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

In the paper

“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].”

What the sources say

• Not checked yetcites [28] Ye, 2013, Mechanisms of insulin resistance in obesity, Front. Med. source

In the paper

“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].”

What the sources say

• Not checked yetcites [3] Czech, 2017, Insulin action and resistance in obesity and type 2 diabetes, Nat. Med. source
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [6] Arcidiacono, 2018, Type 2 diabetes mellitus and cardiovascular disease: Genetic and epigenetic links, Front. Endocrinol. source

In the paper

“T2D, a frequent consequence of IR, is the most common metabolic disease, affecting millions of people throughout the world [26].”

What the sources say

• Not checked yetcites [26] Zheng, 2018, Global aetiology and epidemiology of type 2 diabetes mellitus and its complications, Nat. Rev. Endocrinol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [27] American Diabetes Association (2018). Economic Costs of Diabetes in the U.S. in 2017. Diabetes Care, 41, 917–928. source

In the paper

“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].”

What the sources say

• Not checked yetcites [13] Ogunleye, 2015, Health Benefits of Long-Term Weight-Loss Maintenance, Annu. Rev. Nutr. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [18] Greco, 2014, Early effects of a hypocaloric, Mediterranean diet on laboratory parameters in obese individuals, Mediat. Inflamm. source

In the paper

“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].”

What the sources say

• Not checked yetcites [13] Ogunleye, 2015, Health Benefits of Long-Term Weight-Loss Maintenance, Annu. Rev. Nutr. source
• Not checked yetcites [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
• Not checked yetcites [15] Chen, 2015, Mechanisms Linking Inflammation to Insulin Resistance, Int. J. Endocrinol. source
• Not checked yetcites [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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“However, beyond liver-related morbidity and mortality, patients with NASH have also an increased risk of CVD and CVD-related death [68].”

What the sources say

• Not checked yetcites [68] Adams, 2017, Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases, Gut source

In the paper

“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.”

What the sources say

• Not checked yetcites [55] Vessby, 2001, Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study, Diabetologia source

In the paper

“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].”

What the sources say

• Not checked yetcites [65] Rinella, 2015, Nonalcoholic fatty liver disease: A systematic review, JAMA source
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [51] Holst, 2007, The physiology of glucagon-like peptide 1, Physiol. Rev. source

In the paper

“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.”

What the sources say

• Not checked yetcites [58] Xu, 2018, Flavonoids intake and risk of type 2 diabetes mellitus: A meta-analysis of prospective cohort studies, Medicine (Baltimore) source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [70] Promrat, 2010, Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis, Hepatology source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [34] Boucher, 2017, Mediterranean eating pattern, Diabetes Spectr. source
• Not checked yetcites [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
• Not checked yetcites [36] Pawlak, 2017, Vegetarian diets in the prevention and management of diabetes and its complications, Diabetes Spectr. source

In the paper

“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]”

What the sources say

• Not checked yetcites [96] Weinstein, 2006, Brain imaging in patients with diabetes: A systematic review, Diabetes Care source
• Not checked yetcites [97] Croll, 2018, Better diet quality relates to larger brain tissue volumes: The Rotterdam Study, Neurology source
• Not checked yetcites [98] Gu, 2015, Mediterranean diet and brain structure in a multiethnic elderly cohort, Neurology source
• Not checked yetcites [99] Pelletier, 2015, Mediterranean diet and preserved brain structural connectivity in older subjects, Alzheimers Dement. source
• Not checked yetcites [100] Gardener, 2012, Mediterranean diet and white matter hyperintensity volume in the Northern Manhattan Study, Arch. Neurol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [111] Thangavel, 2017, Targeting Peroxisome Proliferator-Activated Receptors Using Thiazolidinediones: Strategy for Design of Novel Antidiabetic Drugs, Int. J. Med. Chem.
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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.

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“As such, like insulin-sensitive peripheral tissues, the insulin signaling and cerebral structure may be influenced by dietary energy content and food composition [93].”

What the sources say

• Not checked yetcites [93] Folch, 2019, The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer’s Dementia, Front. Aging Neurosci. source

In the paper

“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].”

What the sources say

• Not checked yetcites [115] Rhea, 2019, Role of the Blood-Brain Barrier in Central Nervous System Insulin Resistance, Front. Neurosci. source
• Not checked yetcites [116] Frolich, 1999, A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer’s disease, Ann. N. Y. Acad. Sci. source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [118] Jia, 2013, Cyanidin is an agonistic ligand for peroxisome proliferator-activated receptor-alpha reducing hepatic lipid, Biochim. Biophys. Acta source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [91] Arnemann, 2017, Metabolic brain networks in aging and preclinical Alzheimer’s disease, Neuroimage Clin. source
• Not checked yetcites [92] Adams, 2013, The impact of brief high-intensity exercise on blood glucose levels, Diabetes Metab. Syndr. Obes. source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [88] Ueyama, 2016, Inhibition of MEK1 signaling pathway in the liver ameliorates insulin resistance, J. Diabetes Res. source

In the paper

“After entering the brain tissue, anthocyanins tend to accumulate [103,104,105], with the potential of high local bioavailability for neuroprotective actions [105].”

What the sources say

• Not checked yetcites [103] Passamonti, 2005, Fast access of some grape pigments to the brain, J. Agric. Food Chem. source
• Not checked yetcites [104] Talavera, 2005, Anthocyanin metabolism in rats and their distribution to digestive area, kidney, and brain, J. Agric. Food Chem. source
• Not checked yetcites [105] Kalt, 2008, Identification of anthocyanins in the liver, eye, and brain of blueberry-fed pigs, J. Agric. Food Chem. source

In the paper

“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].”

What the sources say

• Not checked yetcites [95] Berti, 2018, Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults, Neurology source

In the paper

“Although the etiology is still unknown, obesity, IR and hyperinsulinemia are cardinal features of PCOS [124].”

What the sources say

• Not checked yetcites [124] Cassar, 2016, Insulin resistance in polycystic ovary syndrome: A systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies, Hum. Reprod. source

In the paper

“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].”

What the sources say

• Not checked yetcites [124] Cassar, 2016, Insulin resistance in polycystic ovary syndrome: A systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies, Hum. Reprod. source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [138] Banaszewska, 2016, Effects of Resveratrol on Polycystic Ovary Syndrome: A Double-blind, Randomized, Placebo-controlled Trial, J. Clin. Endocrinol. Metab. source

In the paper

“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].”

What the sources say

• Not checked yetcites [160] Koene, 2016, Shared Risk Factors in Cardiovascular Disease and Cancer, Circulation source
• Not checked yetcites [161] Masoudkabir, 2017, Cardiovascular disease and cancer: Evidence for shared disease pathways and pharmacologic prevention, Atherosclerosis source

In the paper

“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”

What the sources say

• Not checked yetcites [152] Chiba, 2010, Development of calorie restriction mimetics as therapeutics for obesity, diabetes, inflammatory and neurodegenerative diseases, Curr. Genom. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [125] Dunaif, 1997, Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis, Endocr. Rev.

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [188] Li, 2018, Endothelial-Vascular Smooth Muscle Cells Interactions in Atherosclerosis, Front. Cardiovasc. Med. source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [169] Paonessa, 2006, Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer, Cancer Res. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [171] Laria, 2018, Secretome Analysis of Hypoxia-Induced 3T3-L1 Adipocytes Uncovers Novel Proteins Potentially Involved in Obesity, Proteomics source
• Not checked yetcites [172] Chiefari, 2018, Transcriptional Regulation of Glucose Metabolism: The Emerging Role of the HMGA1 Chromatin Factor, Front. Endocrinol. (Lausanne) source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [189] Wang, 2015, Origin and differentiation of vascular smooth muscle cells, J. Physiol. source

In the paper

“CREBBP catalyzes the acetylation of HMGA1 [177] and histone H2B [178], exerting a modulatory effect on HMGA1-linked transcriptional programs in breast cancer cells.”

What the sources say

• Not checked yetcites [177] Chiefari, 2018, Cross-talk among HMGA1 and FoxO1 in control of nuclear insulin signaling, Sci. Rep. source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [6] Arcidiacono, 2018, Type 2 diabetes mellitus and cardiovascular disease: Genetic and epigenetic links, Front. Endocrinol. source
• Not checked yetcites [172] Chiefari, 2018, Transcriptional Regulation of Glucose Metabolism: The Emerging Role of the HMGA1 Chromatin Factor, Front. Endocrinol. (Lausanne) source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [180] Liu, 1999, Impaired endothelium-dependent vasodilation in type 2 diabetes. Relation to LDL size, oxidized LDL, and antioxidants, Diabetes Care source
• Not checked yetcites [181] Benjamin, 2004, Clinical correlates and heritability of flow-mediated dilation in the community: The Framingham Heart Study, Circulation source
• Not checked yetcites [182] Lteif, 2005, Obesity, insulin resistance, and the metabolic syndrome: Determinants of endothelial dysfunction in whites and blacks, Circulation source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [189] Wang, 2015, Origin and differentiation of vascular smooth muscle cells, J. Physiol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [7] Arcidiacono, 2012, Insulin resistance and cancer risk: An overview of the pathogenetic mechanisms, Exp. Diabetes Res. source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [169] Paonessa, 2006, Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer, Cancer Res. source

In the paper

“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”

What the sources say

• Not checked yetcites [184] Kolluru, 2012, Endothelial dysfunction and diabetes: Effects on angiogenesis, vascular remodeling, and wound healing, Int. J. Vasc. Med.
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [186] Schwingshackl, 2015, Effects of olive oil on markers of inflammation and endothelial function—A systematic review and metaanalysis, Nutrients source
• Not checked yetcites [37] Trichopoulou, 2005, Mediterranean diet and survival among patients with coronary heart disease in Greece, Arch. Intern. Med. source
• Not checked yetcites [38] Trichopoulou, 2003, Adherence to a Mediterranean diet and survival in a Greek population, N. Engl. J. Med. source

In the paper

“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].”

What the sources say

• Not checked yetcites [169] Paonessa, 2006, Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer, Cancer Res. source

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [201] Imrie, 2010, Insulin resistance, lipotoxicity and endothelial dysfunction, Biochim. Biophys. Acta source

In the paper

“Promoting a healthful lifestyle is a critical first-line strategy for reducing hypertension and its adverse CVD outcomes [193].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [39] Jennings, 2019, Mediterranean-Style Diet Improves Systolic Blood Pressure and Arterial Stiffness in Older Adults, Hypertension source

In the paper

“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]”

What the sources say

• Not checked yetcites [219] Kobayashi, 2005, Insulin resistance in patients with chronic kidney disease, Am. J. Kidney Dis. source
• Not checked yetcites [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 yetcites [221] DeFronzo, 1981, Insulin resistance in uremia, J. Clin. Invest. source

In the paper

“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].”

What the sources say

• Not checked yetcites [214] Elosua, 2017, Mediterranean Diet Improves High-Density Lipoprotein Function in High-Cardiovascular-Risk Individuals: A Randomized Controlled Trial, Circulation source

In the paper

“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].”

What the sources say

• Not checked yetcites [203] Bjornstad, 2018, Pathogenesis of Lipid Disorders in Insulin Resistance: A Brief Review, Curr. Diab. Rep. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [192] Gogoi, 2014, A polyphenol rescues lipid induced insulin resistance in skeletal muscle cells and adipocytes, Biochem. Biophys. Res. Commun. source

In the paper

“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].”

What the sources say

• Not checked yetcites [201] Imrie, 2010, Insulin resistance, lipotoxicity and endothelial dysfunction, Biochim. Biophys. Acta source

In the paper

“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].”

What the sources say

• Not checked yetcites [39] Jennings, 2019, Mediterranean-Style Diet Improves Systolic Blood Pressure and Arterial Stiffness in Older Adults, Hypertension source

In the paper

“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.”

What the sources say

• Not checked yetcites [194] Appel, 2003, Lifestyle modification as a means to prevent and treat high blood pressure, J. Am. Soc. Nephrol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [192] Gogoi, 2014, A polyphenol rescues lipid induced insulin resistance in skeletal muscle cells and adipocytes, Biochem. Biophys. Res. Commun. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [204] Goday, 2017, The Mediterranean Diet decreases LDL atherogenicity in high cardiovascular risk individuals: A randomized controlled trial, Mol. Nutr. Food Res.

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [229] Chauveau, 2018, Mediterranean diet as the diet of choice for patients with chronic kidney disease, Nephrol. Dial. Transpl. source

In the paper

“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].”

What the sources say

• Not checked yetcites [229] Chauveau, 2018, Mediterranean diet as the diet of choice for patients with chronic kidney disease, Nephrol. Dial. Transpl. source

In the paper

“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.”

What the sources say

• Not checked yetcites [232] Williamson, 2017, The role of polyphenols in modern nutrition, Nutr. Bull. source

In the paper

“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].”

What the sources say

• Not checked yetcites [223] Teta, 2015, Insulin resistance as a therapeutic target for chronic kidney disease, J. Ren. Nutr. source
• Not checked yetcites [224] Xu, 2017, Insulin resistance in chronic kidney disease, Nephrology (Carlton) source

In the paper

“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].”

What the sources say

• Not checked yetcites [222] Gluba, 2013, Metabolic syndrome and renal disease, Int. J. Cardiol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [229] Chauveau, 2018, Mediterranean diet as the diet of choice for patients with chronic kidney disease, Nephrol. Dial. Transpl. source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [233] Maruca, 2019, Computer-based techniques for lead identification and optimization I: Basics, Phys. Sci. Rev.

In the paper

“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.”

What the sources say

• Not checked yetcites [230] Kushi, 1995, Health implications of Mediterranean diets in light of contemporary knowledge. 2. Meat, wine, fats, and oils, Am. J. Clin. Nutr. source

In the paper

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

In the paper

“in which HMGA1 acts as a critical regulator”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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”

In the paper

“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].”

What the sources say

• Not checked yetcites [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