mutch D.M., Holloway G.P. Both linoleic and α-linolenic acid prevent insulin resistance but have divergent impacts on skeletal muscle mitochondrial bioenergetics in obese Zucker rats. Am. J. Physiol. Endocrinol. Metab. 2014;307:E102–E114. doi: 10.1152/ajpendo.00032.2014.
    1. Nardi F., Lipina C., Magill D., Hage Hassan R., Hajduch E., Gray A., Hundal H.S. Enhanced Insulin Sensitivity Associated with Provision of Mono and Polyunsaturated Fatty Acids in Skeletal Muscle Cells Involves Counter Modulation of PP2A. PLoS ONE. 2014;9:e92255. doi: 10.1371/journal.pone.0092255.
    1. Berger M.M., Delodder F., Liaudet L., Tozzi P., Schlaepfer J., Chiolero R.L., Tappy L. Three short perioperative infusions of n-3 PUFAs reduce systemic inflammation induced by cardiopulmonary bypass surgery: A randomized controlled trial. Am. J. Clin. Nutr. 2013;97:246–254. doi: 10.3945/ajcn.112.046573.
    1. Sundström L., Myhre S., Sundqvist M., Ahnmark A., McCoull W., Raubo P., Groombridge S.D., Polla M., Nyström A.C., Kristensson L., et al. The acute glucose lowering effect of specific GPR120 activation in mice is mainly driven by glucagon-like peptide 1. PLoS ONE. 2017;12:e0189060. doi: 10.1371/journal.pone.0189060.
    1. Holst J.J. The physiology of glucagon-like peptide 1. Physiol. Rev. 2007;87:1409–1439. doi: 10.1152/physrev.00034.2006.
    1. Færch K., Torekov S.S., Vistisen D., Johansen N.B., Witte D.R., Jonsson A., Pedersen O., Hansen T., Lauritzen T., Sandbæk A., et al. GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study. Diabetes. 2015;64:2513–2525. doi: 10.2337/db14-1751.
    1. Mirabelli M., Chiefari E., Caroleo P., Arcidiacono B., Corigliano D.M., Giuliano S., Brunetti F.S., Tanyolaç S., Foti D.P., Puccio L., et al. Long-Term Effectiveness of Liraglutide for Weight Management and Glycemic Control in Type 2 Diabetes. Int. J. Environ. Res. Public Health. 2020;17:207. doi: 10.3390/ijerph17010207.
    1. Brown T.J., Brainard J., Song F., Wang X., Abdelhamid A., Hooper L., PUFAH Group Omega-3, omega-6, and total dietary polyunsaturated fat for prevention and treatment of type 2 diabetes mellitus: Systematic review and meta-analysis of randomised controlled trials. BMJ. 2019;21:4697. doi: 10.1136/bmj.l4697.
    1. Vessby B., Uusitupa M., Hermansen K., Riccardi G., Rivellese A.A., Tapsell L.C., Nälsén C., Berglund L., Louheranta A., Rasmussen B.M., et al. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study. Diabetologia. 2001;44:312–319. doi: 10.1007/s001250051620.
    1. Alkhatib A., Tsang C., Tiss A., Bahorun T., Arefanian H., Barake R., Khadir A., Tuomilehto J. Functional Foods and Lifestyle Approaches for Diabetes Prevention and Management. Nutrients. 2017;1:1310. doi: 10.3390/nu9121310.
    1. Al-Ishaq R.K., Abotaleb M., Kubatka P., Kajo K., Büsselberg D. Flavonoids and Their Anti-Diabetic Effects: Cellular Mechanisms and Effects to Improve Blood Sugar Levels. Biomolecules. 2019;9:430. doi: 10.3390/biom9090430.
    1. Xu H., Luo J., Huang J., Wen Q. Flavonoids intake and risk of type 2 diabetes mellitus: A meta-analysis of prospective cohort studies. Medicine (Baltimore) 2018;97:e0686. doi: 10.1097/MD.0000000000010686.
    1. Eid H.M., Martineau L.C., Saleem A., Muhammad A., Vallerand D., Benhaddou-Andaloussi A., Nistor L., Afshar A., Arnason J.T., Haddad P.S. Stimulation of AMP-activated protein kinase and enhancement of basal glucose uptake in muscle cells by quercetin and quercetin glycosides, active principles of the antidiabetic medicinal plant Vaccinium vitis-idaea. Mol. Nutr. Food Res. 2010;54:991–1003. doi: 10.1002/mnfr.200900218.
    1. Dhanya R., Arya A.D., Nisha P., Jayamurthy P. Quercetin, a Lead Compound against Type 2 Diabetes Ameliorates Glucose Uptake via AMPK Pathway in Skeletal Muscle Cell Line. Front. Pharm. 2017;8:336. doi: 10.3389/fphar.2017.00336.
    1. Zhang A.J., Rimando A.M., Mizuno C.S., Mathews S.T. α-Glucosidase inhibitory effect of resveratrol and piceatannol. J. Nutr. Biochem. 2017;47:86–93. doi: 10.1016/j.jnutbio.2017.05.008.
    1. Proença C., Freitas M., Ribeiro D., Oliveira E.F.T., Sousa J.L.C., Tomé S.M., Ramos M.J., Silva A.M.S., Fernandes P.A., Fernandes E. α-Glucosidase inhibition by flavonoids: An in vitro and in silico structure–activity relationship study. J. Enzyme. Inhib. Med. Chem. 2017;32:1216–1228. doi: 10.1080/14756366.2017.1368503.
    1. Younossi Z.M., Koenig A.B., Abdelatif D., Fazel Y., Henry L., Wymer M. Global epidemiology of nonalcoholic fatty liver disease-metaanalytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84. doi: 10.1002/hep.28431.
    1. Portillo-Sanchez P., Bril F., Maximos M., Lomonaco R., Biernacki D., Orsak B., Subbarayan S., Webb A., Hecht J., Cusi K. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J. Clin. Endocrinol. Metab. 2015;100:2231–2238. doi: 10.1210/jc.2015-1966.
    1. Rinella M.E. Nonalcoholic fatty liver disease: A systematic review. JAMA. 2015;313:2263–2273. doi: 10.1001/jama.2015.5370.
    1. Vilar-Gomez E., Calzadilla-Bertot L., Wai-Sun Wong V., Castellanos M., Aller-de la Fuente R., Metwally M., Eslam M., Gonzalez-Fabian L., Alvarez-Quiñones Sanz M., Conde-Martin A.F., et al. Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients with Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study. Gastroenterology. 2018;155:443–457.e17. doi: 10.1053/j.gastro.2018.04.034.
    1. Angulo P., Kleiner D.E., Dam-Larsen S., Adams L.A., Bjornsson E.S., Charatcharoenwitthaya P., Mills P.R., Keach J.C., Lafferty H.D., Stahler A., et al. Liver Fibrosis, but No Other Histologic Features, Is Associated with Long-term Outcomes of Patients with Nonalcoholic Fatty Liver Disease. Gastroenterology. 2015;149:389–397.e10. doi: 10.1053/j.gastro.2015.04.043.
    1. Adams L.A., Anstee Q.M., Tilg H., Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66:1138–1153. doi: 10.1136/gutjnl-2017-313884.
    1. Patel N.S., Doycheva I., Peterson M.R., Hooker J., Kisselva T., Schnabl B., Seki E., Sirlin C.B., Loomba R. Effect of weight loss on magnetic resonance imaging estimation of liver fat and volume in patients with nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol. 2015;13:561–568.e1. doi: 10.1016/j.cgh.2014.08.039.
    1. Promrat K., Kleiner D.E., Niemeier H.M., Jackvony E., Kearns M., Wands J.R., Fava J.L., Wing R.R. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121–129. doi: 10.1002/hep.23276.
    1. Ganguli S., DeLeeuw P., Satapathy S.K. A Review of Current and Upcoming Treatment Modalities in Non-Alcoholic Fatty Liver Disease And Non-Alcoholic Steatohepatitis. Hepat. Med. 2019;15:159–178. doi: 10.2147/HMER.S188991.
    1. Asrih M., Jornayvaz F.R. Diets and nonalcoholic fatty liver disease: The good and the bad. Clin. Nutr. 2014;33:186–190. doi: 10.1016/j.clnu.2013.11.003.
    1. Temmerman J.C., Friedman A.N. Very low calorie ketogenic weight reduction diet in patients with cirrhosis: A case series. Nutr. Diabetes. 2013;3:e95. doi: 10.1038/nutd.2013.36.
    1. George E.S., Forsyth A., Itsiopoulos C., Nicoll A.J., Ryan M., Sood S., Roberts S.K., Tierney A.C. Practical Dietary Recommendations for the Prevention and Management of Nonalcoholic Fatty Liver Disease in Adults. Adv. Nutr. 2018;9:30–40. doi: 10.1093/advances/nmx007.
    1. Aller R., Izaola O., de la Fuente B., De Luis Román D.A. Mediterranean diet is associated with liver histology in patients with non-alcoholic fatty liver disease. Nutr. Hosp. 2015;32:2518–2524. doi: 10.3305/nh.2015.32.6.10074.
    1. Kontogianni M.D., Tileli N., Margariti A., Georgoulis M., Deutsch M., Tiniakos D., Fragopoulou E., Zafiropoulou R., Manios Y., Papatheodoridis G. Adherence to the Mediterranean diet is associated with the severity of non-alcoholic fatty liver disease. Clin. Nutr. 2014;33:678–683. doi: 10.1016/j.clnu.2013.08.014.
    1. Ryan M.C., Itsiopoulos C., Thodis T., Ward G., Trost N., Hofferberth S., O’Dea K., Desmond P.V., Johnson N.A., Wilson A.M. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J. Hepatol. 2013;59:138–143. doi: 10.1016/j.jhep.2013.02.012.
    1. Misciagna G., Del Pilar Díaz M., Caramia D.V., Bonfiglio C., Franco I., Noviello M.R., Chiloiro M., Abbrescia D.I., Mirizzi A., Tanzi M., et al. Effect of a Low Glycemic Index Mediterranean Diet on Non-Alcoholic Fatty Liver Disease. A Randomized Controlled Clinici Trial. J. Nutr. Health Aging. 2017;21:404–412. doi: 10.1007/s12603-016-0809-8.
    1. Kaliora A.C., Gioxari A., Kalafati I.P., Diolintzi A., Kokkinos A., Dedoussis G.V. The Effectiveness of Mediterranean Diet in Nonalcoholic Fatty Liver Disease Clinical Course: An Intervention Study. J. Med. Food. 2019;22:729–740. doi: 10.1089/jmf.2018.0020.
    1. European Association for the Study of the Liver (EASL) European Association for the Study of Diabetes (EASD) European Association for the Study of Obesity (EASO) EASL-EASDEASO Clinical Practice Guidelines for the management of nonalcoholic fatty liver disease. J. Hepatol. 2016;64:1388–1402. doi: 10.1016/j.jhep.2015.11.004.
    1. Cicerale S., Lucas L., Keast R. Biological activities of phenolic compounds present in virgin olive oil. Int. J. Mol. Sci. 2010;11:458–479. doi: 10.3390/ijms11020458.
    1. Bulotta S., Celano M., Lepore S.M., Montalcini T., Pujia A., Russo D. Beneficial effects of the olive oil phenolic components oleuropein and hydroxytyrosol: Focus on protection against cardiovascular and metabolic diseases. J. Transl. Med. 2014;12:219. doi: 10.1186/s12967-014-0219-9.
    1. Barbaro B., Toietta G., Maggio R., Arciello M., Tarocchi M., Galli A., Balsano C. Effects of the olive-derived polyphenol oleuropein on human health. Int. J. Mol. Sci. 2014;15:18508–18524. doi: 10.3390/ijms151018508.
    1. Lombardo G.E., Arcidiacono B., De Rose R.F., Lepore S.M., Costa N., Montalcini T., Brunetti A., Russo D., De Sarro G., Celano M. Normocaloric diet restores weight gain and insulin sensitivity in obese mice. Front. Endocrinol. 2016;7:49. doi: 10.3389/fendo.2016.00049.
    1. Lombardo G.E., Lepore S.M., Morittu V.M., Arcidiacono B., Colica C., Procopio A., Maggisano V., Bulotta S., Costa N., Mignogna C., et al. Effects of Oleacein on High-Fat Diet-Dependent Steatosis, Weight Gain, and Insulin Resistance in Mice. Front. Endocrinol. (Lausanne) 2018;9:116. doi: 10.3389/fendo.2018.00116.
    1. Costanzo P., Bonacci S., Cariati L., Nardi M., Oliverio M., Procopio A. Simple and efficient sustainable semi-synthesis of oleacein [2-(3,4-hydroxyphenyl) ethyl (3S,4E)-4-formyl-3-(2-oxoethyl)hex-4-enoate] as potential additive for edible oils. Food Chem. 2018;245:410–414. doi: 10.1016/j.foodchem.2017.10.097.
    1. Lepore S.M., Maggisano V., Bulotta S., Mignogna C., Arcidiacono B., Procopio A., Brunetti A., Russo D., Celano M. Oleacein Prevents High Fat Diet-Induced Adiposity and Ameliorates Some Biochemical Parameters of Insulin Sensitivity in Mice. Nutrients. 2019;11:1829. doi: 10.3390/nu11081829.
    1. Ueyama A., Ban N., Fukazawa M., Hirayama T., Takeda M., Yata T., Muramatsu H., Hoshino M., Yamamoto M., Matsuo M., et al. Inhibition of MEK1 signaling pathway in the liver ameliorates insulin resistance. J. Diabetes Res. 2016;2016:8264830. doi: 10.1155/2016/8264830.
    1. Willette A.A., Kapogiannis D. Does the brain shrink as the waist expands? Ageing Res. Rev. 2015;20:86–97. doi: 10.1016/j.arr.2014.03.007.
    1. Caunca M.R., Gardener H., Simonetto M., Cheung Y.K., Alperin N., Yoshita M., DeCarli C., Elkind M.S.V., Sacco R.L., Wright C.B., et al. Measures of obesity are associated with MRI markers of brain aging: The Northern Manhattan Study. Neurology. 2019;9:e791–e803. doi: 10.1212/WNL.0000000000007966.
    1. Arnemann K.L., Stöber F., Narayan S., Rabinovici G.D., Jagust W.J. Metabolic brain networks in aging and preclinical Alzheimer’s disease. Neuroimage Clin. 2017;17:987–999. doi: 10.1016/j.nicl.2017.12.037.
    1. Adams O.P. The impact of brief high-intensity exercise on blood glucose levels. Diabetes Metab. Syndr. Obes. 2013;6:113–122. doi: 10.2147/DMSO.S29222.
    1. Folch J., Olloquequi J., Ettcheto M., Busquets O., Sánchez-López E., Cano A., Espinosa-Jiménez T., García M.L., Beas-Zarate C., Casadesús G., et al. The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer’s Dementia. Front. Aging Neurosci. 2019;6:236. doi: 10.3389/fnagi.2019.00236.
    1. Kanoski S.E., Zhang Y., Zheng W., Davidson T.L. The effects of a high-energy diet on hippocampal function and blood-brain barrier integrity in the rat. J. Alzheimers Dis. 2010;21:207–219. doi: 10.3233/JAD-2010-091414.
    1. Berti V., Walters M., Sterling J., Quinn C.G., Logue M., Andrews R., Matthews D.C., Osorio R.S., Pupi A., Vallabhajosula S., et al. Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults. Neurology. 2018;90:e1789–e1798. doi: 10.1212/WNL.0000000000005527.
    1. van Harten B., de Leeuw F.E., Weinstein H.C., Scheltens P., Biessels G.J. Brain imaging in patients with diabetes: A systematic review. Diabetes Care. 2006;29:2539–2548. doi: 10.2337/dc06-1637.
    1. Croll P.H., Voortman T., Ikram M.A., Franco O.H., Schoufour J.D., Bos D., Vernooij M.W. Better diet quality relates to larger brain tissue volumes: The Rotterdam Study. Neurology. 2018;90:e2166–e2173. doi: 10.1212/WNL.0000000000005691.
    1. Gu Y., Brickman A.M., Stern Y., Habeck C.G., Razlighi Q.R., Luchsinger J.A., Manly J.J., Schupf N., Mayeux R., Scarmeas N. Mediterranean diet and brain structure in a multiethnic elderly cohort. Neurology. 2015;85:1744–1751. doi: 10.1212/WNL.0000000000002121.
    1. Pelletier A., Barul C., Féart C., Helmer C., Bernard C., Periot O., Dilharreguy B., Dartigues J.F., Allard M., Barberger-Gateau P., et al. Mediterranean diet and preserved brain structural connectivity in older subjects. Alzheimers Dement. 2015;11:1023–1031. doi: 10.1016/j.jalz.2015.06.1888.
    1. Gardener H., Scarmeas N., Gu Y., Boden-Albala B., Elkind M.S., Sacco R.L., DeCarli C., Wright C.B. Mediterranean diet and white matter hyperintensity volume in the Northern Manhattan Study. Arch. Neurol. 2012;69:251–256. doi: 10.1001/archneurol.2011.548.
    1. Staubo S.C., Aakre J.A., Vemuri P., Syrjanen J.A., Mielke M.M., Geda Y.E., Kremers W.K., Machulda M.M., Knopman D.S., Petersen R.C., et al. Mediterranean diet, micronutrients and macronutrients, and MRI measures of cortical thickness. Alzheimers Dement. 2017;13:168–177. doi: 10.1016/j.jalz.2016.06.2359.
    1. Afzal M., Redha A., AlHasan R. Anthocyanins Potentially Contribute to Defense against Alzheimer’s Disease. Molecules. 2019;24:4255. doi: 10.3390/molecules24234255.
    1. Passamonti S., Vrhovsek U., Vanzo A., Mattivi F. Fast access of some grape pigments to the brain. J. Agric. Food Chem. 2005;53:7029–7034. doi: 10.1021/jf050565k.
    1. Talavera S., Felgines C., Texier O., Besson C., Gil-Izquierdo A., Lamaison J.L., Remesy C. Anthocyanin metabolism in rats and their distribution to digestive area, kidney, and brain. J. Agric. Food Chem. 2005;53:3902–3908. doi: 10.1021/jf050145v.
    1. Kalt W., Blumberg J.B., McDonald J.E., Vinqvist-Tymchuk M.R., Fillmore S.A., Graf B.A., O’Leary J.M., Milbury P.E. Identification of anthocyanins in the liver, eye, and brain of blueberry-fed pigs. J. Agric. Food Chem. 2008;56:705–712. doi: 10.1021/jf071998l.
    1. Vepsäläinen S., Koivisto H., Pekkarinen E., Mäkinen P., Dobson G., McDougall G.J., Stewart D., Haapasalo A., Karjalainen R.O., Tanila H., et al. Anthocyanin-enriched bilberry and blackcurrant extracts modulate amyloid precursor protein processing and alleviate behavioral abnormalities in the APP/PS1 mouse model of Alzheimer’s disease. J. Nutr. Biochem. 2013;24:360–370. doi: 10.1016/j.jnutbio.2012.07.006.
    1. Song N., Zhang L., Chen W., Zhu H., Deng W., Han Y., Guo J., Qin C. Cyanidin 3-O-beta-glucopyranoside activates peroxisome proliferator-activated receptor-gamma and alleviates cognitive impairment in the APP(swe)/PS1(DeltaE9) mouse model. Biochim. Biophys. Acta. 2016;1862:1786–1800. doi: 10.1016/j.bbadis.2016.05.016.
    1. Bianconcini A., Lupo A., Capone S., Quadro L., Monti M., Zurlo D., Fucci A., Sabatino L., Brunetti A., Chiefari E., et al. Transcriptional activity of the murine retinol-binding protein gene is regulated by a multiprotein complex containing HMGA1, p54nrb/NonO, protein-associated splicing factor (PSF) and steroidogenic factor 1 (SF1)/liver receptor homologue 1 (LRH-1) Int. J. Biochem. Cell Biol. 2009;41:2189–2203. doi: 10.1016/j.biocel.2009.04.011.
    1. Corigliano D.M., Syed R., Messineo S., Lupia A., Patel R., Reddy C.V.R., Dubey P.K., Colica C., Amato R., De Sarro G., et al. Indole and 2,4-Thiazolidinedione conjugates as potential anticancer modulators. PeerJ. 2018;8:e5386. doi: 10.7717/peerj.5386.
    1. Villapol S. Roles of Peroxisome Proliferator-Activated Receptor Gamma on Brain and Peripheral Inflammation. Cell Mol. Neurobiol. 2018;38:121–132. doi: 10.1007/s10571-017-0554-5.
    1. Thangavel N., Al Bratty M., Akhtar Javed S., Ahsan W., Alhazmi H.A. Targeting Peroxisome Proliferator-Activated Receptors Using Thiazolidinediones: Strategy for Design of Novel Antidiabetic Drugs. Int. J. Med. Chem. 2017;2017:1069718. doi: 10.1155/2017/1069718.
    1. Costa V., Foti D., Paonessa F., Chiefari E., Palaia L., Brunetti G., Gulletta E., Fusco A., Brunetti A. The insulin receptor: A new anticancer target for peroxisome proliferator-activated receptor-g (PPARg) and thiazolidinedione-PPARg agonists. Endocr. Relat. Cancer. 2008;15:325–335. doi: 10.1677/ERC-07-0226.
    1. Nanjan M.J., Mohammed M., Prashantha Kumar B.R., Chandrasekar M.J.N. Thiazolidinediones as antidiabetic agents: A critical review. Bioorg. Chem. 2018;77:548–567. doi: 10.1016/j.bioorg.2018.02.009.
    1. Stumvoll M., Goldstein B.J., van Haeften T.W. Type 2 diabetes: Principles of pathogenesis and therapy. Lancet. 2005;365:1333–1346. doi: 10.1016/S0140-6736(05)61032-X.
    1. Rhea E.M., Banks W.A. Role of the Blood-Brain Barrier in Central Nervous System Insulin Resistance. Front. Neurosci. 2019;4:521. doi: 10.3389/fnins.2019.00521.
    1. Frolich L., Blum-Degen D., Riederer P., Hoyer S. A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer’s disease. Ann. N. Y. Acad. Sci. 1999;893:290–293. doi: 10.1111/j.1749-6632.1999.tb07839.x.
    1. Pearson-Leary J., Jahagirdar V., Sage J., McNay E.C. Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4. Behav. Brain Res. 2018;15:32–39. doi: 10.1016/j.bbr.2017.09.033.
    1. Jia Y., Kim J.Y., Jun H.J., Kim S.J., Lee J.H., Hoang M.H., Kim H.S., Chang H.I., Hwang K.Y., Um S.J., et al. Cyanidin is an agonistic ligand for peroxisome proliferator-activated receptor-alpha reducing hepatic lipid. Biochim. Biophys. Acta. 2013;1831:698–708. doi: 10.1016/j.bbalip.2012.11.012.
    1. Kent K., Charlton K., Roodenrys S., Batterham M., Potter J., Traynor V., Gilbert H., Morgan O., Richards R. Consumption of anthocyanin-rich cherry juice for 12 weeks improves memory and cognition in older adults with mild-to-moderate dementia. Eur. J. Nutr. 2017;56:333–341. doi: 10.1007/s00394-015-1083-y.
    1. Krikorian R., Nash T.A., Shidler M.D., Shukitt-Hale B., Joseph J.A. Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment. Br. J. Nutr. 2010;103:730–734. doi: 10.1017/S0007114509992364.
    1. Krikorian R., Shidler M.D., Nash T.A., Kalt W., Vinqvist-Tymchuk M.R., Shukitt-Hale B., Joseph J.A. Blueberry supplementation improves memory in older adults. J. Agric. Food Chem. 2010;58:3996–4000. doi: 10.1021/jf9029332.
    1. Shenoy S.F., Kazaks A.G., Holt R.R., Chen H.J., Winters B.L., Khoo C.S., Poston W.S., Haddock C.K., Reeves R.S., Foreyt J.P., et al. The use of a commercial vegetable juice as a practical means to increase vegetable intake: A randomized controlled trial. Nutr. J. 2010;9:38. doi: 10.1186/1475-2891-9-38.
    1. de la Rubia Orti J.E., Garcia-Pardo M.P., Drehmer E., Sancho Cantus D., Julian Rochina M., Aguilar M.A., Hu Yang I. Improvement of Main Cognitive Functions in Patients with Alzheimer’s Disease after Treatment with Coconut Oil Enriched Mediterranean Diet: A Pilot Study. J. Alzheimers Dis. 2018;65:577–587. doi: 10.3233/JAD-180184.
    1. Cassar S., Misso M.L., Hopkins W.G., Shaw C.S., Teede H.J., Stepto N.K. Insulin resistance in polycystic ovary syndrome: A systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies. Hum. Reprod. 2016;31:2619–2631. doi: 10.1093/humrep/dew243.
    1. Dunaif A. Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis. Endocr. Rev. 1997;18:774–800. doi: 10.1210/edrv.18.6.0318.
    1. Roberts J.S., Perets R.A., Sarfert K.S., Bowman J.J., Ozark P.A., Whitworth G.B., Blythe S.N., Toporikova N. High-fat high-sugar diet induces polycystic ovary syndrome in a rodent model. Biol. Reprod. 2017 doi: 10.1095/biolreprod.116.142786.
    1. González F., Sia C.L., Shepard M.K., Rote N.S., Minium J. The altered mononuclear cell-derived cytokine response to glucose ingestion is not regulated by excess adiposity in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2014;99:E2244–E2251. doi: 10.1210/jc.2014-2046.
    1. Turner-McGrievy G., Davidson C.R., Billings D.L. Dietary intake, eating behaviors, and quality of life in women with polycystic ovary syndrome who are trying to conceive. Hum. Fertil. (Camb.) 2015;18:16–21. doi: 10.3109/14647273.2014.922704.
    1. Caroleo M., Carbone E.A., Greco M., Corigliano D.M., Arcidiacono B., Fazia G., Rania M., Aloi M., Gallelli L., Segura-Garcia C., et al. Brain-behavior-immune interaction: Serum cytokines and growth factors in patients with eating disorders at extremes of the body mass index (BMI) spectrum. Nutrients. 2019;23:1995. doi: 10.3390/nu11091995.
    1. Escobar-Morreale H.F., Botella-Carretero J.I., Alvarez-Blasco F., Sancho J., San Millán J.L. The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J. Clin. Endocrinol. Metab. 2005;90:6364–6369. doi: 10.1210/jc.2005-1490.
    1. Douglas C.C., Gower B.A., Darnell B.E., Ovalle F., Oster R.A., Azziz R. Role of diet in the treatment of polycystic ovary syndrome. Fertil. Steril. 2006;85:679–688. doi: 10.1016/j.fertnstert.2005.08.045.
    1. Marsh K.A., Steinbeck K.S., Atkinson F.S., Petocz P., Brand-Miller J.C. Effect of a low glycemic index compared with a conventional healthy diet on polycystic ovary syndrome. Am. J. Clin. Nutr. 2010;92:83–92. doi: 10.3945/ajcn.2010.29261.
    1. Mavropoulos J.C., Yancy W.S., Hepburn J., Westman E.C. The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: A pilot study. Nutr. Metab. (Lond.) 2005;16:35. doi: 10.1186/1743-7075-2-35.
    1. McGrice M., Porter J. The Effect of Low Carbohydrate Diets on Fertility Hormones and Outcomes in Overweight and Obese Women: A Systematic Review. Nutrients. 2017;9:204. doi: 10.3390/nu9030204.
    1. Barrea L., Arnone A., Annunziata G., Muscogiuri G., Laudisio D., Salzano C., Pugliese G., Colao A., Savastano S. Adherence to the Mediterranean Diet, Dietary Patterns and Body Composition in Women with Polycystic Ovary Syndrome (PCOS) Nutrients. 2019;11:2278. doi: 10.3390/nu11102278.
    1. Orio F., Muscogiuri G., Palomba S. Could the Mediterranean diet be effective in women with polycystic ovary syndrome? A proof of concept. Eur. J. Clin. Nutr. 2015;69:974. doi: 10.1038/ejcn.2015.53.
    1. Gaskins A.J., Rovner A.J., Mumford S.L., Yeung E., Browne R.W., Trevisan M., Perkins N.J., Wactawski-Wende J., Schisterman E.F., BioCycle Study Group Adherence to a Mediterranean diet and plasma concentrations of lipid peroxidation in premenopausal women. Am. J. Clin. Nutr. 2010;92:1461–1467. doi: 10.3945/ajcn.110.000026.
    1. Banaszewska B., Wrotyńska-Barczyńska J., Spaczynski R.Z., Pawelczyk L., Duleba A.J. Effects of Resveratrol on Polycystic Ovary Syndrome: A Double-blind, Randomized, Placebo-controlled Trial. J. Clin. Endocrinol. Metab. 2016;101:4322–4328. doi: 10.1210/jc.2016-1858.
    1. Wong D.H., Villanueva J.A., Cress A.B., Duleba A.J. Effects of resveratrol on proliferation and apoptosis in rat ovarian theca-interstitial cells. Mol. Hum. Reprod. 2010;16:251–259. doi: 10.1093/molehr/gaq002.
    1. Ortega I., Villanueva J.A., Wong D.H., Cress A.B., Sokalska A., Stanley S.D., Duleba A.J. Resveratrol reduces steroidogenesis in rat ovarian theca-interstitial cells: The role of inhibition of Akt/PKB signaling pathway. Endocrinology. 2012;153:4019–4029. doi: 10.1210/en.2012-1385.
    1. Crandall J., Oram V., Trandafirescu G., Reid M., Kishore P., Hawkins M., Cohen H.W., Barzilai N. Pilot study of resveratrol in older adults with impaired glucose tolerance. J. Gerontol. A Biol. Sci. Med. Sci. 2012;67:1307–1312. doi: 10.1093/gerona/glr235.
    1. Chen S., Zhao X., Ran L., Wan J., Wang X., Qin Y., Shu F., Gao Y., Yuan L., Zhang Q., et al. Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: A randomized controlled trial. Dig. Liver Dis. 2015;47:226–232. doi: 10.1016/j.dld.2014.11.015.
    1. Faghihzadeh F., Adibi P., Hekmatdoost A. The effects of resveratrol supplementation on cardiovascular risk factors in patients with non-alcoholic fatty liver disease: A randomised, double-blind, placebo-controlled study. Br. J. Nutr. 2015;114:796–803. doi: 10.1017/S0007114515002433.
    1. Heebøll S., Kreuzfeldt M., Hamilton-Dutoit S., Kjær Poulsen M., Stødkilde-Jørgensen H., Møller H., Jessen N., Thorsen K., Kristina Hellberg Y., Bønløkke Pedersen S., et al. Placebo-controlled, randomised clinical trial: High-dose resveratrol treatment for non-alcoholic fatty liver disease. Scand. J. Gastroenterol. 2016;51:456–464. doi: 10.3109/00365521.2015.1107620.
    1. Kurzthaler D., Hadziomerovic-Pekic D., Wildt L., Seeber B.E. Metformin induces a prompt decrease in LH-stimulated testosterone response in women with PCOS independent of its insulin-sensitizing effects. Reprod. Biol. Endocrinol. 2014;12:98. doi: 10.1186/1477-7827-12-98.
    1. Hirsch A., Hahn D., Kempná P., Hofer G., Nuoffer J.M., Mullis P.E., Flück C.E. Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain. Endocrinology. 2012;153:4354–4366. doi: 10.1210/en.2012-1145.
    1. Fullerton M.D., Steinberg G.R. SIRT1 takes a backseat to AMPK in the regulation of insulin sensitivity by resveratrol. Diabetes. 2010;59:551–553. doi: 10.2337/db09-1732.
    1. Lan F., Weikel K.A., Cacicedo J.M., Ido Y. Resveratrol-Induced AMP-Activated Protein Kinase Activation Is Cell-Type Dependent: Lessons from Basic Research for Clinical Application. Nutrients. 2017;9:751. doi: 10.3390/nu9070751.
    1. Baur J.A., Pearson K.J., Price N.L., Jamieson H.A., Lerin C., Kalra A., Prabhu V.V., Allard J.S., Lopez-Lluch G., Lewis K., et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–342. doi: 10.1038/nature05354.
    1. Goh K.P., Lee H.Y., Lau D.P., Supaat W., Chan Y.H., Koh A.F. Effects of resveratrol in patients with type 2 diabetes mellitus on skeletal muscle SIRT1 expression and energy expenditure. Int. J. Sport Nutr. Exerc. Metab. 2014;24:2–13. doi: 10.1123/ijsnem.2013-0045.
    1. Zhu X., Wu C., Qiu S., Yuan X., Li L. Effects of resveratrol on glucose control and insulin sensitivity in subjects with type 2 diabetes: Systematic review and meta-analysis. Nutr. Metab. (Lond.) 2017;14:60. doi: 10.1186/s12986-017-0217-z.
    1. Chiba T., Tsuchiya T., Komatsu T., Mori R., Hayashi H., Shimokawa I. Development of calorie restriction mimetics as therapeutics for obesity, diabetes, inflammatory and neurodegenerative diseases. Curr. Genom. 2010;11:562–567. doi: 10.2174/138920210793360934.
    1. Djiogue S., Nwabo Kamdje A.H., Vecchio L., Kipanyula M.J., Farahna M., Aldebasi Y., Seke Etet P.F. Insulin resistance and cancer: The role of insulin and IGFs. Endocr. Relat. Cancer. 2013;20:R1–R17. doi: 10.1530/ERC-12-0324.
    1. Sun W., Lu J., Wu S., Bi Y., Mu Y., Zhao J., Liu C., Chen L., Shi L., Li Q., et al. Association of insulin resistance with breast, ovarian, endometrial and cervical cancers in non-diabetic women. Am. J. Cancer Res. 2016;6:2334–2344.
    1. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492.
    1. Perrotta I., Bruno L., Maltese L., Russo E., Donato A., Donato G. Immunohistochemical analysis of the ubiquitin-conjugating enzyme UbcH10 in lung cancer: A useful tool for diagnosis and therapy. J. Histochem. Cytochem. 2012;60:359–365. doi: 10.1369/0022155412439717.
    1. Brown K.F., Rumgay H., Dunlop C., Ryan M., Quartly F., Cox A., Deas A., Elliss-Brookes L., Gavin A., Hounsome L., et al. The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015. Br. J. Cancer. 2018;118:1130–1141. doi: 10.1038/s41416-018-0029-6.
    1. Castelló A., Pollán M., Buijsse B., Ruiz A., Casas A.M., Baena-Cañada J.M., Lope V., Antolín S., Ramos M., Muñoz M., et al. Spanish Mediterranean diet and other dietary patterns and breast cancer risk: Case-control EpiGEICAM study. Br. J. Cancer. 2014;111:1454–1462. doi: 10.1038/bjc.2014.434.
    1. Toledo E., Salas-Salvadó J., Donat-Vargas C., Buil-Cosiales P., Estruch R., Ros E., Corella D., Fitó M., Hu F.B., Arós F., et al. Mediterranean Diet and Invasive Breast Cancer Risk Among Women at High Cardiovascular Risk in the PREDIMED Trial: A Randomized Clinical Trial. JAMA Intern. Med. 2015;175:1752–1760. doi: 10.1001/jamainternmed.2015.4838.
    1. Koene R.J., Prizment A.E., Blaes A., Konety S.H. Shared Risk Factors in Cardiovascular Disease and Cancer. Circulation. 2016;133:1104–1114. doi: 10.1161/CIRCULATIONAHA.115.020406.
    1. Masoudkabir F., Sarrafzadegan N., Gotay C., Ignaszewski A., Krahn A.D., Davis M.K., Franco C., Mani A. Cardiovascular disease and cancer: Evidence for shared disease pathways and pharmacologic prevention. Atherosclerosis. 2017;263:343–351. doi: 10.1016/j.atherosclerosis.2017.06.001.
    1. Freisling H., Viallon V., Lennon H., Bagnardi V., Ricci C., Butterworth A.S., Sweeting M., Muller D., Romieu I., Bazelle P., et al. Lifestyle factors and risk of multimorbidity of cancer and cardiometabolic diseases: A multinational cohort study. BMC Med. 2020;18:5. doi: 10.1186/s12916-019-1474-7.
    1. Fortin M., Haggerty J., Almirall J., Bouhali T., Sasseville M., Lemieux M. Lifestyle factors and multimorbidity: A cross sectional study. BMC Public Health. 2014;14:686. doi: 10.1186/1471-2458-14-686.
    1. Dhalwani N.N., Zaccardi F., O’Donovan G., Carter P., Hamer M., Yates T., Davies M., Khunti K. Association Between Lifestyle Factors and the Incidence of Multimorbidity in an Older English Population. J. Gerontol. A Biol. Sci. Med. Sci. 2017;72:528–534. doi: 10.1093/gerona/glw146.
    1. World Health Organization . Global Action Plan. for the Prevention and Control. of Noncommunicable Diseases 2013–2020. World Health Organization; Geneva, Switzerland: 2013. [(accessed on 24 February 2020)]. Available online:
    1. Xiao Y., Xia J., Li L., Ke Y., Cheng J., Xie Y., Chu W., Cheung P., Kim J.H., Colditz G.A., et al. Associations between dietary patterns and the risk of breast cancer: A systematic review and meta-analysis of observational studies. Breast Cancer Res. 2019;21:16. doi: 10.1186/s13058-019-1096-1.
    1. Key T.J. Endogenous oestrogens and breast cancer risk in premenopausal and postmenopausal women. Steroids. 2011;76:812–815. doi: 10.1016/j.steroids.2011.02.029.
    1. Gérard C., Brown K.A. Obesity and breast cancer - Role of estrogens and the molecular underpinnings of aromatase regulation in breast adipose tissue. Mol. Cell Endocrinol. 2018;466:15–30. doi: 10.1016/j.mce.2017.09.014.
    1. Paonessa F., Foti D., Costa V., Chiefari E., Brunetti G., Leone F., Luciano F., Wu F., Lee A.S., Gulletta E., et al. Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer. Cancer Res. 2006;66:5085–5093. doi: 10.1158/0008-5472.CAN-05-3678.
    1. Sgarra R., Pegoraro S., Ros G., Penzo C., Chiefari E., Foti D., Brunetti A., Manfioletti G. High Mobility Group A (HMGA) proteins: Molecular instigators of breast cancer onset and progression. Biochim. Biophys. Acta Rev. Cancer. 2018;1869:216–229. doi: 10.1016/j.bbcan.2018.03.001.
    1. Laria A.E., Messineo S., Arcidiacono B., Varano M., Chiefari E., Semple R.K., Rocha N., Russo D., Cuda G., Gaspari M., et al. Secretome Analysis of Hypoxia-Induced 3T3-L1 Adipocytes Uncovers Novel Proteins Potentially Involved in Obesity. Proteomics. 2018;18:e1700260. doi: 10.1002/pmic.201700260.
    1. Chiefari E., Foti D.P., Sgarra R., Pegoraro S., Arcidiacono B., Brunetti F.S., Greco M., Manfioletti G., Brunetti A. Transcriptional Regulation of Glucose Metabolism: The Emerging Role of the HMGA1 Chromatin Factor. Front. Endocrinol. (Lausanne) 2018;9:357. doi: 10.3389/fendo.2018.00357.
    1. Capurso A., Crepaldi G., Capurso C. Benefits of the Mediterranean Diet in the Elderly Patient. Springer; Cham, Switzerland: 2018. Epigenetics/Epigenomics of Olive Oil and the Mediterranean Diet; pp. 115–138. Practical Issues in Geriatrics.
    1. Menendez J.A., Lupu R. Mediterranean dietary traditions for the molecular treatment of human cancer: Anti-oncogenic actions of the main olive oil’s monounsaturated fatty acid oleic acid (18:1n-9) Curr. Pharm. Biotechnol. 2006;7:495–502. doi: 10.2174/138920106779116900.
    1. D’Amore S., Vacca M., Cariello M., Graziano G., D’Orazio A., Salvia R., Sasso R.C., Sabbà C., Palasciano G., Moschetta A. Genes and miRNA expression signatures in peripheral blood mononuclear cells in healthy subjects and patients with metabolic syndrome after acute intake of extra virgin olive oil. Biochim. Biophys. Acta. 2016;1861:1671–1680. doi: 10.1016/j.bbalip.2016.07.003.
    1. Khymenets O., Fitó M., Covas M.I., Farré M., Pujadas M.A., Muñoz D., Konstantinidou V., de la Torre R. Mononuclear cell transcriptome response after sustained virgin olive oil consumption in humans: An exploratory nutrigenomics study. OMICS. 2009;13:7–19. doi: 10.1089/omi.2008.0079.
    1. Chiefari E., Arcidiacono B., Palmieri C., Corigliano D.M., Morittu V.M., Britti D., Armoni M., Foti D.P., Brunetti A. Cross-talk among HMGA1 and FoxO1 in control of nuclear insulin signaling. Sci. Rep. 2018;8:8540. doi: 10.1038/s41598-018-26968-3.
    1. Penzo C., Arnoldo L., Pegoraro S., Petrosino S., Ros G., Zanin R., Wiśniewski J.R., Manfioletti G., Sgarra R. HMGA1 Modulates Gene Transcription Sustaining a Tumor Signalling Pathway Acting on the Epigenetic Status of Triple-Negative Breast Cancer Cells. Cancers. 2019;11:1105. doi: 10.3390/cancers11081105.
    1. Balletshofer B.M., Rittig K., Stock J., Lehn-Stefan A., Overkamp D., Dietz K., Häring H.U. Insulin resistant young subjects at risk of accelerated atherosclerosis exhibit a marked reduction in peripheral endothelial function early in life but not differences in intima-media thickness. Atherosclerosis. 2003;17:303–309. doi: 10.1016/j.atherosclerosis.2003.08.013.
    1. Mäkimattila S., Liu M.L., Vakkilainen J., Schlenzka A., Lahdenperä S., Syvänne M., Mäntysaari M., Summanen P., Bergholm R., Taskinen M.R., et al. Impaired endothelium-dependent vasodilation in type 2 diabetes. Relation to LDL size, oxidized LDL, and antioxidants. Diabetes Care. 1999;22:973–981. doi: 10.2337/diacare.22.6.973.
    1. Benjamin E.J., Larson M.G., Keyes M.J., Mitchell G.F., Vasan R.S., Keaney J.F., Jr., Lehman B.T., Fan S., Osypiuk E., Vita J.A. Clinical correlates and heritability of flow-mediated dilation in the community: The Framingham Heart Study. Circulation. 2004;109:613–619. doi: 10.1161/01.CIR.0000112565.60887.1E.
    1. Lteif A.A., Han K., Mather K.J. Obesity, insulin resistance, and the metabolic syndrome: Determinants of endothelial dysfunction in whites and blacks. Circulation. 2005;112:32–38. doi: 10.1161/CIRCULATIONAHA.104.520130.
    1. Balletshofer B.M., Rittig K., Enderle M.D., Volk A., Maerker E., Jacob S., Matthaei S., Rett K., Häring H.U. Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation. 2000;101:1780–1784. doi: 10.1161/01.CIR.101.15.1780.
    1. Kolluru G., Bir S., Kevil C. Endothelial dysfunction and diabetes: Effects on angiogenesis, vascular remodeling, and wound healing. Int. J. Vasc. Med. 2012;2012:918267. doi: 10.1155/2012/918267.
    1. Palella E., Cimino R., Pullano S.A., Fiorillo A.S., Gulletta E., Brunetti A., Foti D.P., Greco M. Laboratory parameters of hemostasis, adhesion molecules, and inflammation in type 2 diabetes mellitus: Correlation with glycemic control. Int. J. Environ. Res. Public Health. 2020;17:300. doi: 10.3390/ijerph17010300.
    1. Schwingshackl L., Christoph M., Hoffmann G. Effects of olive oil on markers of inflammation and endothelial function—A systematic review and metaanalysis. Nutrients. 2015;7:7651–7675. doi: 10.3390/nu7095356.
    1. Summerhill V., Karagodin V., Grechko A., Myasoedova V., Orekhov A. Vasculoprotective Role of Olive Oil Compounds via Modulation of Oxidative Stress in Atherosclerosis. Front. Cardiovasc. Med. 2018;5:188. doi: 10.3389/fcvm.2018.00188.
    1. Li M., Qian M., Kyler K., Xu J. Endothelial-Vascular Smooth Muscle Cells Interactions in Atherosclerosis. Front. Cardiovasc. Med. 2018;5:151. doi: 10.3389/fcvm.2018.00151.
    1. Wang G., Jacquet L., Karamariti E., Xu Q. Origin and differentiation of vascular smooth muscle cells. J. Physiol. 2015;593:3013–3030. doi: 10.1113/JP270033.
    1. Schlueter C., Hauke S., Loeschke S., Wenk H.H., Bullerdiek J. HMGA1 proteins in human atherosclerotic plaques. Pathol. Res. Pract. 2005;201:101–107. doi: 10.1016/j.prp.2004.11.010.
    1. Iwai K., Morita T., Iritani O., Morimoto S., Nakamura Y., Ishigaki Y. Abstract 11211: CTCF and HMGA1 Opposite Directionally Regulate the Gene Expression of microRNAs at Scaffold/ Matrix-attachment Regions in the Arterial Smooth Muscle Cell. Circulation. 2013;128:A11211.
    1. Gogoi B., Chatterjee P., Mukherjee S., Buragohain A.K., Bhattacharya S., Dasgupta S. A polyphenol rescues lipid induced insulin resistance in skeletal muscle cells and adipocytes. Biochem. Biophys. Res. Commun. 2014;452:382–388. doi: 10.1016/j.bbrc.2014.08.079.
    1. Whelton P.K., Carey R.M., Aronow W.S., Casey D.E., Jr., Collins K.J., Dennison Himmelfarb C., DePalma S.M., Gidding S., Jamerson K.A., Jones D.W., et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:1269–1324. doi: 10.1161/HYP.0000000000000066.
    1. Appel L.J. Lifestyle modification as a means to prevent and treat high blood pressure. J. Am. Soc. Nephrol. 2003;14:S99–S102. doi: 10.1097/01.ASN.0000070141.69483.5A.
    1. Bendinelli B., Masala G., Bruno R.M., Caini S., Saieva C., Boninsegni A., Ungar A., Ghiadoni L., Palli D. A priori dietary patterns and blood pressure in the EPIC Florence cohort: A cross-sectional study. Eur. J. Nutr. 2019;58:455–466. doi: 10.1007/s00394-018-1758-2.
    1. Toledo E., Hu F., Estruch R., Buil-Cosiales P., Corella D., Salas-Salvadó J., Covas M.I., Arós F., Gómez-Gracia E., Fiol M., et al. Effect of the Mediterranean diet on blood pressure in the PREDIMED trial: Results from a randomized controlled trial. BMC Med. 2013;11:207. doi: 10.1186/1741-7015-11-207.
    1. Campesi I., Marino M., Cipolletti M., Romani A., Franconi F. Put “gender glasses” on the effects of phenolic compounds on cardiovascular function and diseases. Eur. J. Nutr. 2018;57:2677–2691. doi: 10.1007/s00394-018-1695-0.
    1. Galvão Cândido F., Xavier Valente F., da Silva L.E., Gonçalves Leão Coelho O., Gouveia Peluzio M.D.C., Gonçalves Alfenas R.C. Consumption of extra virgin olive oil improves body composition and blood pressure in women with excess body fat: A randomized, double-blinded, placebo-controlled clinical trial. Eur. J. Nutr. 2018;57:2445–2455. doi: 10.1007/s00394-017-1517-9.
    1. Storniolo C.E., Roselló-Catafau J., Pintó X., Mitjavila M.T., Moreno J.J. Polyphenol fraction of extra virgin olive oil protects against endothelial dysfunction induced by high glucose and free fatty acids through modulation of nitric oxide and endothelin-1. Redox Biol. 2014;2:971–977. doi: 10.1016/j.redox.2014.07.001.
    1. Jiménez-Morales A.I., Ruano J., Delgado-Lista J., Fernandez J.M., Camargo A., López-Segura F., Villarraso J.C., Fuentes-Jiménez F., López-Miranda J., Pérez-Jiménez F. NOS3 Glu298Asp polymorphism interacts with virgin olive oil phenols to determine the postprandial endothelial function in patients with the metabolic syndrome. J. Clin. Endocrinol. Metab. 2011;96:E1694–E1702. doi: 10.1210/jc.2011-1056.
    1. Imrie H., Abbas A., Kearney M. Insulin resistance, lipotoxicity and endothelial dysfunction. Biochim. Biophys. Acta. 2010;1801:320–326. doi: 10.1016/j.bbalip.2009.09.025.
    1. Arnett D.K., Blumenthal R.S., Albert M.A., Buroker A.B., Goldberger Z.D., Hahn E.J., Himmelfarb C.D., Khera A., Lloyd-Jones D., McEvoy J.W., et al. ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140:e596–e646. doi: 10.1161/CIR.0000000000000678.
    1. Bjornstad P., Eckel R.H. Pathogenesis of Lipid Disorders in Insulin Resistance: A Brief Review. Curr. Diab. Rep. 2018;18:127. doi: 10.1007/s11892-018-1101-6.
    1. Hernáez Á., Castañer O., Goday A., Ros E., Pintó X., Estruch R., Salas-Salvadó J., Corella D., Arós F., Serra-Majem L., et al. The Mediterranean Diet decreases LDL atherogenicity in high cardiovascular risk individuals: A randomized controlled trial. Mol. Nutr. Food Res. 2017;61:9. doi: 10.1002/mnfr.201601015.
    1. Meisinger C., Baumert J., Khuseyinova N., Loewel H., Koenig W. Plasma Oxidized Low-Density Lipoprotein, a Strong Predictor for Acute Coronary Heart Disease Events in Apparently Healthy, Middle-AgedMen from the General Population. Circulation. 2005;112:651–657. doi: 10.1161/CIRCULATIONAHA.104.529297.
    1. Galeano N.F., Al-Haideri M., Keyserman F., Rumsey S.C., Deckelbaum R.J. Small dense low density lipoprotein has increased affinity for LDL receptor-independent cell surface binding sites: A potential mechanism for increased atherogenicity. J. Lipid Res. 1998;39:1263–1273.
    1. Hoogeveen R.C., Gaubatz J.W., Sun W., Dodge R.C., Crosby J.R., Jiang J., Couper D., Virani S.S., Kathiresan S., Boerwinkle E., et al. Small dense low-density lipoprotein-cholesterol concentrations predict risk for coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study. Arterioscler. Thromb. Vasc. Biol. 2014;34:1069–1077. doi: 10.1161/ATVBAHA.114.303284.
    1. Gaforio J.J., Visioli F., Alarcón-de-la-Lastra C., Castañer O., Delgado-Rodríguez M., Fitó M., Hernández A.F., Huertas J.R., Martínez-González M.A., Menendez J.A., et al. Virgin Olive Oil and Health: Summary of the III International Conference on Virgin Olive Oil and Health Consensus Report, JAEN (Spain) 2018. Nutrients. 2019;11:2039. doi: 10.3390/nu11092039.
    1. Hernáez Á., Fernández-Castillejo S., Farràs M., Catalán Ú., Subirana I., Montes R., Solà R., Muñoz-Aguayo D., Gelabert-Gorgues A., Díaz-Gil Ó., et al. Olive Oil Polyphenols Enhance High-Density Lipoprotein Function in Humans: A Randomized Controlled Trial. Arterioscler. Thromb. Vasc. Biol. 2014;34:2115–2119. doi: 10.1161/ATVBAHA.114.303374.
    1. Fitó M., Cladellas M., de la Torre R., Martí J., Alcántara M., Pujadas-Bastardes M., Marrugat J., Bruguera J., López-Sabater M.C., Vila J., et al. Antioxidant effect of virgin olive oil in patients with stable coronary heart disease: A randomized, crossover, controlled, clinical trial. Atherosclerosis. 2005;181:149–158. doi: 10.1016/j.atherosclerosis.2004.12.036.
    1. Weinbrenner T., Fitó M., de la Torre R., Saez G.T., Rijken P., Tormos C., Coolen S., Albaladejo M.F., Abanades S., Schroder H., et al. Olive oils high in phenolic compounds modulate oxidative/antioxidative status in men. J. Nutr. 2004;134:2314–2321. doi: 10.1093/jn/134.9.2314.
    1. Marrugat J., Covas M.I., Fitó M., Schröder H., Miró-Casas E., Gimeno E., López-Sabater M.C., de la Torre R., Farré M. SOLOS Investigators. Effects of differing phenolic content in dietary olive oils on lipids and LDL oxidation—A randomized controlled trial. Eur. J. Nutr. 2004;43:140–147. doi: 10.1007/s00394-004-0452-8.
    1. Rader D.J. Mediterranean Approach to Improving High-Density Lipoprotein Function. Circulation. 2017;135:644–647. doi: 10.1161/CIRCULATIONAHA.117.026278.
    1. Hernáez Á., Castañer O., Elosua R., Pintó X., Estruch R., Salas-Salvadó J., Corella D., Arós F., Serra-Majem L., Fiol M., et al. Mediterranean Diet Improves High-Density Lipoprotein Function in High-Cardiovascular-Risk Individuals: A Randomized Controlled Trial. Circulation. 2017;135:633–643. doi: 10.1161/CIRCULATIONAHA.116.023712.
    1. Castro-Barquero S., Tresserra-Rimbau A., Vitelli-Storelli F., Doménech M., Salas-Salvadó J., Martín-Sánchez V., Rubín-García M., Buil-Cosiales P., Corella D., Fitó M., et al. Dietary Polyphenol Intake is Associated with HDL-Cholesterol and A Better Profile of other Components of the Metabolic Syndrome: A PREDIMED-Plus Sub-Study. Nutrients. 2020;12:689. doi: 10.3390/nu12030689.
    1. Vitale M., Masulli M., Rivellese A.A., Bonora E., Cappellini F., Nicolucci A., Squatrito S., Antenucci D., Barrea A., Bianchi C., et al. Dietary intake and major food sources of polyphenols in people with type 2 diabetes: The Study. Eur. J. Nutr. 2018;57:679–688. doi: 10.1007/s00394-016-1355-1.
    1. PREDIMED study investigators Intake of Total Polyphenols and Some Classes of Polyphenols Is Inversely Associated with Diabetes in Elderly People at High Cardiovascular Disease Risk. J. Nutr. 2015;146:767–777. doi: 10.3945/jn.115.223610.
    1. Gansevoort R.T., Correa-Rotter R., Hemmelgarn B.R., Jafar T.H., Heerspink H.J., Mann J.F., Matsushita K., Wen C.P. Chronic kidney disease and cardiovascular risk: Epidemiology, mechanisms, and prevention. Lancet. 2013;382:339–352. doi: 10.1016/S0140-6736(13)60595-4.
    1. Kobayashi S., Maesato K., Moriya H., Ohtake T., Ikeda T. Insulin resistance in patients with chronic kidney disease. Am. J. Kidney Dis. 2005;45:275–280. doi: 10.1053/j.ajkd.2004.09.034.
    1. Shinohara K., Shoji T., Emoto M., Tahara H., Koyama H., Ishimura E., Miki T., Tabata T., Nishizawa Y. Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease. J. Am. Soc. Nephrol. 2002;13:1894–1900. doi: 10.1097/01.ASN.0000019900.87535.43.
    1. DeFronzo R.A., Alvestrand A., Smith D., Hendler R., Hendler E., Wahren J. Insulin resistance in uremia. J. Clin. Invest. 1981;67:563–568. doi: 10.1172/JCI110067.
    1. Gluba A., Mikhailidis D.P., Lip G.Y., Hannam S., Rysz J., Banach M. Metabolic syndrome and renal disease. Int. J. Cardiol. 2013;164:141–150. doi: 10.1016/j.ijcard.2012.01.013.
    1. Teta D. Insulin resistance as a therapeutic target for chronic kidney disease. J. Ren. Nutr. 2015;25:226–229. doi: 10.1053/j.jrn.2014.10.019.
    1. Xu H., Carrero J.J. Insulin resistance in chronic kidney disease. Nephrology (Carlton) 2017;22(Suppl. 4):31–34. doi: 10.1111/nep.13147.
    1. Schrauben S.J., Jepson C., Hsu J., Wilson F.P., Zhang X., Lash J.P., Robinson B.M., Townsend R.R., Chen J., Fogelfeld L., et al. Insulin resistance and chronic kidney disease progression, cardiovascular events, and death: Findings from the chronic renal insufficiency cohort study. BMC Nephrol. 2019;20:60. doi: 10.1186/s12882-019-1220-6.
    1. Cheng H.T., Huang J.W., Chiang C.K., Yen C.J., Hung K.Y., Wu K.D. Metabolic syndrome and insulin resistance as risk factors for development of chronic kidney disease and rapid decline in renal function in elderly. J. Clin. Endocrinol. Metab. 2012;97:1268–1276. doi: 10.1210/jc.2011-2658.
    1. Kobayashi H., Tokudome G., Hara Y., Sugano N., Endo S., Suetsugu Y., Kuriyama S., Hosoya T. Insulin resistance is a risk factor for the progression of chronic kidney disease. Clin. Nephrol. 2009;71:643–651. doi: 10.5414/CNP71643.
    1. Kelly J.T., Palmer S.C., Wai S.N., Ruospo M., Carrero J.J., Campbell K.L., Strippoli G.F. Healthy dietary patterns and risk of mortality and ESRD in CKD: A meta-analysis of cohort studies. Clin. J. Am. Soc. Nephrol. 2017;12:272–279. doi: 10.2215/CJN.06190616.
    1. Chauveau P., Aparicio M., Bellizzi V., Campbell K., Hong X., Johansson L., Kolko A., Molina P., Sezer S., Wanner C., et al. Mediterranean diet as the diet of choice for patients with chronic kidney disease. Nephrol. Dial. Transpl. 2018;33:725–735. doi: 10.1093/ndt/gfx085.
    1. Kushi L.H., Lenart E.B., Willett W.C. Health implications of Mediterranean diets in light of contemporary knowledge. 2. Meat, wine, fats, and oils. Am. J. Clin. Nutr. 1995;61(Suppl. 6):1416S–1427S. doi: 10.1093/ajcn/61.6.1416S.
    1. Krishnamurthy V.M., Wei G., Baird B.C., Murtaugh M., Chonchol M.B., Raphael K.L., Greene T., Beddhu S. High dietary fiber intake is associated with decreased inflammation and all-cause mortality in patients with chronic kidney disease. Kidney Int. 2012;81:300–306. doi: 10.1038/ki.2011.355.
    1. Williamson G. The role of polyphenols in modern nutrition. Nutr. Bull. 2017;42:226–235. doi: 10.1111/nbu.12278.
    1. Maruca A., Ambrosio F.A., Lupia A., Romeo I., Rocca R., Moraca F., Talarico C., Bagetta D., Catalano R., Costa G., et al. Computer-based techniques for lead identification and optimization I: Basics. Phys. Sci. Rev. 2019;4:6. doi: 10.1515/psr-2018-0113.
    1. Garcia-Cortes M., Robles-Diaz M., Ortega-Alonso A., Medina-Caliz I., Andrade R.J. Hepatotoxicity by dietary supplements: A tabular listing and clinical characteristics. Int. J. Mol. Sci. 2016;17:537. doi: 10.3390/ijms17040537.
    1. Cory H., Passarelli S., Szeto J., Tamez M., Mattei J. The Role of Polyphenols in Human Health and Food Systems: A Mini-Review. Front. Nutr. 2018;5:87. doi: 10.3389/fnut.2018.00087.
    1. Bode A.M., Dong Z. Toxic phytochemicals and their potential risks for human cancer. Cancer Prev. Res. (Phila) 2015;8:1–8. doi: 10.1158/1940-6207.CAPR-14-0160.
    1. Azqueta A., Collins A. Polyphenols and DNA Damage: A Mixed Blessing. Nutrients. 2016;8:785. doi: 10.3390/nu8120785.

Source: PubMed

3
Se inscrever