Abstract
Information regarding the use of functional foods and nutraceuticals (FFN) in combating disease is rarely communicated to health care practitioners as medicinal strategies for patients. Metabolic syndrome (MetS) is an ideal paradigm for demonstrating the therapeutic properties of FFN. Encompassing multiple etiologies, including atherogenic dyslipidemia, insulin resistance, and hypertension, MetS affects over a third of American adults. However, as disease-related risk factors accumulate over time, guidelines for treating disorders of MetS progressively de-emphasize the use of FFN. Using marine omega-3 fatty acids, plant sterols, fiber, and tomato extract as examples, the purpose of this review is to endorse FFN as long-term adjunctive therapies to pharmaceutical treatment for disorders and risk factors for MetS. An additional goal is to compare physiological and molecular targets of FFN against corresponding prescription medications. Results reveal that FFN are viable treatment strategies for disorders of MetS, complementing pharmacological interventions by targeting and improving the biological processes that foster the development of disease. Thus, efficacious FFN therapies should be emphasized throughout all stages of treatment as adjuncts to pharmacotherapy for disorders of MetS. Accordingly, new developments in FFN research must be implemented into clinical guidelines with the prospect of improving disease prognoses as accessories to prescription medications.
| Abbreviations | ||
| ABCG | = | ATP-binding cassette G transporters |
| AMP | = | Adenosine monophosphate |
| AMPK | = | AMP-activated protein kinase |
| ATP | = | Adenosine triphosphate |
| BP | = | blood pressure |
| CVD | = | cardiovascular disease |
| DBP | = | diastolic blood pressure |
| DHA | = | docohexaenoic acid |
| EPA | = | eicosapentaenoic acid |
| FDA | = | U.S. Food and Drug Administration |
| FFN | = | functional foods and nutraceuticals |
| FXR | = | farnesol X receptor |
| GLUT-1 | = | glucose transporter 1 |
| GPR | = | G-coupled proteins |
| HCH | = | hypercholesterolemia |
| HDL | = | high-density lipoprotein |
| HMG-CoA | = | 3-hydroxy-3-methylgutaryl- coenzyme A |
| HNF-4α | = | hepatocyte nuclear factor 4α |
| HTG | = | hypertriglyceridemia |
| IR | = | insulin resistance |
| JNCBP | = | The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure |
| LDL | = | low-density lipoprotein |
| LDL-C | = | low-density lipoprotein cholesterol |
| LXR | = | liver X receptor |
| MetS | = | metabolic syndrome |
| MOM-3 | = | marine-derived omega-3 fatty acids |
| NADPH | = | nicotinamide adenine dinucleotide phosphate |
| NCEP | = | The National Cholesterol Education Program |
| NEFA | = | non-esterified fatty acids |
| NFκB | = | nuclear factor kappa-light-chain-enhancer of activated B cells |
| NO | = | nitric oxide |
| PPAR | = | peroxisome proliferator-activated receptor |
| RS | = | resistant starch |
| SBP | = | systolic blood pressure |
| SCFA | = | short-chain fatty acids |
| sdLDL | = | small dense low-density lipoprotein |
| SREBP 1c | = | sterol regulatory element-binding protein 1c |
| TG | = | triglyceride |
| VLDL | = | very-low-density lipoprotein |
| VLDL-C | = | very-low-density lipoprotein cholesterol |
Key messages
Similar to pharmaceutical agents, functional foods and nutraceuticals (FFN) possess physiological and molecular targets that modulate clinical end-points associated with chronic disease. Despite current research demonstrating that FFN combined with pharmaceuticals can benefit patients better than pharmaco-monotherapy, FFN-based therapies are de-emphasized as risk factors for chronic disease accumulate over time.
In the context of metabolic syndrome, a multifaceted disease state, FFN including marine-derived omega-3 fatty acids, plant sterols, fiber, and tomato extract have been shown to target metabolic processes associated with atherogenic dyslipidemia, hypercholesterolemia, insulin resistance, vascular dysfunction, and hypertension.
FFN should be emphasized throughout all stages of treatment as adjuncts to pharmacotherapy. For this to happen, however, new developments in FFN research must be communicated to health care practitioners and implemented into clinical guidelines so that they may be utilized by modern medicine as tools for combating disease.
Introduction
Nutraceuticals are bioactive compounds that confer protection from chronic disease via mechanisms beyond simply providing nutrition. A food becomes ‘functional’ when levels of one or more nutraceuticals are present at concentrations such that regular consumption elicits a positive biological effect. Nonetheless, nutraceuticals can also be isolated from functional foods and added to other food matrices or concentrated for distribution in capsules or tablets. Similar to pharmaceutical agents, research clearly demonstrates that functional foods and nutraceuticals (FFN) possess physiological and molecular targets that modulate clinical end-points associated with chronic disease. Despite current research demonstrating that FFN combined with pharmaceuticals can benefit patients better than pharmaco-monotherapy (Citation1–3), information regarding the efficacy of FFN-based therapies is rarely communicated to health care practitioners and implemented into disease treatment regimens. Metabolic syndrome (MetS) is an ideal and timely example for asserting FFN efficacy in treating chronic disease given that MetS is a multifaceted ailment affecting a third of American adults (Citation4).
MetS is characterized as a combination of medical disorders including central obesity, insulin resistance (IR), hypertension, as well as atherogenic dyslipidemia, itself characterized as hypertriglyceridemia (HTG), low HDL-C and high levels of circulating small dense LDL-C (sdLDL) (Citation5,Citation6) (). Hypercholesterolemia (HCH), more specifically high levels of circulating low-density lipoprotein cholesterol (LDL-C), has been described as a therapeutic target for atherogenic dyslipidemia (Citation6,Citation7). Moreover, patients with MetS demonstrate an progressive trend towards lower antioxidant activity with onset of MetS co-morbidities (Citation8). Finally, antioxidant status has been associated with the pathogenesis of IR and hypertension (Citation9). Clinical guidelines such as The National Cholesterol Education Program (NCEP) and The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNCBP) recommend a spectrum of life-style and pharmaceutical therapies for treating specific disorders of MetS (Citation7,Citation10). While life-style interventions are emphasized during the initial stages of treatment for MetS-related disorders, dietary interventions, specifically FFN, become overshadowed by pharmacological agents as risk factors for chronic disease accumulate over time. For example, current NCEP guidelines recommend plant sterols and stanols (PS) as therapeutic options to clinicians for reducing circulating levels of LDL-C. However, PS are not emphasized as a constituent of the Therapeutic Life-style Change Diet or during the later stages of HCH treatment (Citation7). Similarly, the JNCBP's algorithm for the treatment of hypertension accentuates a combination of pharmacological agents when blood pressure levels (BP) are <140/90 mmHg with no mention of FFN (Citation10). In addition, the JNCBP advocates the use of additional drugs until an ideal BP is achieved. That being said, specific FFN have been identified as efficacious and safe adjunctive therapies for disorders of MetS. Noteworthy are supplemental marine-derived omega-3 fatty acids (MOM-3) and PS. The former has been shown to be a potent treatment for HTG as well as possess secondary cardio-protective benefits including improvements in antioxidant status, vascular function, and inflammatory biomarkers. The latter is an efficacious treatment for HCH, a fact that is supported by over 50 years of research. Other FFN showing promise include supplemental fiber for treating IR and tomato extracts for hypertension.
Figure 1. MetS as a multifaceted disease encompassing central obesity, atherogenic dyslipidemia, hypertension, and insulin resistance. Low antioxidant status can contribute to the development of hypertension and insulin resistance, while hypercholesterolemia, specifically high LDL-C, is a primary target for atherogenic dyslipidemia.
Accordingly, the first objective of this review is to describe the efficacy of MOM-3, PS, fiber, and tomato extract in reducing HTG, HCH, IR, oxidative stress, hypertension, and improving vascular function (). The second objective is to provide a comparison of physiological, metabolic, and molecular targets between the described FFN and corresponding prescription medications currently used for treating disorders of MetS. Finally, this review will discuss studies that have examined the use of pharmacological agents in conjunction with FFN therapies for treating HTG, HCH, IR, and hypertension.
Marine-derived omega-3 fatty acids, triglycerides, and vascular health
Marine-derived omega-3 fatty acids for the treatment of hypertriglyceridemia
Supplemental MOM-3, eicosapentaenoic acid (C20: 5n-3) (EPA), and docohexaenoic acid (22:6n-3) (DHA) have been shown to be efficacious in treating HTG (Citation11). Effects of MOM-3 on circulating triglyceride (TG) concentrations are dose-dependent, with TG-lowering efficacy being demonstrated with dosages ranging from 1.3 to 12.0 g/d (Citation12–15). In a comprehensive review of 65 human clinical studies, Harris et al. (Citation16) demonstrated that MOM-3 consistently reduce TG levels by 25% and 34% in normal and HTG patients, respectively, concluding that additional trials are no longer needed to demonstrate MOM-3's TG-lowering efficacy. Concerns regarding the safety of supplemental MOM-3 stem from Greenland Inuit peoples having significantly longer bleeding times (Citation17). However, in a dose-dependent study whereby MOM-3 was administered at 4.5, 7.5, and 12 g/d, blood coagulation times only increased when volunteers received the highest dose of MOM-3 (Citation14). Hence, 3–4 g/d of supplemental MOM-3 can be regarded as a safe and efficacious treatment for HTG.
Medications versus marine-derived omega-3s for the treatment of hypertriglyceridemia: mechanisms of action
Primary medications used to treat HTG include statins and fibrates. As 3-hydroxy-3-methylgutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins inhibit hepatic cholesterol synthesis. Unlike statins, fibrates are ligands for nuclear receptors, activating hepatic peroxisome proliferator-activated receptor-α (PPAR-α) and inhibiting hepatocyte nuclear factor 4α (HNF-4α), resulting in higher lipoprotein lipase levels, high-density lipoprotein cholesterol (HDL-C) levels, fatty acid β-oxidation, as well as reduced very-low-density lipoprotein (VLDL) secretion and lower expression of genes involved in carbohydrate and lipid metabolism (Citation18–20) ().
Table I. Summary comparison of triglyceride-lowering mechanisms of action between marine-derived omega-3 fatty acids and prescription medications.
MOM-3 reduce TG levels by modulating the expression of nuclear receptors. Alongside an increase in PPAR-α and inhibition of HNF-4α gene expression, MOM-3 up-regulate and down-regulate farnesol X receptor (FXR) and liver X receptor (LXR) expression, respectively, resulting in an inhibition of sterol regulatory element-binding protein 1c (SREBP 1c) activity and expression (Citation21). SREBP 1c up-regulates the expression of genes involved i n TG synthesis (Citation21–23). Together, the effects of MOM-3 on FXR and PPAR-α also enhance hepatic TG uptake and TG oxidation, respectively (Citation21). Altogether, MOM-3 act on similar molecular targets to pharmaceutical therapy to modulate intracellular TG metabolism and decrease circulating TG levels ().
Medications versus marine-derived omega-3 fatty acids on oxidant status, vascular function, and inflammation
Statins have been shown to reduce C-reactive protein by 67% (Citation24), DNA damage by 20% to 40% (Citation25,Citation26), superoxide anion by 36% (Citation27), auto- antibodies against LDL oxidation by 19% (Citation28), and conjugated diene production by 41% (Citation29). Increases in glutathione peroxidase activity by 38% (Citation29), paraoxonase levels by 32% (Citation30), α-tocopherol levels by 29% and retinol levels by 40% (Citation31) have also been observed with statin therapy. Statins enhance vascular function by inhibiting thromboxane A2 production and inducing vasodilation via increasing nitric oxide synthase levels (Citation32). Additional cardio-protective effects of statins include increased circulating HDL-C levels 3% to 10% (Citation33,Citation34) as well as reductions in sdLDL 24% to 57% (Citation35–38). Compared to large LDL subfractions, sdLDL are better able to infiltrate arteriole walls, possess higher susceptibility to oxidation, and thus initiate development of atherosclerotic plaques. Given that oxidative stress promotes inflammation and has been linked to atherosclerosis (Citation39) and cancer (Citation40,Citation41), statins have been given considerable attention for promoting improvements in oxidative biomarkers in conjunction with their lipid-lowering properties.
Similar to statins, MOM-3 supplementation has been shown to improve antioxidant status via increasing glutathione peroxidase by 30% (Citation42). Supplemental MOM-3 have also been shown to reduce lipid peroxidation by 19% (Citation42), ultraviolet light-induced DNA damage by 70%, and p53 gene expression by 50% (Citation43). MOM-3 consumption also fosters the production of anti-inflammatory signaling molecules including trienoic prostaglandins and 5-series leukotrienes while reducing levels of urinary F2-isoprostanes (Citation44). Products of omega-6 fatty acid oxidation, F2-isoprostanes are biomarkers for the production of pro-inflammatory dienoic prostaglandins (Citation45). MOM-3 promote vasodilation by inhibiting thromboxane A2 production and promoting thromboxane A3 and B3 synthesis (Citation45,Citation46). In addition, Nomura et al. (Citation47) showed that supplementation with 1.8 g/d EPA significantly reduced markers of coagulation including CD62P, CD63, annexin V, as well as platelet and monocyte-derived microparticles, which are prothrombotic. In the same study, EPA decreased E-selectin levels, a biomarker of vascular damage (Citation47). Finally, MOM-3 have been shown to reduce levels of sdLDL by 21% to 37% (Citation48,Citation49) and remnant-like lipoprotein particles by 21% (Citation50), which, as outlined above, are both atherosclerotic. Therefore, MOM-3 can be considered a valuable means for improving vascular function.
Combining marine-derived omega-3 fatty acids and medications as adjunctive treatments for hypertriglyceridemia and other risk factors for cardiovascular disease
Recent studies have emerged advocating adjunctive statin/MOM-3 therapy for treating HTG. The extent to which MOM-3 amplify the TG-lowering effects of statin monotherapy is demonstrated in , showing that combination MOM-3/statin treatments reduce TG an additional 10% to 30% compared with statin therapy alone (Citation1,Citation51–57). Combination therapy has also been shown to further reduce levels of total circulating cholesterol (−4% to −30%) (Citation1,Citation52,Citation54,Citation55), VLDL-C (−20% to −40%) (Citation1,Citation52,Citation53), VLDL-TG (−53%) (Citation56), ApoB100 (−32%), and ApoB48 (−36%) (Citation56), as well as increase HDL-C levels (4% to 18%) (Citation1,Citation52,Citation56) compared to statins alone. These findings indicate that MOM-3 therapy may help improve patients’ overall lipid profiles. In addition, combining MOM-3 with pitavastatin was shown to synergistically improve vascular function by reducing prothrombotic platelet-derived microparticles as well as increasing levels of adiponectin (Citation58). Adiponectin increases NO levels, promoting vasodilation (Citation59,Citation60), as well as decreases monocytes from adhesion to endothelial cells (Citation61). Furthermore, 3.6 g/d MOM-3 further reduced TG and homocysteine levels 28% and 29%, respectively, in patients already receiving statin and fibrate therapy (Citation57). Recently Lovaza® became the first prescription MOM-3 supplement approved by the U.S. Food and Drug Administration (FDA), substantiating the notion that FFN are potent therapies for treating disorders of MetS. The above studies highlight MOM-3 as a potent complementary therapy to pharmacological medications for HTG and other cardiovascular risk factors.
Table II. Summary of studies MOM-3 as a beneficial adjunctive therapy to statin therapy when treating hypertriglyceridemia.
Plant sterols/stanols and hypercholesterolemia
Plant sterols and stanols as treatments for hypercholesterolemia
In 1954, Best et al. (Citation62) first demonstrated that supplemental PS reduce total cholesterol levels in humans. Since then, over 100 clinical trials have shown that PS consumption significantly decreases LDL-C by 5% to 15% (Citation63). A recent meta-analysis confirmed that PS-derived reductions in LDL-C are dose-dependent with maximum efficacy peaking at 2.0–2.5 g/d (Citation64). Typically, food-based vehicles are used to administer PS. However, PS capsules are available and have also been shown to be efficacious for reducing LDL-C (Citation65,Citation66).
Medications versus plant sterols for the treatment of hypercholesterolemia: mechanisms of action
Statins, bile acid resins, niacin, and cholesterol absorption inhibitors (ezetimibe) are among the most popular treatments for HCH (). As outlined above, statins inhibit hepatic cholesterol synthesis, while bile acid resins bind bile and inhibit cholesterol reabsorption in the large intestine (Citation67). Niacin reduces hepatic lipid synthesis and adipocyte lipolysis (Citation68). Ezetimibe reduces biliary cholesterol absorption by interacting with enterocyte Niemann-Pick C1-like protein 1 transporters, resulting in an increase in hepatic LDL uptake (Citation67). Similar to ezetimibe PS are believed to displace dietary cholesterol from being incorporated into mixed micelles in the small intestine (Citation69) (). Absorption of PS into the circulation is poor at 0.1%–1.9% (Citation70) thus the majority of PS action occurs in the lumen through competition. Evidence suggests that PS act as LXR agonists and induce the expression of enterocyte ATP-binding cassette G transporters (Citation71) which subsequently pump PS from the enterocytes back into the gastrointestinal lumen (Citation72).
Table III. Summary comparison of LDL-lowering mechanisms of action between plant sterols and stanols and prescription medications.
Medications and plant sterols: mechanisms for reducing vascular plaque formation
The LDL-C-lowering effects of PS and statins may also confer protection against the formation of atherosclerotic plaques via nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and monocyte chemoattractant protein-1 (MCP-1) pathways. LDL-cholesterol levels have been shown to increase MCP-1 expression directly as well as indirectly via NFκB. Endothelial expression of MCP-1 has been implicated for increasing vascular lipid accumulation, macrophage recruitment, and atherosclerotic plaque growth (Citation73). Studies demonstrate that statin treatment decreases atherosclerotic plaque formation alongside reduced NFκB and MCP-1 expression (Citation74–76). Although not demonstrated in vivo, in vitro experiments show that PS inhibited MCP-1 production in umbilical venous endothelial cells treated with oxidized LDL (Citation77). The authors hypothesize that PS could modulate NFκB activity or expression and would suggest that, similar to statins, PS reduce MCP-1 through LDL-C-lowering and NFκB-related pathways. Further studies are needed to determine if combination PS/statin therapy can produce an additive effect on MCP-1 expression.
Combining plant sterols/stanols and prescription medications as adjunctive treatments for hypercholesterolemia
The magnitude of PS/statin therapy on LDL-C is demonstrated in . Studies reveal that when PS are combined with statins, LDL-C levels are reduced an additional 5% to 17%, compared to statins alone (Citation3,Citation65,Citation78–82). PS efficacy is not affected by the type or dose of statin administered, with LDL-C reductions being observed in patients taking simvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin, rosuvastatin, and cerivastatin (Citation3,Citation65,Citation78–82). Simons et al. (Citation81) demonstrated that combination PS/statin therapy is additive, reducing LDL-C levels by 39%, which is equivalent to the effect of doubling the dose of statins. Furthermore, the proportion of patients with LDL-C levels <4 mmol/L increased from 33% in subjects receiving statins alone to 67% and 72% for patients receiving combination statin/plant sterol or statin/plant stanol therapy, respectively (Citation80). Plant sterols should be touted as a safe and efficacious adjunctive therapy to statin treatment for HCH, a major contributor to the development of MetS.
Table IV. Summary of studies showing plant sterols and stanols as a beneficial adjunctive therapy to statin therapy for the treatment of hypercholesterolemia.
The area of concomitant PS therapy with other HCH medications has been understudied. Ezetimibe/PS therapy has been found to reduce LDL-C levels 25%, but was insignificant compared to ezetimibe therapy alone (222%) (Citation83). Given that PS and ezetimibe both inhibit cholesterol absorption it is possible that the effects of PS on LDL-C were overshadowed by the action of ezetimibe. Conversely, PS/fibrate therapy has been shown to reduce LDL-C levels 11.1% compared to 7.7% after PS therapy alone (Citation84). Studies combining PS with bile acid sequestrants or niacin have yet to be published. Undoubtedly, further research exploring the benefits of using PS together with lipid-lowering medications other than statins is warranted. Until then, patients prescribed statin medications can be advised, with confidence, to ingest PS to produce greater reductions in LDL-C compared to statins alone.
Fiber and insulin resistance
Soluble and insoluble fiber and resistant starch as treatments for insulin resistance
Recently soluble fiber, insoluble fiber, and resistant starches have been explored for their effects on IR. Insulin resistance, a MetS co-morbidity, has been long associated with the development of other metabolic disorders and disease risk factors, including polycystic ovary syndrome, type II diabetes, cardiovascular disease (CVD), hypertension, obesity, and inflammation (Citation85,Citation86). As such, in 1992, Rupp et al. (Citation87) emphasized the need for dietary interventions that target and subsequently reduce IR. Recent insights into the biological effects of non-digestible carbohydrates suggest fibers can significantly improve IR.
Epidemiological studies have found associations between fiber intake and IR. A case-control study showed that higher consumption of soluble fiber amongst vegetarians from whole grains, pulses, oats, and barley preserved insulin sensitivity independent of age (Citation88). On the other hand, non-vegetarians began to show evidence of IR between 31 and 40 years of age (Citation88). Cross-sectional data from the Framingham Offspring Cohort noted an inverse association between cereal fiber intake and IR (Citation89), while a cross-sectional analysis of men and women from the Inter99 study showed a relationship between low-fiber consumption and the probability of developing IR (Citation90).
An association between supplemental fiber intake and IR has also been shown in randomized clinical trials. Studies utilizing euglycemic-hyperinsulinemic clamps demonstrate a 14% and 8% decrease in IR with resistant starch and cereal fiber, respectively (Citation91,Citation92). Moreover, homeostasis-modeling assessment, a non-invasive method for measuring IR using fasted blood samples, showed a 33% and 24% reduction in IR after 3 weeks of consuming 3 g/d β-glucan and 4 wks of a fiber-rich (20 g/d) meal replacement beverage, respectively (Citation93,Citation94). Similarly, despite no effect on postprandial glycemia, high-fiber bread increased postprandial insulin economy (Citation95). Furthermore, using the minimal model index as a measure of IR, 60 g/d resistant starch ingested 24 hrs prior to a fiber-free meal was shown to decrease postprandial IR 69%, compared to controls (Citation96). Resistant starch has also been shown to increase muscle and adipose glucose clearance by 44% and 87%, respectively (Citation91). In another study, lack of effect of 1.5 g/d β-glucan on IR could have been secondary to the low dose administered to subjects (Citation97). An acute dose-dependent study demonstrated that only the maximum dose of 10 g/d β-glucan was able to blunt postprandial insulin responses, despite no effect on postprandial glucose response (Citation98). Overall, data suggest that the dose and duration of intake of fiber impact when and if changes in IR will be observed.
Fibers versus prescription medications for treating insulin resistance: mechanisms of action
In addition to treating hyperglycemia, metformin and thiazolidinediones are prescription medications that have also been shown to decrease IR. The exact mechanisms by which metformin reduces IR remain to be completely understood. Studies suggest that metformin stimulates adenosine monophosphate (AMP)- activated protein kinase (AMPK) (Citation99–101), tyrosine kinase phosphorylation at the β-subunit on the insulin receptor (Citation102–104), as well as muscle atypical protein kinase C activation (Citation105). Similar to metformin, thiazolidinediones activate AMPK (Citation106) (). Moreover, thiazolidinediones target adipose tissue and act as a PPAR-γ ligand (Citation107), reducing free fatty acid release (Citation108) as well as the expression of IR-related substances such as leptin (Citation109), tumor necrosis factor (TNF)-α (Citation110,Citation111), and resistin (Citation112). It has also been suggested that thiazolidinediones decrease inhibitory insulin receptor substrate protein 1 serine phosphorylation (Citation113) and increase glucose disposal via higher expression of glucose transporter (GLUT)-1 in adipose (Citation114) and skeletal muscle (Citation115).
Table V. Summary comparison of insulin resistance-lowering mechanisms of action between fiber and prescription medications.
Short-chain fatty acids (SCFA), primarily acetate, butyrate, and propionate, are metabolites of microbial fermentation of dietary fiber in the large intestine and are thought to be important signaling molecules responsible for fiber-mediated decreases in IR (Citation116). Since high levels of circulating non-esterified free fatty acids (NEFA) have been linked to IR (Citation117), it has been suggested that SCFA reduce circulating NEFA (). Conclusive evidence of this phenomenon has yet to be presented in vivo. However, compared to controls, Robertson et al. (Citation91) observed a significant increase in SCFA production in subjects consuming 30 g/d RS alongside an increase in propionate and acetate uptake by adipose and muscle tissue, respectively. At the same time, subjects noted a decrease in adipose-derived NEFA and an increase in skeletal muscle and adipose glucose clearance. Interestingly, Robertson et al. also observed an increase in circulating ghrelin after resistant starch (RS) supplementation (Citation91) and noted that higher ghrelin levels associate with reduced IR (Citation118–120). Rat adipocytes showed an increase in PPAR-γ expression and lipogenesis after cells were treated with ghrelin (Citation121). Moreover, recent studies point towards SCFA acting as ligands for adipose G-coupled proteins (GPR). Robertson (Citation116) has also suggested that interactions between SCFA and adipose GPR43 could be of importance in decreasing NEFA levels while stimulating adipogenesis (Citation122) and adipocyte differentiation (Citation123). Adipocyte differentiation has been implicated in decreasing IR, since adipocyte size inversely correlates with IR (Citation124,Citation125). SCFA secondary to microbial fermentation of supplementary fiber may thus modulate IR by targeting adipose tissue metabolism.
Muscle and hepatic carbohydrate metabolism have also been implicated as possible sites of action for fiber-derived SCFA for decreasing IR. In fact, Thorburn et al. (Citation126) attributed colonic carbohydrate fermentation of barley after an evening meal to a reduction in hepatic glucose output during an oral glucose tolerance test the following morning. Rats fed psyllium showed a significant reduction in IR combined with an increase in skeletal muscle GLUT-4 transporters (Citation127). Enhanced skeletal muscle 5’ AMP-activated protein kinase in mice supplemented with butyrate was reflected with an increase in adaptive thermogenesis, fat oxidation, mitochondrial activity, and biogenesis in muscle and brown adipose as well as reduced adiposity (Citation128). Overall, available evidence suggests that SCFA produced during colonic fermentation of fibers reduces IR by mechanisms acting in adipose, liver, and muscle.
Combining fibers and prescription medications as adjunctive treatments for insulin resistance
To date, combining fiber and prescription medication for treating IR has yet to be explored. It is therefore worth noting that testing such a combination for potential additive or synergistic effects on adipose, muscle, and hepatic tissues would be highly important for developing treatment strategies for MetS. Studies outlined above support the notion that dietary fibers possess similar as well as diverse molecular targets compared to medications, suggesting that combination fiber/pharmaceutical therapies would positively modulate various facets of insulin metabolism and reduce IR.
Tomato extract and hypertension
Tomato extract as a treatment for hypertension
Having an elevated blood pressure ≥135/85 mmHg is considered a co-morbidity for MetS (Citation5). Recently, tomato extract has shown promise as a treatment for grade 1 hypertensive and pre-hypertensive patients. Following a 4 wk placebo, grade 1 hypertensive patients were given a tomato extract for 8 wks. The major constituent of the 250 mg supplement was lycopene at 15 mg/capsule suspended in tomato oil. In addition, the lycopene content in one capsule is reported to be equivalent to six large tomatoes. Other substances included vitamin E (6 mg), β-carotene (0.4 mg), and PS (1.5 mg). The tomato-based supplement reduced systolic (SBP) and diastolic blood pressure (DBP) 7% and 6%, respectively (Citation129). When given the placebo for a second time, blood pressure reverted back to levels observed prior to receiving the tomato-based treatment, strongly suggesting that the tomato extract was the efficacious agent (Citation129). In a follow-up study by Paran et al. (Citation2), the same tomato-derived supplement reduced SBP from 139.4 mmHg to 130.0 mmHg (26%) and DBP from 79.8 to 76.0 (-5%). Subjects who received the tomato supplement during the first treatment phase had reduced SBP and DBP, only to have BP increase during phase two while on the placebo. The reverse was observed in patients receiving the placebo followed by the treatment. Researchers also noted a negative correlation between blood lycopene levels and SBP (Citation2). In addition to hypertension being an risk factor for myocardial infarction (MI), results from the EURAMIC study concluded that lycopene was the only carotenoid that significantly and independently lowered the risk of MI, producing an odds ratio of 0.5 (Citation130). A recent investigation into the relationship between lipid-soluble antioxidants and atherosclerosis risk showed a negative correlation between lycopene and carotid intima-media thickness in hypertensive patients (Citation131). These data demonstrate the potential for using tomato extracts for the treatment of hypertension.
Medications versus tomato extract for the treatment of hypertension: mechanism of action
Current prescription medications used for treating hypertension include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, calcium blockers, β-blockers, and thiazides (). ACE inhibitors prevent the production of angiotensin II, a potent vasoconstrictor (Citation132). Angiotensin II receptor antagonists block angiotensin II from binding to its receptor in vascular smooth muscle, while calcium blockers decrease cardiac and arteriole muscle contraction. β-Blockers reduce cardiac output, inhibit kidney-mediated renin release, and inhibit vasoconstriction (Citation132). Finally, thiazides are diuretics that inhibit sodium reabsorption in the kidney, promoting diuresis and a decrease in blood volume (Citation132).
Table VI. Summary comparison of blood pressure-lowering mechanisms between lycopene and tomato extracts and prescription medications.
Researchers hypothesize that high levels of antioxidants found in tomato extracts account for their hypotensive properties (Citation2,Citation129) (). Pro-oxidation is a known risk factor for hypertension, with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, xanthin oxidase, mitochondrial-derived oxidants, and uncoupled endothelial nitric oxide synthase being amongst a few of the contributors to the production of reactive oxygen species (Citation133). Lycopene is considered the most potent antioxidant amongst carotenoids (Citation134). Bose et al. (Citation135) showed that 200 g/d cooked tomatoes improved antioxidant defense systems in hypertensive patients by increasing activities of superoxide dismutase, glutathione, glutathione reductase, and glutathione peroxidase. A recent editorial proposed that inhibition of peroxynitrate formation secondary to nitric oxide oxidation as a plausible mechanism for tomato's hypotensive effects since nitric oxide is a known vasodilator (Citation136). Furthermore, mice fed an atherosclerotic diet with tomato had reduced lipid peroxide levels and maintained acetylcholine-mediated vasodilation compared to mice not receiving tomato (Citation137).
Lycopene may work in concert with other tomato-derived bioactives including flavonoids, vitamins, other carotenoids, and minerals, such as potassium, and may produce better results than supplements with lycopene alone (Citation2,Citation136). A study examining the phytochemical content of the DASH diet attributed its hypotensive effects to higher levels of flavonoids and carotenoids, including lycopene (Citation138), indicating high intakes of tomatoes. In general, the antioxidant action of tomato extract ascribes to its hypotensive effects. Additional research is, however, needed to define specific mechanisms of action.
Medications versus tomato extract as adjunctive therapies for hypertension
To date, only one study has examined the combination of hypotensive medications and tomato extracts for treatment of hypertension. The Paran et al. (Citation2) study described above recruited subjects on low-dose calcium blockers and angiotensin-converting enzyme inhibitors alone, or in combination with diuretics. In the same study, it should be noted that the 6% and 5% reductions in SBP and DBP observed with tomato extract are comparable to average reductions in SBP and DBP with prescription medications at 8.8% and 4.4% for thiazides, 9.2% and 6.7% for β-blockers, 8.5% and 4.7% for ACE inhibitors, 10.3% and 5.7% for angiotensin II-converting enzyme antagonists, and 8.8 and 5.9% for calcium blockers, respectively (Citation139)—thus suggesting that concentrated tomato extract can complement hypotensive medications. Although current research regarding tomato extract as a treatment for hypertension is still in its infant stages, present evidence suggests that the hypotensive mechanisms of tomato extracts are distinct from those induced by pharmaceutical agents and their combination could be additive.
Safety and regulatory aspects of implementing functional foods and nutraceuticals as adjunctive therapies to pharmacotherapy
In the present review, FFN have been described as efficacious adjuncts to pharmaceuticals in treating disease. Hence, concerns over safety are well founded, especially since FFN modulate biological pathways. The position that a biological compound is safe because it is ‘natural’ or ‘food-derived’ is misleading. Hence, it is our position that therapeutic FFN must be evaluated by the appropriate regulatory agencies to establish dosages for efficacy and toxicity, indications for treatment, FFN–drug and FFN–food interactions, and distribution. The last-mentioned is a complicated issue. Part of the FFN appeal is their potential for circumventing high costs associated with pharmaco-monotherapy (Citation140) and, in some instances, the need for a physician's prescription. However, the question remains: ‘should FFN only be available through a physician, or incorporated into food products for purchase in supermarkets?’ Obviously, safety is a corner-stone to this debate and, as for medications that are available over the counter or with a prescription, FFN must be evaluated on an individual basis regarding efficacy, effectiveness, and ultimately safety. Indeed, regulatory agencies are beginning to recognize FFN as therapeutic agents. Canada, Europe, China, Japan, and the United States have all implemented stringent regulatory guidelines for health claims surrounding FFN (Citation141–146). However, for FFN to be recognized as treatments for disease, regulatory agencies responsible for approving drugs should also bear the responsibility for evaluating therapeutic FFN. As described, the recent approval of Lovaza®, a fish-oil supplement that is available in the United States only with a prescription with an indication for treating HTG, is evidence that FFN are gaining recognition by the medical community.
Regarding the FFN described in the present review, both fish-oil and PS have undergone rigorous assessment by regulatory agencies. In addition to their availability with a prescription in the United States, fish-oil supplements are also sold over the counter. Moreover, DHA and EPA are added to foods as ingredients. Whether fish-oil supplements are consumed with or without a prescription is dependent on how the fish-oil will be utilized. As prescription fish-oil supplements are indicated as a treatment for HTG, over-the-counter supplements and functional foods containing fish-oil are likely utilized by the public for the purpose of preventing disease.
Many countries, including the United States, the European Union, Australia, Japan, Switzerland, South Africa, Turkey, Israel, Norway, and Brazil, have approved PS as a safe LDL-C-lowering agent and allow PS to be incorporated into food-based matrices for sale in supermarkets. Thus, the next steps are to heighten the medical community's awareness to PS LDL-C-lowering efficacy so that they are implemented as a key therapy in treatment regimens for HCH. As for fiber and tomato extracts, their use as insulin sensitizers and hypotensive agents represent newer developments in FFN research and have yet to undergo reviews for health claims. The current literature suggests that doses of lycopene and fiber discussed in the present review possess minimal safety concerns (Citation147,Citation148).
Similar to prescription medications, FFN–food interactions must be thoroughly evaluated by regulatory agencies. Rats fed high doses of lycopene alongside alcohol demonstrated greater levels of hepatic CYP2E1 protein, TNF-α mRNA, and histological evidence of hepatic inflammation compared to rats fed lycopene alone (Citation149). Given that FFN will likely be utilized as adjuncts to prescription medications, FFN–drug indications must also be examined. Grapefruit is well known for its ability to produce drug toxicity when combined with certain medicines (Citation150). A recent review has identified over 80 herbal remedies that demonstrate ill effects when taken together with certain prescription medications (Citation151). Further work is required in this area.
The debate surrounding the regulatory aspects and logistics for implementation of FFN into treatment guidelines is beyond the scope of the present review. Using MetS as an example, the goal of this review was to demonstrate that FFN are viable, efficacious adjuncts to pharmacotherapy that deserve attention by the medical community. Nonetheless, new efficacious FFN entities must be evaluated by regulatory agencies, establishing dosages, proper utilization by physicians and patients, as well as safety to ensure FFN are implemented to treatment guidelines with confidence.
Summary and conclusions
The present review demonstrates that FFN should be viewed as more than life-style interventions, but as adjunctive therapies to pharmacological agents for treating disease. In addition, this review substantiates FFN ability to target molecular processes that foster the development of disease. In the context of MetS, MOM-3 modulate the expression of transcription factors that affect TG metabolism. Consequently, studies repeatedly show that combination MOM-3/statin therapy is more effective than statins alone for treating HTG. MOM-3 also improve overall vascular health, a risk factor for hypertension. Over 50 years of research supports the use of PS for treating HCH. Similar to MOM-3, therapeutic strategies that utilize both PS and statins are more effective than statins alone for reducing circulating LDL-C levels, a primary target for decreasing atherogenic dyslipidemia. Moreover, Volpe et al. (Citation152) suggest that the use of PS may delay the onset or reduce the dosage of prescriptions required for treating HCH. The observation that fiber-fermentation products modulate IR at multiple sites of glucose disposal supports the notion that the benefits of fiber consumption extend beyond that of gastrointestinal health. Although studies that examine fiber/metformin and fiber/thiazolidinedione therapies are required, it is hypothesized that fiber intake would complement pharmacological strategies for treating IR since fiber and corresponding medications target different facets of IR and glucose disposal. Finally, the observation that tomato extracts lower blood pressure to the same extent as hypertensive medication is encouraging. Even more encouraging is the observation that tomato extracts were able to reduce hypertension in subjects already taking one or more hypertensive medications.
In conclusion, efficacious FFN can modulate clinical end-points associated with disease. Thus, FFN should be emphasized throughout all stages of treatment as adjuncts to pharmacotherapy. For this to happen, however, efficacious FFN must be acknowledged by medical and regulatory agencies and undergo proper review to ensure their safety. In the end, new developments in FFN research must be communicated to health care practitioners so that they may be utilized by modern medicine as tools for combating disease.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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