Quercetin as a Modulator of Insulin Resistance: History
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Contributor:
Paolo Bellavite
,
Serafino Fazio
,
Flora Affuso

Insulin resistance (IR) and the associated hyperinsulinemia are early pathophysiological changes which, if not well treated, can lead to type 2 diabetes, endothelial dysfunction and cardiovascular disease. Qtn is a flavonoid, belonging to the flavonol group. Known for its antioxidant and anti-inflammatory properties, Qtn is proposed as a dietary supplement in antiaging and immunostimulant formulations. 

  • insulin resistance
  • Quercetin
  • diabetes

1. Introduction

Over the last decades, great progress has been made in the prevention and treatment of cardiovascular diseases, which, in Italy, has led to a drop in cardiovascular mortality of about 53% between 1980 and 2010. However, data updated by the Central Statistical Office of the Istituto Superiore di Sanità (ISS) still indicate high mortality from cardiovascular diseases, accounting for about 39% of total deaths in Italy [1]. In the member countries of the European Union, cardiovascular diseases currently claim 2 million lives each year and account for 42% of total deaths [2]. Therefore, although much has been done, a lot more remains to be achieved in terms of the prevention and treatment of cardiovascular risk factors. While significant progress has been made in treating dyslipidemias, diabetes mellitus and hypertension, little is being done in the field of early screening and treatment of insulin resistance/hyperinsulinaemia (IR/Hyperin), as independent risk factors for cardiovascular diseases [3][4].
Insulin resistance (IR) is a silent pandemic and a serious public health concern: it has been reported that between 15.5 and 51% of adults in highly developed countries are affected [5]. IR not only affects obese individuals but normal or underweight people as well, since several different mechanisms underlie the pathogenesis of this disorder. Chronic inflammation, sedentariness, alterations in intestinal microbiota and, above all, genetic factors can be quite frequent [5][6][7]. Although overweight and obesity are commonly associated with diabetes, a Kaiser Permanente study found that this connection differs widely according to race or ethnicity. Indeed, normal-weight Hawaiians and Pacific Islanders were three times more likely to have diabetes than normal-weight white people. In fact, diabetes prevalence with normal BMI was 18% for Hawaiians/Pacific Islanders versus just 5% for Whites. Prevalence was also higher among Blacks, (13.5%), Hispanics (12.9%), Asians (10.1%) and American Indians/Alaskan natives (9.6%) [6].

2. Quercetin as a Modulator of Insulin Resistance

Qtn is a flavonoid, belonging to the flavonol group. Qtn (molecular formula C15H10O7, mass: 302.236 g/mol, density: 1.8 g/cm³) is the aglycone component of various glycosides, including rutin and quercitrin, and is found in abundant quantities in the diet because it is present in many edible vegetables, such as red onions, capers, broccoli, chicory excel, lettuce and apples. It is also found in non-edible vegetables, such as horse chestnuts, calendula, hawthorn, chamomile, St. John’s wort (Hypericum perforatum) and Ginkgo biloba. The fava d’Anta bean (Dimorphandra mollis) is particularly rich in Qtn, so much so that it is also used as an economically convenient raw material for its purification.
Known for its antioxidant and anti-inflammatory properties, Qtn is proposed as a dietary supplement in antiaging and immunostimulant formulations. Numerous studies demonstrate its potential usefulness in the treatment and prevention of various morbid conditions: allergies, atherosclerosis, arthritis, Alzheimer’s disease, psoriasis, lupus and many of the pathologies linked to aging.
Qtn inhibits numerous steps leading to the release of histamine and the production of pro-inflammatory prostaglandins and leukotrienes, as well as the enzymes 5-lipoxygenase and phospholipase A2. At the same time, it exerts a powerful direct and indirect antioxidant action, protecting the activity of the endogenous antioxidant enzymatic systems: catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase.
Preventing or treating IR means preventing diabetes and its complications. IR is linked to metabolic syndrome, endothelial dysfunction and vascular disease in reciprocal and synergistic relationships [8][9][10][11]. Indeed, subjects with metabolic syndrome have significantly higher levels of insulin, endothelin and pro-thrombotic markers and low levels of nitric oxide [12]. It has been shown that individuals with these characteristics are also commonly prone to chronic inflammatory states and oxidative stress phenomena, probably due to mitochondrial nutrient metabolism disturbance [13].
In this context, it is interesting that good results have been obtained in clinical studies with the integration of various polyphenols [14][15][16][17], including Qtn [10][18][19]. A meta-analysis [20] identified nine studies on this topic, which overall demonstrated that Qtn supplementation did not affect fasting blood glucose or IR. However, in subgroup analyses, Qtn supplementation slightly—but significantly—reduced fasting glucose in studies of 8-week duration and using Qtn in doses equal to or greater than 500 mg/day. Better effects were found in individuals <45 years of age. The supplementation of Qtn nutrition on blood pressure and endothelial function among patients with metabolic syndrome was studied with a meta-analysis [15]. The authors found a significant reduction in systolic but not diastolic blood pressure.
Qtn has been detected in plasma, in pharmacologically active doses, after consumption of food or supplements and interacts with many molecular targets in the gut, skeletal muscle, adipose tissue and liver to control glucose homeostasis [21].
Based on the IR mechanisms already described and the experimental evidence, it is clear that the action mechanisms of Qtn are pleiotropic [22][23]. Qtn affects signaling pathways involved in IR and the pathogenesis of type 2 diabetes, such as nuclear factor erythroid 2-related factor2 (Nrf2) (involved in antioxidant systems), nuclear factor kB (NF-kB) (inflammatory cytokine transcription factor), AMPK and Akt [24].
Schematically, it is possible to group the actions of Qtn according to three different strands: antioxidant action, regulation of protein phosphorylation chains and anti-inflammatory action.

2.1. Antioxidant Action and Inhibition of NADPH Oxidase

Oxidative stress contributes to IR in various ways. High-fat diets increase mitochondrial H2O2 production and cause a reduction in the glutathione (GSH)/glutathione disulfide (GSSG) ratio [25]. Since the activity of many protein kinases and phosphatases is regulated by the redox state of cysteine thiols, a more oxidized cellular environment may favor the serine/threonine phosphorylation events that characterize the negative feedback of insulin action. Mitochondrial H2O2 clearance, either by pharmacological means or by transgenic expression of catalase in mitochondria (MCAT mice), protects against HFD-induced muscle IR [26].
Like all flavonols, Qtn has powerful direct antioxidant effect, as a scavenger of toxic oxygen derivatives, and indirect effects, mediated by the stimulation of the Nrf2/ARE system. In a model of IR induced in liver cells by oleic acid overload [27] Qtn increased glucose uptake and reduced triglyceride accumulation. At the same time, it increased the content of cellular glutathione and antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) and reduced the generation of lipid peroxides. In endothelial cells, palmitate induces IR and increases the production of ROS—phenomena counteracted by Qtn and quercetin-3-O-glucuronide [28].
High-fat diets are among the most followed experimental models for inducing obesity, glucose intolerance and IR. Oxidative stress and an impaired skeletal muscle mitochondrial function may play a pivotal role in the onset of IR during diet-induced obesity. In a model of this type, regarding C57BL/6J mice fed with high fat content (45% of energy derived from them) [29], it was observed that the primary defect was the reduced ability of insulin to release glucose from the liver. In this case, adding Qtn to the diet (1.2%) for 8 weeks failed to normalize the metabolism. One possible explanation lies in the dosages. Indeed, in HFD-fed mice, a low dose of Qtn reduced IR and attenuated HFD-induced increases in fat mass and body weight [30]. Interestingly, such positive effects were not observed with a much higher dose (600 ug/mouse/day, corresponding to about 30 mg/kg). Among the biochemical parameters measured, the one most closely related to the metabolic effects of low-dose Qtn was the increase in peroxisome proliferator receptor gamma 1 alpha coactivator (PGC1α) in the muscle. PGC1α is a transcriptional coactivator that coordinates mitochondrial biogenesis and function. Of course, the results of experimental models may depend on important details, as evidenced by the fact that Qtn supplementation alters the intestinal microbiota and through this type of modification reduces inflammation in C57BL/6J mice made obese with HFD [31].
A mixture of resveratrol + Qtn has beneficial effects in oxidative stress induced by a sucrose-rich diet in rats [32]. The antioxidant properties were verified with decreased lipid peroxidation and increased catalase, superoxide dismutase, glutathione-S-transferase, glutathione reductase and overexpression of the main factor Nrf2, which increases antioxidant enzymes and GSH.
Bile duct ligation (BDL) is a surgical model performed in rodents to produce IR, accompanied by increased oxidative stress, which results in liver fibrosis. The molecular mechanism of liver injury by BDL also involves the activation of superoxide production by NADPH oxidase (NOX1) [33]. Qtn at a dose of 30 mg/kg/day significantly alleviated liver injury in BDL rats, reduced liver enzyme toxicity, and reduced mRNA and protein expression of Rac1, Rac1-GTP and NOX1. In the same model, the work of Khodarahmi et al. [34] demonstrated that the antidiabetic impact of Qtn was associated with increased IRS-1 and decreased NOX1 expression levels, together with down regulation of Rac1-GTP, Rac1, HIF-1alpha and ERK1. Qtn also inhibited NADPH oxidase expression or function in a rat polycystic ovary-related IR model [35], in a Dichlorodiphenyltrichloroethane (DDT) liver toxicity model [36] and in rat cardiomyocytes with T2DM induced with a high-calorie diet and streptozocin [37].
A further possible contribution of Qtn in the treatment of diabetes and IR is the inhibition of ferroptosis, a mechanism involving cellular damage related to oxidative stress in pancreatic beta cells [38].
However, the role of antioxidant supplementation in humans remains controversial, and studies have produced conflicting results on metabolic disease-related mortality [26]. Therefore, it is likely that the beneficial action of Qtn is not linked only to its capacity as a direct antioxidant. A particularly interesting action is the inhibition of the enzyme NADPH oxidase, responsible for the production of ROS during inflammatory reactions, [39] but also implicated in numerous crucial physiological processes, including cell signaling, regulation of gene expression [40] and even cardiac pathophysiology [41][42]. The inopportune activation of NADPH oxidase is part of the mechanisms that link overeating, oxidative stress and inflammation, which are positively regulated by the Mediterranean diet and by polyphenols [43].

2.2. Regulation of Cell Signaling Pathways

The valuable actions of Qtn in preventing or reversibilizing IR have many targets that inhibit oxidative stress and “unblock” signal transduction pathways via the protein kinase pathways described above. Dai et al. investigated the role of IR in TNF-α-induced C2C12 skeletal muscle and cell damage [44]. Phosphorylation of AMPK was significantly inhibited in treated cells, while Qtn enhanced glucose uptake in a dose-dependent manner through activation of Akt and AMP-activated (AMPK) pathways. In in vitro mixed cells, very low doses of Qtn (0.1 nM and 1 nM) significantly increase glucose uptake via translocation of the GLUT4 channel to the plasma membrane [45]. Qtn primarily activated the AMPK signaling pathway at lower doses, but it also activated IRS-1/PI3K/Akt signaling at 10 nM. In the same paper, oral administration of Qtn glycoside to mice at 10 and 100 mg/kg body weight significantly induced the translocation of GLUT4 to the skeletal muscle plasma membrane.
Nanomolar active doses are within the range of Qtn concentration, which has been found to be reached during therapeutic intervention trials in humans [46][47]. Despite absorption of Qtn in reportedly 9–20% of food intake, concentrations of Qtn in the blood range from 300 to 750 nmol/L after consumption of 80–100 mg of Qtn equivalent [45]. Qtn in plasma reached 431 nmol/L (0.13 μg/mL) after 1-week supplementation with 150 mg/d pure Qtn [48], 0.63 μmol/L (0.19 μg/mL) after 1-week supplementation with 80 mg/day Qtn equivalents from onions [49] and reached a maximum of 1.5 μmol/L (0.45 μg/mL) after 28 days of supplementation with high doses of Qtn (>1 g/d) [50].
In another laboratory system, myotubes from healthy donors were cultured for 24 h without and with resveratrol or Qtn to evaluate their effects on glucose metabolism, as well as the expression of key metabolic proteins and genes [51]. Both polyphenols increased insulin-stimulated glycogen synthesis and reduced lactic acid production in human myotubes. In these experiments, Qtn increased AMPK, IRS-1 and AS160 phosphorylation under basal conditions and GSK3beta under insulin-stimulated conditions. Resveratrol tended to increase the phosphorylation rates of AMPK and GSK3beta.
Another elegant evidence of the intervention of Qtn on insulin signaling systems was offered in the model of IR established in C2C12 skeletal muscle cells by stimulation with palmitic acid (PA) [52]. A non-cytotoxic dose of Qtn has been found to promote glucose uptake and inhibit oxidative stress. Qtn inhibited the methyladenosine and METTL3, while it increased the protein expression of PRKD2, GLUT4 and p-Akt. Additionally, Qtn had promoter effects on superoxide dismutase (SOD), GSH. Other authors induced IR in liver cells with palmitic acid (PA) and Qtn significantly increased glucose uptake and expression of glucose transporter 2 (GLUT2) and GLUT4 [53]. A novel observation is that Qtn suppresses phosphorylation of IRS-1 on serine 612 (that is an inhibitory signal), instead it promotes phosphorylation on tyrosine and the expression of PI3K, as well as Akt and GSK3beta. Finally, the molecular docking result showed that Qtn could bind to insulin receptors, interacting with three residues, including GLU-1135, PRO-1129 and ASP-1170, in the active pocket of the receptor. In short, the data confirm that Qtn improved the IR by increasing the signaling pathway leading to glucose uptake and glycogen production and perhaps by direct modulation of receptor sensitivity. Additionally, in the umbilical cord endothelial cell model, palmitate induced IR [28], while Qtn and quercetin-3-O-glucuronide positively regulated IRS-1 phosphorylation and restored downstream Akt/eNOS activation, leading to an insulin-mediated increase in NO level.
In the HepG2 cell model of non-alcoholic-fatty-liver disease (NAFLD) [54], Qtn enhances tyrosine phosphorylation in the insulin signaling pathway and reduces the expression levels of the protein-1c-binding sterol regulatory element (SREBP-1c) compared to the control group. SREBP-1c is a transcription factor that is the master regulator of lipid metabolism, encoded by the sterol regulatory element binding transcription factor 1 (SREBF1) gene. SREBF1 gene variations modulate insulin sensitivity in response to fish oil supplementation [55]. Other authors reported that the beneficial effect of Qtn on glucose metabolism involves a downregulation of SREBP-1c in adipocytes [56], hepatocytes [57] and diabetic rats [58], or affected by NAFLD [59][60].

2.3. Regulation of Inflammation Associated with Metabolic Disorders

Even a systemic inflammatory state can favor IR [44]. Multiple biological mechanisms link inflammation to IR because signal transduction systems are vulnerable to cytokines and also to other substances such as C-reactive protein. Tumor necrosis factor causes IR by inducing transcription of inflammatory genes and directly impairing insulin signaling via the insulin receptor substrate (IRS)-1/2 [61][62]. In IR models, the anti-inflammatory effect of Qtn is evidenced by the inhibition of the production of key cytokines and c-reactive protein.
In addition to what has already been seen about NADPH oxidase, there is much evidence that Qtn acts by regulating the production of inflammatory mediators. In studies on human basophils, very low doses of Qtn, such that they can be achieved with dietary supplementation, are able to inhibit histamine release [63][64], probably by inhibition of phosphoinositide-3 kinase-delta (PI3Kδ) [65]. There is extensive evidence that Qtn suppresses the release of pro-inflammatory markers such as IL-1beta, IL-6 and TNF-α [66]. Chemokines associated with macrophage M1 polarization such as CCL-2 and CXCL-10 were also effectively reduced by Qtn treatment [67].
One of the links between the 2 phenomena could be the inhibition of signaling pathways mediated through IRS-1 [68]. These authors demonstrated that C-reactive protein (hsCRP) can cause IR by increasing the phosphorylation of 2 serines, Ser(307) and Ser(612), on the IRS-1 by Jun N-terminal Kinase (JNK) and ERK1/2, respectively, leading to an inhibition of the IRS-1/PI-3K/Akt/GSK-3 pathway, and thereby, impaired translocation of GLUT4 and glucose uptake.
One of the first works to demonstrate the anti-inflammatory effect in a model of IR was that of Chuang et al. [69]. Treatment of primary cultures of newly differentiated human adipocytes with Qtn prevents TNF-α from directly activating ERK and NF-kB, which are potent inducers of gene expression of IL-6, IL-8 and MCP-1 and negative regulators of insulin signaling. Qtn prevented TNF-α-mediated serine phosphorylation of the insulin receptor substrate-1 and protein tyrosine phosphatase-1B (PTP1B) gene expression, whose importance has been highlighted in the previous section.
IR induced by oleic acid (OA) in culture medium induces fatty liver condition in HepG2 cells, increased lipid peroxidation and inhibition of glucose uptake and cell proliferation. These changes are counteracted by Qtn, with increased cell growth and increased glucose influx mediated by insulin [27]. Qtn reduced TNF-α and IL-8 by 59.74% and 41.11%, respectively, and inhibited the generation of lipid peroxides by 50.5%. Hence, Qtn effectively reversed the symptoms of NAFLD by reducing triacylglycerol accumulation, IR and inflammatory cytokine secretion in hepatocyte cells.
IR is a clinical feature of polycystic ovary syndrome (PCOS), possibly related to common factors controlling insulin receptor signaling, ovarian steroidogenesis and pituitary LH release [70]. Wang and collaborators [35] demonstrated that Qtn can reduce IR in PCOS, induced in rats with dehydroepiandrosterone administration. Qtn improved IR, reduced blood insulin levels, moderated the Toll-like/NF-kB receptor signaling pathway and inflammatory cytokines. Additionally, Qtn increases the levels of AMPK and sirtuin (SIRT-1) in the ovarian tissue of PCOS rats [71]. Experimental studies in women with PCOS [72][73][74] and systematic reviews suggest that Qtn is able to help correct hormonal disturbances and metabolic disorders in PCOS also in humans [16][75][76].
Experimental metabolic disorders, including IR, can be induced by particulate matter (PM) administration [77]. Male C57BL/6 mice were exposed to filtered ambient air or PM for 18 weeks. Chronic exposure to PM caused inflammation in systemic and visceral white adipose tissue, with increased serum IL-6 and TNF-α levels and macrophage infiltration characterized by NLRP3 inflammasome activation. The metabolism of glucose into fat was impaired and IR occurred throughout the body. Qtn administration significantly inhibited inflammation and the NLRP3 inflammasome and ameliorated the signaling abnormalities characteristic of IR.

This entry is adapted from the peer-reviewed paper 10.3390/molecules28114491

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