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Cited by 272Nutritional Studies and DietNatural Antidiabetic Agents StudiesAdipokines, Inflammation, and Metabolic Diseases

Mediterranean diet nutrients to turn the tide against insulin resistance and related diseases

Open access
Mirabelli, Maria, Chiefari, Eusebio, Arcidiacono, Biagio, Corigliano, Domenica Maria, Brunetti, Francesco Saverio, Maggisano, Valentina, Russo, Diego, Foti, Daniela Patrizia +1 more·2020·Nutrients
DOI 10.3390/nu12041066PMC PMC7230471
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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.

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TL;DR

This narrative review argues that the Mediterranean diet (MedDiet) and selected nutrients—unsaturated fatty acids, flavonoids/anthocyanins, resveratrol, EVOO-derived oleacein, and polyphenols—can improve insulin resistance (IR) and related conditions such as T2D, NAFLD, cognitive impairment, PCOS, breast cancer, endothelial dysfunction, dyslipidemia, hypertension, and CKD. It emphasizes compound-specific mechanisms, including possible HMGA1-mediated gene regulation, while noting that clinical and safety evidence remains incomplete.

Key findings

  • IR affects approximately 25%–35% of Westernized populations and is linked to obesity, T2D, CVD, NAFLD, cognitive impairment, PCOS, CKD, and some cancers; MedDiet has been associated with greater IR improvement in obese individuals than other low-energy diets, even with <5% body weight loss.
  • A meta-analysis of 8 prospective cohorts (312,015 participants; 19,953 incident T2D cases over 4–28 years) found the highest total flavonoid intake associated with an 11% lower T2D risk, with a 5% risk reduction per 300 mg/day increment.
  • In a randomized placebo-controlled trial, 1500 mg/day resveratrol for 3 months decreased testosterone and DHEAS excess by ~23% in PCOS women; in mice, 20 mg/day oleacein for 5 weeks protected against abdominal fat accumulation, weight gain, and liver steatosis.
  • In PREDIMED, breast cancer incidence rates were 1.1 per 1000 person-years for EVOO-enriched MedDiet, 1.8 for nuts-enriched MedDiet, and 2.9 for control; in NU-AGE, 1-year SBP decreased by −4.7 mmHg in the intervention group versus a 0.9 mmHg increase in controls.

Methods

  • Narrative review, not a systematic review or meta-analysis; it synthesizes mechanistic, epidemiological, animal-model, and clinical evidence on MedDiet components and IR-related diseases.
  • Evidence discussed includes in vitro studies, experimental animal models, randomized controlled trials, prospective cohorts, cross-sectional studies, and meta-analyses, with findings summarized in Tables 1–2 and Figures 1–5.
  • Main analysis is qualitative synthesis from a compound-centric perspective, linking nutrients such as PUFAs/MUFAs, flavonoids, anthocyanins, resveratrol, oleacein, and other polyphenols to IR-related pathways and outcomes.

Limitations

  • Stated in paper: current knowledge about how MedDiet functional components modulate insulin action and signaling is still limited; further in vivo studies are needed to determine therapeutic potential in humans and tissue-level biological activities.
  • Stated in paper: safety and effective dosing of isolated polyphenol supplements are uncertain, with risks including hepatotoxicity, stroke/premature death, and carcinogenesis at high doses; longer follow-up and larger sample sizes are needed for promising supplements.
  • Evident from text: as a narrative review, it does not report a systematic search strategy, risk-of-bias assessment, or quantitative pooling; some cited evidence is inconclusive, such as the CRIC study finding no significant association between baseline HOMA-IR and CKD progression, CVD events, or mortality in non-diabetic CKD patients.

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Registry

Crossref · 10.3390/nu12041066

Cites

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Claims the paper makes

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  • Premisecitation

    Even in European countries surrounding the Mediterranean Sea, half of children and adolescents show only low adherence to the Mediterranean dietary tradition.

    “Nonetheless, even in European countries surrounding the Mediterranean Sea, half of the children and adolescents show only a low adherence to this healthy dietary tradition [24], with a high rate of pediatric overweight and development of obesity and related complications in adult life.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Archero, F., Ricotti, R., Solito, A., Carrera, D., Civello, F., Di Bella, R., Bellone, S., and Prodam, F. (2018). Adherence to the Mediterranean Diet among School Children and Adolescents Living in Northern Italy and Unhealthy Food Behaviors Associated to Overweight. Nutrients, 10. source

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  • Premisecitation

    The Mediterranean diet is associated with greater improvement of insulin resistance in obese individuals compared with other nutritional interventions.

    “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 stated in: § 1. Introduction · boosted
      “As part of a hypocaloric regimen, the Mediterranean diet (MedDiet) has proved to be associated with a greater improvement of IR in obese individuals when compared to other low-energy dietary approaches [17], even after a mild decrement of body weight of less than 5% [18].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Shai, 2008, Dietary Intervention Randomized Controlled Trial (DIRECT) Group. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet, N. Engl. J. Med. source

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    • cites [18] Greco, 2014, Early effects of a hypocaloric, Mediterranean diet on laboratory parameters in obese individuals, Mediat. Inflamm. source

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  • Premisecitation

    Consumption of fish, nuts and dairy products can be related to better body composition and fitness performance in adolescents, in terms of speed/agility and cardiorespiratory endurance.

    “The consumption of fish, nuts and dairy products, representing a fundamental aspect in the MedDiet, can be related to a better body composition and fitness performance in adolescents, in terms of speed/agility and cardiorespiratory endurance [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Galan-Lopez, P., Sanchez-Oliver, A.J., Pihu, M., Gisladottir, T., Dominguez, R., and Ries, F. (2019). Association between Adherence to the Mediterranean Diet and Physical Fitness with Body Composition Parameters in 1717 European Adolescents: The AdolesHealth Study. Nutrients, 12. source

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  • Premisecitation

    Adherence to the Mediterranean eating style can give health advantages starting from young age.

    “As recently evidenced in cross-sectional investigations, adherence to the Mediterranean eating style can give health advantages starting from young age [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Galan-Lopez, P., Sanchez-Oliver, A.J., Pihu, M., Gisladottir, T., Dominguez, R., and Ries, F. (2019). Association between Adherence to the Mediterranean Diet and Physical Fitness with Body Composition Parameters in 1717 European Adolescents: The AdolesHealth Study. Nutrients, 12. source

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  • Premisecitation

    In obese individuals destined to become diabetics, pancreatic beta-cells may compensate for impaired peripheral insulin responsiveness by secreting more insulin, leading to hyperinsulinemia, a biological marker of insulin resistance often indicative of pre-diabetic status.

    “At first, in obese individuals destined to become diabetics, pancreatic β-cells may compensate for the impaired peripheral insulin responsiveness by secreting more insulin into the bloodstream in an effort to reduce blood glucose levels, thus leading to hyperinsulinemia, a biological marker of IR, often indicative of a pre-diabetic status [29,30].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Leahy, 2005, Pathogenesis of type 2 diabetes mellitus, Arch. Med. Res. source

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    • cites [30] Arcidiacono, 2015, Cooperation between HMGA1, PDX-1, and MafA is essential for glucose- induced insulin transcription in pancreatic beta cells, Front. Endocrinol. source

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    Premisecitation

    Dysfunctional adipose tissue in obesity is associated with hypertrophy and hyperplasia of adipocytes, chronic inflammatory cell infiltration, and activation of the cytokine network, representing the main determinant of insulin resistance and the major risk factor for type 2 diabetes and its complications.

    “Dysfunctional adipose tissue in obesity is associated with hypertrophy and hyperplasia of adipocytes, chronic inflammatory cell infiltration, and activation of the cytokine network, representing the main determinant of IR and the major risk factor for the development of T2D and its complications [28].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Ye, 2013, Mechanisms of insulin resistance in obesity, Front. Med. source

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    Premisecitation

    Insulin resistance is consistently associated with obesity and obesity-related complications such as type 2 diabetes, cardiovascular disease, certain cancers, infertility, non-alcoholic fatty liver disease, and cognitive impairment.

    “IR affects approximately 25%–35% of Westernized populations [2] and is consistently associated with obesity [3] and obesity-related complications, such as type 2 diabetes (T2D) mellitus [4], cardiovascular disease (CVD) [5,6], certain types of cancer [7], infertility [8], non-alcoholic fatty liver disease (NAFLD) [9,10], and cognitive impairment [11].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [3] Czech, 2017, Insulin action and resistance in obesity and type 2 diabetes, Nat. Med. source

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    • cites [4] Brunetti, 1993, Identification of unique nuclear regulatory proteins for the insulin receptor gene, which appear during myocyte and adipocyte differentiation, J. Clin. Invest. source

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    • cites [5] Hong, S.H., and Choi, K.M. (2020). Sarcopenic Obesity, Insulin Resistance, and Their Implications in Cardiovascular and Metabolic Consequences. Int. J. Mol. Sci., 21. source

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    • cites [6] Arcidiacono, 2018, Type 2 diabetes mellitus and cardiovascular disease: Genetic and epigenetic links, Front. Endocrinol. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Type 2 diabetes is a frequent consequence of insulin resistance and the most common metabolic disease, affecting millions of people worldwide.

    “T2D, a frequent consequence of IR, is the most common metabolic disease, affecting millions of people throughout the world [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Zheng, 2018, Global aetiology and epidemiology of type 2 diabetes mellitus and its complications, Nat. Rev. Endocrinol. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The Mediterranean diet term reflects food combinations typical of Mediterranean populations in the early 1960s, in which adult life expectancy was among the highest in the world, with lower rates of cardiovascular disease and other chronic aging-related diseases.

    “The “Mediterranean diet” term reflects food combinations typical of Mediterranean populations, such as Greeks, Southern Italians and Spanish, in the early 1960s, in which adult life expectancy was found, together with the Japanese population, to be among the highest in the world, with lower rates of CVD and other chronic aging-related diseases [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Menotti, 2015, How the Seven Countries Study contributed to the definition and development of the Mediterranean diet concept: A 50-year journey, Nutr. Metab. Cardiovasc. Dis. source

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    Premisecitation

    In type 2 diabetes, chronic hyperglycemia is associated with co-morbidities such as dyslipidemia, hypertension, and micro- and macrovascular complications, which impair quality and expectancy of life.

    “In T2D, chronic hyperglycemia is associated with a variety of co-morbidities, such as dyslipidemia, hypertension, micro- and macrovascular complications, which profoundly impair the quality and expectancy of life for affected patients, with huge costs for the health system [27].”
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    • cites [27] American Diabetes Association (2018). Economic Costs of Diabetes in the U.S. in 2017. Diabetes Care, 41, 917–928. source

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    Premisecitation

    Energy-reduced diets, as part of a healthy lifestyle, may almost invariably facilitate weight loss and reduce insulin resistance in patients with obesity.

    “Although surgical and pharmacological strategies [12] have been shown to be useful, energy reduced diets, as part of a healthy lifestyle, may almost invariably facilitate weight loss and reduce IR in these patients [13].”
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    • cites [13] Ogunleye, 2015, Health Benefits of Long-Term Weight-Loss Maintenance, Annu. Rev. Nutr. source

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    Premisecitation

    The reduction in insulin levels and the homeostatic model assessment index triggered by the Mediterranean diet are precocious and sustainable over time.

    “Also, the reduction in insulin levels and other measures of IR, i.e., the homeostatic model assessment (HOMA) index, triggered by this dietary approach, are precocious and sustainable over time [17,18].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Shai, 2008, Dietary Intervention Randomized Controlled Trial (DIRECT) Group. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet, N. Engl. J. Med. source

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    • cites [18] Greco, 2014, Early effects of a hypocaloric, Mediterranean diet on laboratory parameters in obese individuals, Mediat. Inflamm. source

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    Premisecitation

    A moderate weight loss of only 5%-10% can lead to health advantages in obese individuals, including improvement in cardiometabolic parameters, reduction of blood pressure, increase in longevity, and positive changes in insulin sensitivity and inflammatory biomarkers.

    “Even a moderate weight loss of only 5%–10% can lead to several health advantages in obese individuals, which include improvement in cardiometabolic parameters, reduction of blood pressure, and increase in longevity [13], in addition to positive changes in insulin sensitivity and inflammatory biomarkers [14,15,16].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [13] Ogunleye, 2015, Health Benefits of Long-Term Weight-Loss Maintenance, Annu. Rev. Nutr. source

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    • cites [14] Heggen, 2012, Effect of a low-fat versus a low-gycemic-load diet on inflammatory biomarker and adipokine concentrations, Metab. Syndr. Relat. Disord. source

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    • cites [15] Chen, 2015, Mechanisms Linking Inflammation to Insulin Resistance, Int. J. Endocrinol. source

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    • cites [16] Accattato, F., Greco, M., Pullano, S.A., Carè, I., Fiorillo, A.S., Pujia, A., Montalcini, T., Foti, D.P., Brunetti, A., and Gulletta, E. (2017). Effects of acute physical exercise on oxidative stress and inflammatory status in young, sedentary obese subjects. PLoS ONE, 12. source

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    Premisenone given

    In obesity, unbalanced production of pro- and anti-inflammatory adipocytokines can lead to insulin resistance and its related metabolic complications, which are potentially reversible through weight-loss programs.

    “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.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Quercetin can enhance the uptake of glucose in skeletal myocytes through an AMPK-dependent up-regulation of glucose transporter GLUT-4, which may occur independently of insulin signaling under oxidative stress conditions.

    “Also, quercetin can enhance the uptake of glucose in skeletal myocytes through an AMPK-dependent up-regulation of glucose transporter GLUT-4, which may occur independently of the insulin signaling under oxidative stress conditions [60].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Dhanya, 2017, Quercetin, a Lead Compound against Type 2 Diabetes Ameliorates Glucose Uptake via AMPK Pathway in Skeletal Muscle Cell Line, Front. Pharm. source

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    Premisecitation

    Patients with NASH have an increased risk of cardiovascular disease and cardiovascular disease-related death.

    “However, beyond liver-related morbidity and mortality, patients with NASH have also an increased risk of CVD and CVD-related death [68].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Adams, 2017, Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases, Gut source

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    Premisecitation

    Favorable effects of substituting unsaturated fatty acids for saturated fatty acids on insulin sensitivity can be seen only at a total fat intake below 37% of energy, whereas higher fat intake increases the risk of insulin resistance independently of quality.

    “In fact, favorable effects of substituting unsaturated fatty acids for saturated fatty acids on insulin sensitivity can be seen only at a total fat intake below 37% of energy [55], whereas higher quantity of fat intake increases the risk of IR independently of quality.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Vessby, 2001, Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study, Diabetologia source

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    Premisecitation

    Approximately 25%-30% of individuals with NAFLD can progress to NASH, whereas the same proportion of individuals with NASH can progress to cirrhosis and hepatocellular carcinoma, especially those with liver fibrosis.

    “Approximately 25%–30% of individuals with NAFLD can progress to NASH [65], whereas the same proportion of individuals with NASH can progress to cirrhosis and hepatocellular carcinoma, especially those with liver fibrosis [66,67].”
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    • cites [65] Rinella, 2015, Nonalcoholic fatty liver disease: A systematic review, JAMA source

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    • cites [66] Castellanos, 2018, Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients with Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study, Gastroenterology source

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    • cites [67] Angulo, 2015, Liver Fibrosis, but No Other Histologic Features, Is Associated with Long-term Outcomes of Patients with Nonalcoholic Fatty Liver Disease, Gastroenterology source

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    Premisecitation

    GLP-1 stimulates insulin release from pancreatic beta-cells, increasing glucose uptake from skeletal muscles and limiting postprandial hyperglycemia.

    “By stimulating insulin release from pancreatic β-cells, with immediate consequences of increased glucose uptake from skeletal muscles, raised GLP-1 levels may in turn limit postprandial hyperglycemia [51].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Holst, 2007, The physiology of glucagon-like peptide 1, Physiol. Rev. source

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    Premisecitation

    A beneficial effect in reducing the risk of type 2 diabetes was significant for anthocyanidins, flavan-3-ols, flavonols, and isoflavones, but not for other flavonoid subclasses.

    “With regard to flavonoid subclasses, a beneficial effect in reducing the risk of T2D was significant for anthocyanidins, flavan-3-ols, flavonols, and isoflavones, but not for other subclasses, suggesting that different bioactive molecular pathways may be triggered by these nutrient compounds in relation to their chemical structure.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Xu, 2018, Flavonoids intake and risk of type 2 diabetes mellitus: A meta-analysis of prospective cohort studies, Medicine (Baltimore) source

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    Premisecitation

    The glyco-metabolic benefits of the Mediterranean diet appear sustainable over time, independent of body weight change, as they do not occur with other successful nutritional interventions for weight loss.

    “These glyco-metabolic benefits appear to be sustainable over time, independent of body weight change, as they do not occur with other successful nutritional interventions for weight loss [17].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Shai, 2008, Dietary Intervention Randomized Controlled Trial (DIRECT) Group. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet, N. Engl. J. Med. source

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    Premisecitation

    In patients with NAFLD, a modest weight loss can produce a significant decrease in liver fat content, with improved serum aminotransferase activity and beneficial health effects.

    “In patients with NAFLD, a modest weight loss can produce a significant decrease in liver fat content, with improved serum aminotransferase activity and beneficial health effects [69,70].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Patel, 2015, Effect of weight loss on magnetic resonance imaging estimation of liver fat and volume in patients with nonalcoholic steatohepatitis, Clin. Gastroenterol. Hepatol. source

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    • cites [70] Promrat, 2010, Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis, Hepatology source

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    Premisecitation

    A meta-analysis of 24 randomized controlled trials evidenced better glycemic control, serum lipid profile, and systolic blood pressure among diabetics on high-MUFA or high-PUFA plant-based diets over low-fat, high-carbohydrate diets.

    “Confirmation of the antidiabetic effect of these nutrients has been given by a meta-analysis of 24 randomized controlled trials, evidencing better glycemic control, serum lipid profile, and systolic blood pressure among diabetics on high-MUFAs or high-PUFAs plant-based diets over low-fat, high-carbohydrate ones [43].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Qian, 2016, 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 source

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    Premisecitation

    Quercetin can activate the insulin-independent AMPK pathway of skeletal muscle cells, slowing the oxygen consumption of adenosine diphosphate in isolated mitochondria.

    “Similar to resveratrol, other flavonoids and the biguanide metformin that is recommended as the first-line intervention for diabetes treatment and prevention, quercetin can activate the insulin-independent 5′ adenosine monophosphate-activated protein kinase (AMPK) pathway of skeletal muscle cells, slowing the oxygen consumption of adenosine diphosphate in isolated mitochondria [59].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Eid, 2010, 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. source

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    Premisecitation

    The Mediterranean diet and other plant-based nutritional approaches are associated with positive outcomes in clinical research conditions and can be endorsed as suitable treatment measures to achieve glycemic control, minimizing the need for pharmacological medications.

    “With this in mind, the MedDiet [33,34], and other plant-based [35,36] nutritional approaches, all associated with positive outcomes in clinical research conditions, can be endorsed as suitable treatment measures to achieve glycemic control, so that the need for pharmacological medications would be minimized.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [33] Esposito, 2009, 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. source

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    • cites [34] Boucher, 2017, Mediterranean eating pattern, Diabetes Spectr. source

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    • cites [35] Rinaldi, 2016, 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 source

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    • cites [36] Pawlak, 2017, Vegetarian diets in the prevention and management of diabetes and its complications, Diabetes Spectr. source

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    Premisecitation

    Cross-sectional studies have found positive associations between higher adherence to the Mediterranean diet and larger brain volumes, cerebral connectivity, or fewer white matter lesions at older ages.

    “Also, cross-sectional studies have found positive associations between higher adherence to the MedDiet and larger brain volumes [96,97,98], cerebral connectivity [99], or fewer white matter lesions [100] at older ages, whereas hypercaloric diets, high in meat, carbohydrate and sugars intake and low in fish and vegetables contents, are associated with brain atrophy [94] and cortical thickness [101]”
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    • cites [96] Weinstein, 2006, Brain imaging in patients with diabetes: A systematic review, Diabetes Care source

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    • cites [97] Croll, 2018, Better diet quality relates to larger brain tissue volumes: The Rotterdam Study, Neurology source

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    • cites [98] Gu, 2015, Mediterranean diet and brain structure in a multiethnic elderly cohort, Neurology source

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    • cites [99] Pelletier, 2015, Mediterranean diet and preserved brain structural connectivity in older subjects, Alzheimers Dement. source

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    • cites [100] Gardener, 2012, Mediterranean diet and white matter hyperintensity volume in the Northern Manhattan Study, Arch. Neurol. source

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    Premisecitation

    PPARγ is predominantly expressed in adipocytes, wherein it modulates lipid metabolism in the form of release, transport, and storage of free fatty acids.

    “Although present in most cell types, such as vessels, neurons, macrophages, microglia and astrocytes, in which it attenuates the expression of proinflammatory mediators [110], PPARγ is predominantly expressed in adipocytes, wherein modulates lipid metabolism in form of release, transport, and storage of free fatty acids (FFAs) [111,112].”
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    • cites [111] Thangavel, 2017, Targeting Peroxisome Proliferator-Activated Receptors Using Thiazolidinediones: Strategy for Design of Novel Antidiabetic Drugs, Int. J. Med. Chem.

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    • cites [112] Costa, 2008, The insulin receptor: A new anticancer target for peroxisome proliferator-activated receptor-g (PPARg) and thiazolidinedione-PPARg agonists, Endocr. Relat. Cancer source

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    Premisecitation

    Mice on a high-fat diet treated with 20 mg/day oleacein for 5 weeks were protected from abdominal fat accumulation, weight gain, and liver steatosis compared with untreated controls, with evidence of improved insulin action on the liver and preserved glucose and lipid homeostasis.

    “Although this concept is still at early developmental stages, mice on high fat diet (HFD), treated with 20 mg/day oleacein for 5 weeks, were protected from abdominal fat accumulation, weight gain, and liver steatosis when compared to untreated controls, with evidence of improved insulin action on the liver and preserved glucose and lipid homeostasis [87].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Lepore, S.M., Maggisano, V., Bulotta, S., Mignogna, C., Arcidiacono, B., Procopio, A., Brunetti, A., Russo, D., and Celano, M. (2019). Oleacein Prevents High Fat Diet-Induced Adiposity and Ameliorates Some Biochemical Parameters of Insulin Sensitivity in Mice. Nutrients, 11. source

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    Interpretationcitation

    The Mediterranean diet eating pattern, rich in unsaturated fatty acids and plant-based polyphenols, has emerged as the most appropriate nutritional approach for NAFLD, gaining the support of the European Association for the Study of Liver and the European Association for the Study of Diabetes.

    “As such, the MedDiet eating pattern, which is rich in unsaturated fatty acids and plant-based polyphenols, has recently emerged as the most appropriate nutritional approach for NAFLD, gaining the support of the European Association for the Study of Liver (EASL) and the European Association for the Study of Diabetes (EASD) [80].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO) (2016). EASL-EASDEASO Clinical Practice Guidelines for the management of nonalcoholic fatty liver disease. J. Hepatol., 64, 1388–1402.

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    Premisecitation

    Hypocaloric diets and/or diets of higher quality, with low fat and sugar intakes, are associated with larger brain volumes, better white matter integrity, and better cerebral health in animal models.

    “Hypocaloric diets and/or diets of higher quality, with low fat and sugar intakes, are associated with larger brain volumes, better white matter integrity, and better cerebral health [94] in animal models.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Kanoski, 2010, The effects of a high-energy diet on hippocampal function and blood-brain barrier integrity in the rat, J. Alzheimers Dis. source

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  • May combine two claims.

    Premisecitation

    Insulin signaling and cerebral structure may be influenced by dietary energy content and food composition.

    “As such, like insulin-sensitive peripheral tissues, the insulin signaling and cerebral structure may be influenced by dietary energy content and food composition [93].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Folch, 2019, The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer’s Dementia, Front. Aging Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Peripheral insulin resistance is strongly related to brain dysfunction, either due to reduced insulin transport into the brain or to altered local insulin receptor sensitivity and activation.

    “However, peripheral IR is strongly related to brain dysfunction, either due to reduced insulin transport into the brain [115] or to altered local insulin receptor sensitivity and activation [116].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [115] Rhea, 2019, Role of the Blood-Brain Barrier in Central Nervous System Insulin Resistance, Front. Neurosci. source

      Not checked in the free run.

    • cites [116] Frolich, 1999, A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer’s disease, Ann. N. Y. Acad. Sci. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Alzheimer's risk is directly proportional to the duration and magnitude of hyperglycemia in type 2 diabetes, but is also detectable in pre-clinical stages of type 2 diabetes, during compensatory hyperinsulinemia and peripheral insulin resistance.

    “This latter risk is directly proportional to the duration and magnitude of hyperglycemia in T2D, but is also detectable in pre-clinical stages of T2D, during compensatory hyperinsulinemia and peripheral IR.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cyanidin-3-O-glucopyranoside, acting as a potent natural agonist for PPARγ with peripheral and central insulin-sensitizing effects, reduces liver fat and fasting glucose concentrations in treated animals and increases cerebral glucose uptake.

    “In line with these considerations, cyanidin-3-O-glucopyranoside, by acting as a potent natural agonist for PPARγ with peripheral and central insulin-sensitizing effects, has been shown not only to reduce liver fat [118] and fasting glucose concentrations [107] of treated animals, but also to increase cerebral glucose uptake [107].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [118] Jia, 2013, Cyanidin is an agonistic ligand for peroxisome proliferator-activated receptor-alpha reducing hepatic lipid, Biochim. Biophys. Acta source

      Not checked in the free run.

    • cites [107] Song, 2016, 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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obese individuals suffering from type 2 diabetes have higher levels of cerebrovascular disease, smaller total and regional brain volumes, decreased cerebral connectivity and metabolic brain networks, increased beta-amyloid deposition and tau phosphorylation, accelerated rates of cognitive impairment, and especially in women a higher risk of developing Alzheimer's dementia.

    “Also, obese individuals suffering from T2D, have higher levels of cerebrovascular disease, smaller total and regional brain volumes, decreased cerebral connectivity and metabolic brain networks [91], increased β-amyloid deposition and tau phosphorylation, accelerated rates of cognitive impairment and, especially in women, higher risk of developing Alzheimer’s dementia [92].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [91] Arnemann, 2017, Metabolic brain networks in aging and preclinical Alzheimer’s disease, Neuroimage Clin. source

      Not checked in the free run.

    • cites [92] Adams, 2013, The impact of brief high-intensity exercise on blood glucose levels, Diabetes Metab. Syndr. Obes. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The semi-synthesis of oleacein has proven to be sustainable.

    “Additionally, the semi-synthesis of oleacein has proven to be sustainable [86], laying the foundation for the future implementation of novel functional foods and nutraceuticals.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Costanzo, 2018, 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. source

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  • May combine two claims.

    Interpretationcitation

    The inhibition of phospho-ERK suggests greater responsiveness to insulin and less severity of insulin resistance in situations of chronic high-fat hypernutrition.

    “Also, phospho-ERK, a serine/threonine kinase downstream effector of the mitogen-activated protein kinase (MAPK) cascade, was inhibited in liver tissue of treated mice, thereby suggesting greater responsiveness to insulin and less severity of IR, in situations of chronic high-fat hypernutrition [88].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Ueyama, 2016, Inhibition of MEK1 signaling pathway in the liver ameliorates insulin resistance, J. Diabetes Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After entering the brain tissue, anthocyanins tend to accumulate, with the potential of high local bioavailability for neuroprotective actions.

    “After entering the brain tissue, anthocyanins tend to accumulate [103,104,105], with the potential of high local bioavailability for neuroprotective actions [105].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [103] Passamonti, 2005, Fast access of some grape pigments to the brain, J. Agric. Food Chem. source

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    • cites [104] Talavera, 2005, Anthocyanin metabolism in rats and their distribution to digestive area, kidney, and brain, J. Agric. Food Chem. source

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    • cites [105] Kalt, 2008, Identification of anthocyanins in the liver, eye, and brain of blueberry-fed pigs, J. Agric. Food Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adherence to the Mediterranean diet may reduce the progression of well-established neuroimaging biomarkers of cognitive impairment, including beta-amyloid deposition and cerebral glucose utilization via positron emission tomography, and provide 1.5 to 3.5 years of protection against Alzheimer's dementia in middle-aged cognitively normal individuals.

    “Although the human evidence is less consistent, adherence to the MedDiet may reduce the progression of well-established neuroimaging biomarkers of cognitive impairment, including β-amyloid deposition and cerebral glucose utilization via positron emission tomography, and provide 1.5 to 3.5 years of protection against Alzheimer’s dementia, in middle-aged cognitively normal individuals [95].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Berti, 2018, Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults, Neurology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obesity, insulin resistance, and hyperinsulinemia are cardinal features of PCOS.

    “Although the etiology is still unknown, obesity, IR and hyperinsulinemia are cardinal features of PCOS [124].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] Cassar, 2016, Insulin resistance in polycystic ovary syndrome: A systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies, Hum. Reprod. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PCOS is characterized by hyperandrogenism, chronic anovulation and/or sonographic evidence of small cysts in one or both ovaries, and is the most common endocrinological disorder among women of reproductive age and the main cause of female infertility.

    “PCOS, characterized by hyperandrogenism, chronic anovulation and/or sonographic evidence of small cysts in one or both ovaries, is the most common endocrinological disorder among women of reproductive age and the main cause of female infertility [124].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Cassar, 2016, Insulin resistance in polycystic ovary syndrome: A systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies, Hum. Reprod. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    It cannot be excluded that some benefits on cognitive processes may have been caused by detrimental effects of nutritional deficiencies in control subjects, rather than the surplus consumption of anthocyanins in interventional groups.

    “Nonetheless, it cannot be excluded that some benefits on cognitive processes may have been caused by detrimental effects of nutritional deficiencies in control subjects, rather than the surplus consumption of anthocyanins in interventional groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The beneficial cognitive effects of the Mediterranean diet in elderly patients with dementia may be augmented by isocaloric dietary supplementation of medium-chain saturated fatty acids in the form of coconut oil, which correlates with an immediate increase of circulating ketone bodies.

    “On a different note, the beneficial cognitive effects of the MedDiet in elderly patients with dementia may be augmented by the isocaloric dietary supplementation of medium-chain saturated fatty acids in the form of coconut oil, which correlates with an immediate increase of circulating ketone bodies [123].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Drehmer, 2018, 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. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In PCOS women, resveratrol treatment significantly decreased insulin concentrations and increased insulin sensitivity (Matsuda insulin sensitivity index).

    “However, significant decrement in insulin concentrations and a consistent increase of insulin sensitivity, in terms of Matsuda insulin sensitivity index values, were noted in PCOS women after treatment with resveratrol [138].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Banaszewska, 2016, Effects of Resveratrol on Polycystic Ovary Syndrome: A Double-blind, Randomized, Placebo-controlled Trial, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Frequent clustering of cancer and cardiometabolic diseases within the same individual indicates common etiological pathways, in which insulin resistance and inflammation are of paramount importance.

    “Nonetheless, the frequent clustering of cancer and cardiometabolic diseases within the same individual indicates common etiological pathways, in which IR and inflammation are of paramount importance [160,161].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [160] Koene, 2016, Shared Risk Factors in Cardiovascular Disease and Cancer, Circulation source

      Not checked in the free run.

    • cites [161] Masoudkabir, 2017, Cardiovascular disease and cancer: Evidence for shared disease pathways and pharmacologic prevention, Atherosclerosis source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Nutritional interventions with AMPK activators, such as resveratrol and other plant-based polyphenols, may mimic caloric restriction and secure similar effects on health and wellbeing as a calorie-deprived dietary regimen, potentially offsetting safety limitations and sustainability of long-term very-low-energy diet programs for weight loss.

    “Based on these considerations, nutritional interventions with AMPK activators, such as resveratrol and other plant-based polyphenols, may mimic caloric restriction and secure similar effects on health and wellbeing as a calorie-deprived dietary regimen [152], potentially offsetting safety limitations and sustainability of long-term very-low-energy diet programs for weight loss, typically encount”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152] Chiba, 2010, Development of calorie restriction mimetics as therapeutics for obesity, diabetes, inflammatory and neurodegenerative diseases, Curr. Genom. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Brain exposure to ketone bodies can replace the brain's normal reliance on glucose and potentially reverse the pathological alterations of Alzheimer's disease, ultimately improving cognitive performances in affected patients, with a greater impact on women than men, after only 21 days of coconut oil supplementation.

    “Brain exposure to ketone bodies can replace the brain’s normal reliance on glucose and potentially reverse the pathological alterations of Alzheimer’s disease, ultimately improving the cognitive performances in affected patients, with a greater impact on women than men, after only 21 days of coconut oil supplementation [123].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Drehmer, 2018, 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. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In PCOS women, even a modest weight reduction may exert significant beneficial effects on insulin resistance, hyperandrogenism, and menstrual problems, allowing the complete resolution of all symptoms of PCOS in some cases.

    “On the other hand, in PCOS women, even a modest weight reduction may exert significant beneficial effects on IR, hyperandrogenism and menstrual problems, allowing the complete resolution of all symptoms of PCOS in some cases [130].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Sancho, 2005, The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insulin regulates ovarian function through interactions with gonadotropins, and raised insulin levels amplify luteinizing hormone-induced ovarian androgen production, ultimately preventing ovulation.

    “Insulin regulates the ovarian function through interactions with gonadotropins, and, in case of raised levels, amplifies the luteinizing hormone (LH)-induced ovarian androgen production, ultimately preventing ovulation [125].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Dunaif, 1997, Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis, Endocr. Rev.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a large prospective European cohort study, adiposity was strongly associated with risk of developing a first chronic IR-related disease, especially T2D (HR 2.13 per 5% increase in BMI), more weakly with CVD (HR 1.20), and cancer (HR 1.03).

    “As expected, adiposity was strongly associated with risk of developing a first chronic, IR-related disease, especially T2D, with a hazard ratio (HR) of 2.13 (95% CI, 2.1 to 2.17) per 5% increases in BMI, and more weakly with CVD (HR 1.20 [95% CI, 1.17 to 1.23]) and cancer (HR 1.03 [95% CI, 1.01 to 1.05]) [162].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Freisling, H., Viallon, V., Lennon, H., Bagnardi, V., Ricci, C., Butterworth, A.S., Sweeting, M., Muller, D., Romieu, I., and Bazelle, P. (2020). Lifestyle factors and risk of multimorbidity of cancer and cardiometabolic diseases: A multinational cohort study. BMC Med., 18. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Smooth muscle cells perform essential functions in sustaining vascular homeostasis in cooperation with endothelial cells, and their reciprocal interactions may represent novel therapeutic targets for anti-atherogenic interventions.

    “However, in a synergistic cooperation with endothelial cells, smooth muscle cells (SMCs) perform also essential functions in sustaining vascular homeostasis, so that their reciprocal interactions may represent novel therapeutic targets for anti-atherogenic interventions [188].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [188] Li, 2018, Endothelial-Vascular Smooth Muscle Cells Interactions in Atherosclerosis, Front. Cardiovasc. Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Plant-based diets regulate molecular mechanisms involved in estrogen metabolism and other cell signaling pathways and gene expression patterns, which could be upstream or downstream of the insulin receptor signal.

    “Overall, these findings support the role of plant-based diets in regulating not only molecular mechanisms involved in estrogen metabolism, but also other cell signaling transduction pathways and gene expression patterns, which could be either upstream or downstream of the insulin receptor (INSR) signal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Acute intake of 50 mL of polyphenol-rich EVOO alters the transcriptional regulatory network associated with glucose and lipid metabolism in peripheral blood mononuclear cells, paralleling beneficial effects on glucose and HOMA-IR.

    “In particular, the acute intake of 50 mL of polyphenol-rich EVOO [175] has been proved to alter the transcriptional regulatory network associated with glucose and lipid metabolism in peripheral blood mononuclear cells, and this paralleled the beneficial effects on glucose and HOMA-IR.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Vacca, 2016, 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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    INSR can exert oncogenic potential by directly affecting cell metabolism and/or by synergizing with other oncogenes, with adverse impact on tumor growth and differentiation.

    “In these circumstances, INSR can exert its oncogenic potential, by directly affecting cell metabolism and/or by synergizing with other oncogenes, with adverse impact on tumor growth and differentiation [169].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Paonessa, 2006, Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer, Cancer Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HMGA1 regulates insulin transcription in pancreatic β-cells, expression of IGF1-binding proteins involved in glucose disposal in peripheral tissues, adipokines related to IR, and genes relevant for cholesterol biosynthesis.

    “HMGA1 regulates both insulin transcription in pancreatic β-cells and expression levels of IGF1-binding proteins involved in glucose disposal in peripheral tissues [170,171], other than a variety of adipokines related to IR and genes relevant for cholesterol biosynthesis [171,172].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [170] Sgarra, 2018, High Mobility Group A (HMGA) proteins: Molecular instigators of breast cancer onset and progression, Biochim. Biophys. Acta Rev. Cancer source

      Not checked in the free run.

    • cites [171] Laria, 2018, Secretome Analysis of Hypoxia-Induced 3T3-L1 Adipocytes Uncovers Novel Proteins Potentially Involved in Obesity, Proteomics source

      Not checked in the free run.

    • cites [172] Chiefari, 2018, Transcriptional Regulation of Glucose Metabolism: The Emerging Role of the HMGA1 Chromatin Factor, Front. Endocrinol. (Lausanne) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endothelial dysfunction is a key initiating event in vascular remodeling leading to atherosclerosis and one of the earliest signs of insulin resistance.

    “Endothelial dysfunction is a key initiating event in the vascular remodeling processes that lead to atherosclerosis, as well as one of the earliest signs of IR [179].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [179] Balletshofer, 2003, 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 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    EVOO modulates AGO2, a master regulator of microRNA biogenesis and protein synthesis, so microRNA expression could be affected by EVOO, with pleiotropic consequences on IR, inflammation, and tumorigenesis.

    “Also, given that one of the genes modulated by EVOO is the argonaute RISC catalytic component 2 (AGO2), a master regulator of microRNAs biogenesis and protein synthesis, it is unsurprising that microRNA expression could be also affected by EVOO, with pleiotropic consequences on IR, inflammation and tumorigenesis [175].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Vacca, 2016, 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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Differentiated SMCs in adult blood vessels proliferate at extremely low rates, produce small amounts of extracellular matrix, and display a contractile phenotype.

    “Normally, differentiated SMCs within adult blood vessels proliferate at extremely low rates and produce only a small amount of extracellular matrix components, displaying a contractile phenotype [189].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [189] Wang, 2015, Origin and differentiation of vascular smooth muscle cells, J. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CREBBP catalyzes acetylation of HMGA1 and histone H2B, exerting a modulatory effect on HMGA1-linked transcriptional programs in breast cancer cells.

    “CREBBP catalyzes the acetylation of HMGA1 [177] and histone H2B [178], exerting a modulatory effect on HMGA1-linked transcriptional programs in breast cancer cells.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [177] Chiefari, 2018, Cross-talk among HMGA1 and FoxO1 in control of nuclear insulin signaling, Sci. Rep. source

      Not checked in the free run.

    • cites [178] Penzo, C., Arnoldo, L., Pegoraro, S., Petrosino, S., Ros, G., Zanin, R., Wiśniewski, J.R., Manfioletti, G., and Sgarra, R. (2019). HMGA1 Modulates Gene Transcription Sustaining a Tumor Signalling Pathway Acting on the Epigenetic Status of Triple-Negative Breast Cancer Cells. Cancers, 11. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HMGA1 has been proposed as a convincing molecular link between T2D and CVD and a potential intervention target for multiple IR-related diseases.

    “In addition, covering a broad spectrum of mechanistic roles in IR, glucose homeostasis, lipid metabolism and atherogenesis, HMGA1 has been recently proposed as a convincing molecular link between two overlapping pathological traits, such as T2D and CVD [6], other than a potential intervention target for multiple IR-related diseases [172].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Arcidiacono, 2018, Type 2 diabetes mellitus and cardiovascular disease: Genetic and epigenetic links, Front. Endocrinol. source

      Not checked in the free run.

    • cites [172] Chiefari, 2018, Transcriptional Regulation of Glucose Metabolism: The Emerging Role of the HMGA1 Chromatin Factor, Front. Endocrinol. (Lausanne) source

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  • May combine two claims.

    Premisecitation

    HMGA proteins are implicated in the multistep processes of tumorigenesis and are susceptible to microRNA-dependent suppression in normal tissues.

    “Although no data are currently available regarding a potential overlap between cancer and T2D [172], HMGA proteins are also implicated in the multistep processes of tumorigenesis and are susceptible of microRNAs-dependent suppression in normal tissues [173].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Capurso, A., Crepaldi, G., and Capurso, C. (2018). Epigenetics/Epigenomics of Olive Oil and the Mediterranean Diet. Benefits of the Mediterranean Diet in the Elderly Patient, Springer. Practical Issues in Geriatrics. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clinical studies show impaired endothelium-dependent dilatation in T2D patients and related high-risk conditions, including obesity, prediabetes, or first-degree familial history of diabetes.

    “Clinical studies have evidenced an impaired endothelium-dependent dilatation in both T2D patients [180] and related high-risk conditions, including obesity, prediabetes or first-degree familial history of diabetes [181,182,183].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [180] Liu, 1999, Impaired endothelium-dependent vasodilation in type 2 diabetes. Relation to LDL size, oxidized LDL, and antioxidants, Diabetes Care source

      Not checked in the free run.

    • cites [181] Benjamin, 2004, Clinical correlates and heritability of flow-mediated dilation in the community: The Framingham Heart Study, Circulation source

      Not checked in the free run.

    • cites [182] Lteif, 2005, Obesity, insulin resistance, and the metabolic syndrome: Determinants of endothelial dysfunction in whites and blacks, Circulation source

      Not checked in the free run.

    • cites [183] Balletshofer, 2000, Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under pathophysiological conditions, vascular SMCs switch to a de-differentiated, proliferative, secretory phenotype, facilitating migration to the intima and contributing to atherosclerotic lesions.

    “Nonetheless, under pathophysiological conditions, such as vascular remodeling after endothelial dysfunction, or immunological and mechanical damage, vascular SMCs switch to a de-differentiated, proliferative, and secretory phenotype, which facilitates their ability to migrate to the intima and contribute to the development of atherosclerotic lesions [189].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [189] Wang, 2015, Origin and differentiation of vascular smooth muscle cells, J. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obese postmenopausal women have relatively high serum levels of estradiol and an increased risk of breast cancer, particularly the estrogen/progesterone receptor-dependent (ER+ and/or PR+) subtype.

    “Obese postmenopausal women have both relatively high serum levels of estradiol and an increased risk of breast cancer, particularly the estrogen/progesterone receptor-dependent (ER+ and/or PR+) subtype [7,168].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Arcidiacono, 2012, Insulin resistance and cancer risk: An overview of the pathogenetic mechanisms, Exp. Diabetes Res. source

      Not checked in the free run.

    • cites [168] Brown, 2018, Obesity and breast cancer - Role of estrogens and the molecular underpinnings of aromatase regulation in breast adipose tissue, Mol. Cell Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    INSR overexpression occurs in human breast cancer and other epithelial tumors, independently of ER status, and increases the response to circulating insulin, especially when insulin is abnormally high, as in obesity and T2D.

    “INSR overexpression, which occurs in human breast cancer and other epithelial tumors, independently of ER status, remarkably increases the response to circulating insulin, especially when the hormone is abnormally high, as in obesity and T2D.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [169] Paonessa, 2006, Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer, Cancer Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endothelial dysfunction is associated with oxidative stress, reduced nitric oxide bioavailability, increased anticoagulant properties and platelet aggregation, increased expression of adhesion molecules, increased secretion of proinflammatory chemokines and cytokines.

    “According to current understanding, endothelial dysfunction is associated with oxidative stress and reduced nitric oxide bioavailability, increased anticoagulant properties and platelet aggregation, increased expression of adhesion molecules (i.e., P- and E-selectin, intercellular adhesion molecule-1 (ICAM-1) and leukocyte adhesion molecules [i.e., vascular cell adhesion molecule-1 (VCAM-1), incre”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [184] Kolluru, 2012, Endothelial dysfunction and diabetes: Effects on angiogenesis, vascular remodeling, and wound healing, Int. J. Vasc. Med.

      Not checked in the free run.

    • cites [185] Palella, E., Cimino, R., Pullano, S.A., Fiorillo, A.S., Gulletta, E., Brunetti, A., Foti, D.P., and Greco, M. (2020). Laboratory parameters of hemostasis, adhesion molecules, and inflammation in type 2 diabetes mellitus: Correlation with glycemic control. Int. J. Environ. Res. Public Health, 17. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Regular consumption of EVOO (approximately 1-50 mg daily) could favorably affect circulating inflammatory biomarkers and flow-mediated vasodilation, contributing to the CVD protective effects of the MedDiet.

    “A systematic review and meta-analysis [186] reported that a regular consumption of EVOO (approximately between 1 and 50 mg daily) could favorably affect circulating inflammatory biomarkers, known as acute-phase reactants, and the flow-mediated vasodilation, thus contributing to the CVD protective effects of the MedDiet, observed in epidemiological studies [37,38].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [186] Schwingshackl, 2015, Effects of olive oil on markers of inflammation and endothelial function—A systematic review and metaanalysis, Nutrients source

      Not checked in the free run.

    • cites [37] Trichopoulou, 2005, Mediterranean diet and survival among patients with coronary heart disease in Greece, Arch. Intern. Med. source

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    • cites [38] Trichopoulou, 2003, Adherence to a Mediterranean diet and survival in a Greek population, N. Engl. J. Med. source

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  • May combine two claims.

    Premisecitation

    INSR is predominantly involved in regulation of glucose metabolism in response to insulin and is expressed at high levels in muscle, adipose tissue, and liver, and at low levels in epithelial cells.

    “INSR is predominantly involved in the regulation of glucose metabolism in response to insulin and is expressed at high levels in the classical insulin target tissues muscle, adipose tissue and liver, whereas in epithelial cells, it is usually expressed at low levels [169].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Paonessa, 2006, Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer, Cancer Res. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The anti-hypertensive actions of EVOO and EVOO-related functional compounds appear related to increased endothelial synthesis of nitric oxide and decreased endothelial synthesis of endothelin-1.

    “The anti-hypertensive actions of EVOO, and EVOO-related functional compounds, appear to be related to an increased endothelial synthesis of nitric oxide (NO), a potent vasodilator [198,199], which is disrupted in carriers of Glu298Asp polymorphism in the endothelial NO synthase (eNOS) gene [200] as well as under IR conditions [201], together with a decreased endothelial synthesis of the vasoconst”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [198] 2018, 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. source

      Not checked in the free run.

    • cites [199] Storniolo, 2014, 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. source

      Not checked in the free run.

    • cites [200] Ruano, 2011, 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. source

      Not checked in the free run.

    • cites [201] Imrie, 2010, Insulin resistance, lipotoxicity and endothelial dysfunction, Biochim. Biophys. Acta source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Promoting a healthful lifestyle is a critical first-line strategy for reducing hypertension and its adverse CVD outcomes.

    “Promoting a healthful lifestyle is a critical first-line strategy for reducing hypertension and its adverse CVD outcomes [193].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] Whelton, 2018, 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 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Other plant-based dietary polyphenols may concurrently interact with HMGA1 and NF-kB functions, but their biological activities are likely cell type or tissue-dependent, opening potential for CVD prevention.

    “It is conceivable that other plant-based dietary polyphenols concurrently interact with HMGA1 and NF-kB functions, but their biological activities are likely to be cell type or tissue-dependent, opening a yet unexplored potential for CVD prevention.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the NU-AGE trial, at 1-year follow-up, SBP decreased by −4.7 mmHg (95% CI −7.8 to −1.5) in the intervention group, while control group had a 0.9 mmHg increase (95% CI −2.2 to 4.1).

    “Specifically, at 1-year follow-up, SPB decreased by −4.7 mmHg (95% CI, −7.8 to −1.5) in the interventional group, whereas in control group participants, requested to continue with their usual eating habits, a 0.9 mmHg (95% CI, −2.2 to 4.1) SBP increase was observed [39].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Jennings, 2019, Mediterranean-Style Diet Improves Systolic Blood Pressure and Arterial Stiffness in Older Adults, Hypertension source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insulin action defects have been reported in the early stages of CKD and in CKD progressors.

    “In the last decades, insulin action defects have been reported in the early stages of CKD [219,220] as well as in CKD progressors [221]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [219] Kobayashi, 2005, Insulin resistance in patients with chronic kidney disease, Am. J. Kidney Dis. source

      Not checked in the free run.

    • cites [220] Shinohara, 2002, Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease, J. Am. Soc. Nephrol. source

      Not checked in the free run.

    • cites [221] DeFronzo, 1981, Insulin resistance in uremia, J. Clin. Invest. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Compared to a low-fat diet, adherence to either EVOO-enriched or nut-enriched MedDiet was associated with a trend of decrement in HDL levels and a significant increase in cholesterol efflux capacity, which was linked to reduced risk of first CVD events.

    “In this regard, when compared to a low-fat diet, adherence to either EVOO-enriched or nut-enriched MedDiet was associated with a trend of decrement in HDL levels, along with a significant increase in CEC [214], which was linked to a reduced risk of first CVD events [214].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [214] Elosua, 2017, Mediterranean Diet Improves High-Density Lipoprotein Function in High-Cardiovascular-Risk Individuals: A Randomized Controlled Trial, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Irrespective of T2D, a complex interplay between insulin resistance and plasma lipid abnormalities exists, and this could be a novel target for cardioprotective interventions.

    “It has been also recognized that, irrespective of T2D, a complex interplay between IR and plasma lipid abnormalities exists, and this could be a novel target for cardioprotective interventions [203].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Bjornstad, 2018, Pathogenesis of Lipid Disorders in Insulin Resistance: A Brief Review, Curr. Diab. Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Small LDL particles have decreased affinity for LDL receptors, longer permanence in the bloodstream, are easily oxidized, and more capable to traverse the endothelial barrier compared to normal size LDL.

    “Also, compared to normal size LDL, small LDL particles possess decreased affinity for LDL receptors and have a longer permanence in the bloodstream, where are easily oxidized, becoming more capable to traverse the endothelial barrier [206].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206] Galeano, 1998, 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. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Saturated fatty acids impair insulin biological activity through kinase-independent phosphorylation of PKCε, which migrates to the nucleus and phosphorylates HMGA1.

    “Saturated fatty acids impair insulin biological activity through a kinase independent phosphorylation of the isoform ε of protein kinase C (PKCε) enzyme, which, in its phosphorylated form, migrates to the nuclear region and phosphorylates HMGA1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] Gogoi, 2014, A polyphenol rescues lipid induced insulin resistance in skeletal muscle cells and adipocytes, Biochem. Biophys. Res. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The NO/ET-1 imbalance alters vascular tone and drives hypertension, and can be induced by increased plasma levels of free fatty acids and glucose, features of insulin resistance states.

    “The NO/ET-1 unbalance, which alters the vascular tone and drives hypertension, can be induced by increased plasma levels of FFAs and glucose, two well-known features of IR states [201].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [201] Imrie, 2010, Insulin resistance, lipotoxicity and endothelial dysfunction, Biochim. Biophys. Acta source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the NU-AGE study, gender differences were observed in response to the MedDiet: reduced SBP in males, and decreased arterial stiffness but not peripheral BP in females.

    “In addition, marked gender differences were observed in response to the MedDiet in this study, with reduced SBP in males, and decreased arterial stiffness, but not peripheral BP, in females, which agrees with arterial structure dimorphisms and hormonal influences on BP [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Jennings, 2019, Mediterranean-Style Diet Improves Systolic Blood Pressure and Arterial Stiffness in Older Adults, Hypertension source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The MedDiet offers considerable and secure benefits against the risk of hypertension and CVD.

    “However, if targeting whole food combinations in a dietary pattern may have synergistic and cumulative effects on BP over individual foods and nutrients [194], this is even more pronounced for the MedDiet, which offers considerable and secure benefits against the risk of hypertension and CVD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [194] Appel, 2003, Lifestyle modification as a means to prevent and treat high blood pressure, J. Am. Soc. Nephrol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ferulic acid attenuates insulin resistance in adipocytes of HFD-fed mice by targeting pathways mediated by fetuin-A and NF-kB, reducing proinflammatory cytokine secretion and improving glyco-metabolic status.

    “On the other hand, ferulic acid is also able to attenuate IR in adipocytes of HFD-fed mice, by targeting different pathways, such as those mediated by fetuin-A and NF-kB, ultimately reducing the secretion of proinflammatory cytokines with favorable consequences on the glyco-metabolic status [192].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Gogoi, 2014, A polyphenol rescues lipid induced insulin resistance in skeletal muscle cells and adipocytes, Biochem. Biophys. Res. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    EVOO with high polyphenols is probably the most important food for modulating BP and conferring vasoprotection, being able to improve body composition and reduce BP in obese hypertensive women.

    “EVOO with high polyphenols is probably the most important food from this point of view, being able to improve body composition and reduce BP in obese hypertensive women [198].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [198] 2018, 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. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The PREDIMED trial demonstrated beneficial effects of EVOO-enriched MedDiet on primary prevention of CVD in at-risk individuals, related at least in part to an improved and less atherogenic lipid profile (LDL resistance to oxidation, size, cytotoxicity).

    “In particular, the PREDIMED trial demonstrated beneficial effects of the EVOO-enriched MedDiet on primary prevention of CVD in at-risk individuals, which appears to be related, at least in part, to an improved and less atherogenic lipid profile, in terms of resistance against oxidation, size and cytotoxicity of low-density lipoprotein (LDL) particles [204].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [204] Goday, 2017, The Mediterranean Diet decreases LDL atherogenicity in high cardiovascular risk individuals: A randomized controlled trial, Mol. Nutr. Food Res.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    The present knowledge about the role of MedDiet functional components in modulating insulin action and signaling pathways is still limited.

    “the present knowledge about their role in the modulation of insulin action and signaling pathways is still limited”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In Mediterranean countries, red meat and processed meats are consumed less than vegetables, fish, and white meat, potentially conveying lower dietary sodium, phosphate, and potassium, which are concerns in CKD.

    “Also, in Mediterranean Countries, red meat and processed meats are consumed less than vegetables, fish and white meat, and this may convey a lower amount of dietary sodium, phosphate and potassium, which represent a major concern in patients with CKD due to an intrinsic risk of water-electrolyte decompensation [229].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229] Chauveau, 2018, Mediterranean diet as the diet of choice for patients with chronic kidney disease, Nephrol. Dial. Transpl. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The MedDiet has been promoted by ERA-EDTA as the most appropriate choice for the nutritional management of CKD.

    “Based on these considerations, the MedDiet has been recently promoted by the European Renal Association–European Dialysis Transplant Association (ERA-EDTA) as the most appropriate choice for the nutritional management of CKD [229].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] Chauveau, 2018, Mediterranean diet as the diet of choice for patients with chronic kidney disease, Nephrol. Dial. Transpl. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Novel in silico approaches have been proposed to identify potential health effects of bioactive compounds from plant-based natural products.

    “given the recent characterization of a large number of diverse bioactive compounds from plant-based natural products, which would challenge the feasibility of a large-scale in vitro testing for the identification of potential health effects [232], novel in silico approaches have been proposed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Williamson, 2017, The role of polyphenols in modern nutrition, Nutr. Bull. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In CKD, leptin accumulates to a larger extent than adiponectin, and this abnormal ratio may favor the onset of insulin resistance and metabolic disorders.

    “In particular, leptin accumulates to a larger extent than adiponectin in CKD, and this highly abnormal ratio may favor the onset of IR and metabolic disorders [223,224].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [223] Teta, 2015, Insulin resistance as a therapeutic target for chronic kidney disease, J. Ren. Nutr. source

      Not checked in the free run.

    • cites [224] Xu, 2017, Insulin resistance in chronic kidney disease, Nephrology (Carlton) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    It has been proposed that insulin resistance can promote kidney damage through hemodynamic mechanisms, including sympathetic nervous system overactivity, increased sodium retention, glomerular hyperfiltration, and elevated vascular permeability.

    “and it has been proposed that IR can promote kidney damage through hemodynamic mechanisms, including a sympathetic nervous system overactivity, increased sodium retention, glomerular hyperfiltration and elevated vascular permeability [222].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [222] Gluba, 2013, Metabolic syndrome and renal disease, Int. J. Cardiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High consumption of fresh fruits and vegetables typical of Mediterranean traditions enhances the risk of hyperkalemia in advanced stages of CKD, so low potassium alternatives or boiling cooking methods should be considered when adapting the MedDiet to patients with reduced kidney function.

    “However, as underlined by ERA-EDTA itself, the high consumption of fresh fruits and vegetables typical of the Mediterranean traditions and culinarian style, enhances the risk of hyperkalemia in advanced stages of CKD, so that low potassium alternatives or boiling cooking methods should be still cautiously considered when adapting the MedDiet to patients with reduced kidney function [229].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229] Chauveau, 2018, Mediterranean diet as the diet of choice for patients with chronic kidney disease, Nephrol. Dial. Transpl. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Uncertainties surround the likelihood of metabolic benefits and safety of unsaturated fatty acid-enriched diets and polyphenol-based synthetic supplements at a general population scale.

    “uncertainties surround the likelihood of metabolic benefits and safety of unsaturated fatty acid-enriched diets and polyphenol-based synthetic supplements at a general population scale.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Methods such as molecular docking, virtual screening, and molecular dynamics simulation can provide a critical basis for understanding the complex interaction of these compounds with cellular enzymes and regulatory molecules.

    “Methods such as molecular docking, virtual screening, and molecular dynamics simulation, can provide a critical basis for understanding the complex interaction of these compounds with cellular enzymes and regulatory molecules [233].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [233] Maruca, 2019, Computer-based techniques for lead identification and optimization I: Basics, Phys. Sci. Rev.

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Lower consumption of dairy, red meat, and processed meat would reduce proinflammatory saturated fatty acid intake, possibly ameliorating atherogenic lipid levels and systolic blood pressure, while abundant dietary fiber would mitigate the systemic inflammatory milieu.

    “A lower consumption of dairy, red meat and meat processed products would also reduce the proinflammatory saturated fatty acid intake, possibly ameliorating the atherogenic lipid levels and systolic blood pressure [230], where the abundant supply of dietary fiber would mitigate the systemic inflammatory milieu.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [230] Kushi, 1995, Health implications of Mediterranean diets in light of contemporary knowledge. 2. Meat, wine, fats, and oils, Am. J. Clin. Nutr. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    Older people with mild cognitive decline may take advantage of nutritional supplements for correcting dietary inadequacies and deficiencies in a practical manner.

    “even if older people with mild cognitive decline may take advantage of nutritional supplements for correcting dietary inadequacies and deficiencies in a practical manner”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    HMGA1 acts as a critical regulator in the ability of plant-based polyphenols to affect gene transcription patterns.

    “in which HMGA1 acts as a critical regulator”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NHANES III showed that total dietary fiber intake was low in most cohort participants (median 14.5 g/day), and higher dietary fiber consumption was associated with lower serum C-reactive protein and lower mortality risk in the CKD subpopulation.

    “Indeed, the Third National Health and Nutrition Examination Survey (NHANES III) showed that the total dietary fiber intake was low in most cohort participants (median 14.5 g of fiber/day), and higher dietary fiber consumption was associated with lower serum levels of C reactive protein, a widely used clinical marker of inflammation, and lower risk of mortality in the subpopulation with CKD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [231] Krishnamurthy, 2012, High dietary fiber intake is associated with decreased inflammation and all-cause mortality in patients with chronic kidney disease, Kidney Int. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The identification of nutrients that regulate molecular pathways relevant for glucose homeostasis, cognitive functions, tumorigenesis or atherogenesis may contribute to the formulation of functional food-based dietary guidelines for managing the clinical spectrum of IR.

    “The identification of nutrients, regulating molecular pathways particularly relevant for glucose homeostasis, cognitive functions, tumorigenesis or atherogenesis, in either an individual or cooperative manner, may contribute to the formulation of functional food-based dietary guidelines for managing the clinical spectrum of IR, reducing the need for pharmacological interventions, with a favorable”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Emerging evidence suggests that fruit and vegetable-rich diets, such as the MedDiet, may be helpful to delay CKD progression and prevent complications.

    “In this regard, emerging evidence suggests that fruit and vegetable-rich diets, such as the MedDiet, may be helpful to delay CKD progression and prevent complications [228].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [228] Kelly, 2017, Healthy dietary patterns and risk of mortality and ESRD in CKD: A meta-analysis of cohort studies, Clin. J. Am. Soc. Nephrol. source

      Not checked in the free run.

93 of 93

  • The paper relies on this without support.

    The molecular mechanisms underlying the metabolic benefits of Mediterranean diet-derived functional nutrients are compound-specific and, in some cases, involve gene expression through the nuclear high-mobility group A1 protein.

    “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.”

  • The paper relies on this without support.

    Protein intake in the MedDiet is very close to that of traditional controlled protein diets for CKD (~0.8 g/kg/day).

    “Protein intake in the MedDiet is very close to that of traditional controlled protein diets for CKD (~0.8 g/kg/day).”

  • The paper relies on this without support.

    CKD is a major risk factor for insulin resistance development due to imbalance of circulating pro-inflammatory cytokines and adipokines following reduced kidney function.

    “CKD is also considered a major risk factor for IR development, given the unbalance of circulating pro-inflammatory cytokines and adipokines that follows the reduction in kidney function.”
3 of 3

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Authors
Mirabelli, M., Chiefari, E., Arcidiacono, B., Corigliano, D. M., Brunetti, F. S., Maggisano, V., Russo, D., Foti, D. P., & Brunetti, A.
Affiliations
Magna Graecia University (IT)
Corresponding author
Brunetti, Antonio
ORCID
Venue
Nutrients
Publisher
MDPI AG
Published
2020-04-12
Volume
12
Issue
4
Pages
1066
ISSN
2072-6643 (ISSN-L)
DOI
10.3390/nu12041066
PMC
PMC7230471
OpenAlex
W3015424411
Cited by
272
References
254
Citations by year
2026: 30 · 2025: 47 · 2024: 44 · 2023: 55 · 2022: 44 · 2021: 35 · 2020: 14 · 2019: 3
FWCI
6.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Nutrients (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • European Commission (2014‐2020, FSE 2014-2020)
  • Regione Calabria
  • European Regional Development Fund (FSE 2014-2020, 2014-2020’)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
Mediterranean diet, insulin resistance, type 2 diabetes, obesity, extra virgin olive oil, polyphenols, resveratrol, oleacein, anthocyanins, polyunsaturated fatty acids, non-alcoholic fatty liver disease, polycystic ovary syndrome, chronic kidney disease, breast cancer, HMGA1, adipokines, weight loss, functional foods
MeSH terms
Olive Oil, Diabetes Mellitus, Type 2, Female, Humans, Insulin Resistance, Male, Nutritional Physiological Phenomena, Nuts, Obesity, Vegetables, Gene Expression, HMGA1a Protein, Diet, Mediterranean, Polyphenols

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