Functional food ingredients as adjunctive therapies to pharmacotherapy for treating disorders of...
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review ArTiCLe
Functional food ingredients as adjunctive therapies to pharmacotherapy for treating disorders of metabolic syndrome
Christopher p. F. Marinangeli & peter J. h. Jones
The Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba, 196 Innovation Drive, Winnipeg, Manitoba, R3T 2N2, Canada
Annals of Medicine, 2010; 42: 317–333
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Abstractinformation 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 dem-onstrating the therapeutic properties of FFn. encompassing multiple etiologies, including atherogenic dyslipidemia, insu-lin 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 prog-noses as accessories to prescription medications.
Key words: Functional foods, hypercholesterolemia, hypertension, hypertriglyceridemia, insulin resistance, metabolic syndrome, nutraceutical
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 con-sumption elicits a positive biological effect. nonethe-less, nutraceuticals can also be isolated from functional foods and added to other food matrices or concen-trated for distribution in capsules or tablets. similar to pharmaceutical agents, research clearly demonstrates that functional foods and nutraceuticals (FFn) pos-sess physiological and molecular targets that modulate clinical end-points associated with chronic disease. Despite current research demonstrating that FFn
Correspondence: Dr peter J. h. Jones phD, richardson Centre for FunctionWinnipeg, MB r3t 2n2, Canada. Fax: 1 204 474 7552. e-mail: peter_jone
(Received 28 November 2009; accepted 30 March 2010)
issn 0785-3890 print/issn 1365-2060 online © 2010 informa UK ltd.Doi: 10.3109/07853890.2010.484026
combined with pharmaceuticals can benefit patients better than pharmaco-monotherapy (1–3), informa-tion regarding the efficacy of FFn-based therapies is rarely communicated to health care practitioners and implemented into disease treatment regimens. Meta-bolic 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 (4).
Mets is characterized as a combination of medi-cal disorders including central obesity, insulin resis-tance (ir), hypertension, as well as atherogenic dyslipidemia, itself characterized as hypertriglyceri-demia (htg), low hDl-C and high levels of circu-lating small dense lDl-C (sdlDl) (5,6) (Figure 1).
al Foods and nutraceuticals, University of Manitoba, 196 innovation Drive, [email protected]
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318 C. P. F. Marinangeli & P. J. H. Jones
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Abbreviations
aBCg atp-binding cassette g transportersaMp adenosine monophosphateaMpK aMp-activated protein kinaseatp adenosine triphosphateBp blood pressureCVD cardiovascular diseaseDBp diastolic blood pressureDha docohexaenoic acidepa eicosapentaenoic acidFDa U.s. Food and Drug administrationFFn functional foods and nutraceuticalsFXr farnesol X receptorglUt-1 glucose transporter 1gpr g-coupled proteinshCh hypercholesterolemiahDl high-density lipoproteinhMg-Coa 3-hydroxy-3-methylgutaryl-
coenzyme ahnF-4a hepatocyte nuclear factor 4ahtg hypertriglyceridemiair insulin resistanceJnCBp the Joint national Committee on prevention,
Detection, evaluation, and treatment of high Blood pressure
lDl low-density lipoproteinlDl-C low-density lipoprotein cholesterollXr liver X receptorMets metabolic syndromeMoM-3 marine-derived omega-3 fatty acidsnaDph nicotinamide adenine dinucleotide phosphatenCep the national Cholesterol education programneFa non-esterified fatty acidsnFκB nuclear factor kappa-light-chain-enhancer of
activated B cellsno nitric oxideppar peroxisome proliferator-activated receptorrs resistant starchsBp systolic blood pressuresCFa short-chain fatty acidssdlDl small dense low-density lipoproteinsreBp 1c sterol regulatory element-binding protein 1ctg triglycerideVlDl very-low-density lipoproteinVlDl-C very-low-density lipoprotein cholesterol
Key messages
similar to pharmaceutical agents, func- •tional foods and nutraceuticals (FFn) possess phy siological 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 associ-ated with atherogenic dyslipidemia, hyper-cholesterolemia, insulin resistance, vascular dysfunction, and hypertension.FFn should be emphasized throughout all •stages of treatment as adjuncts to pharma-cotherapy. For this to happen, however, new developments in FFn research must be communicated to health care practitio-ners and implemented into clinical guide-lines so that they may be utilized by modern medicine as tools for combating disease.
hypercholesterolemia (hCh), more specifically high levels of circulating low-density lipoprotein choles-terol (lDl-C), has been described as a therapeutic target for atherogenic dyslipidemia (6,7). Moreover, patients with Mets demonstrate an progressive trend towards lower antioxidant activity with onset of Mets co-morbidities (8). Finally, antioxidant status has been associated with the pathogenesis of ir and hypertension (9). 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 spe-cific disorders of Mets (7,10). While life-style interventions are emphasized during the initial stages of treatment for Mets-related disorders, dietary inter-ventions, specifically FFn, become overshadowed by pharmacological agents as risk factors for chronic dis-ease 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 (7). similarly, the JnCBp’s algorithm
for the treatment of hypertension accentuates a com-bination of pharmacological agents when blood pres-sure levels (Bp) are 140/90 mmhg with no mention of FFn (10). 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 sta-tus, 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
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Functional foods as adjuncts to pharmacotherapy 319
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FFn showing promise include sup plemental fiber for treating ir and tomato extracts for hypertension.
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 (Figure 1). the second objective is to provide a com-parison of physiological, metabolic, and molecular targets between the described FFn and corre-sponding prescription medications currently used for treating disorders of Mets. Finally, this review will discuss studies that have examined the use of pharma-cological 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 (11). effects of MoM-3 on circulating triglyc-eride (tg) concentrations are dose-dependent, with tg-lowering efficacy being demonstrated with dos-ages ranging from 1.3 to 12.0 g/d (12–15). in a com-prehensive review of 65 human clinical studies, harris et al. (16) demonstrated that MoM-3 consis-tently 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 (17). 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 (14). 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, sta-tins inhibit hepatic cholesterol synthesis. Unlike statins, fibrates are ligands for nuclear receptors, activating hepatic peroxisome prolifer ator-acti-vated receptor-a (ppar-a) and inhibiting hepato-cyte nuclear factor 4a (hnF-4a), resulting in higher lipoprotein lipase levels, high-density lipoprotein cholesterol (hDl-C) levels, fatty acid b-oxidation, as well as reduced very-low-density lipoprotein (VlDl) secretion and lower expression of genes involved in carbohydrate and lipid metabolism (18–20) (table i).
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.
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320 C. P. F. Marinangeli & P. J. H. Jones
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MoM-3 reduce tg levels by modulating the expression of nuclear receptors. alongside an increase in ppar-a and inhibition of hnF-4a gene expression, MoM-3 up-regulate and down-regulate farnesol X receptor (FXr) and liver X receptor (lXr) expression, respectively, resulting in an inhi-bition of sterol regulatory element-binding protein 1c (sreBp 1c) activity and expression (21). sreBp 1c up-regulates the expression of genes involved i n tg synthesis (21–23). together, the effects of MoM-3 on FXr and ppar-a also enhance hepatic tg uptake and tg oxidation, respectively (21). altogether, MoM-3 act on similar molecular targets to pharmaceutical therapy to modulate intra-cellular tg metabolism and decrease circulating tg levels (table i).
Medications versus marine-derived omega-3 fatty acids on oxidant status, vascular function, and inflammation
statins have been shown to reduce C-reactive pro-tein by 67% (24), Dna damage by 20% to 40% (25,26), superoxide anion by 36% (27), auto- antibodies against lDl oxidation by 19% (28), and conjugated diene production by 41% (29). increases in glutathione peroxidase activity by 38% (29), paraoxonase levels by 32% (30), a-tocopherol levels by 29% and retinol levels by 40% (31) 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 (32). additional cardio-protective effects of statins include increased circulating hDl-C levels 3% to 10% (33,34) as well as reductions in sdlDl 24% to 57% (35–38). Compared to large lDl subfractions, sdlDl are better able to infiltrate arteriole walls, possess higher susceptibility to oxidation, and thus initiate develop-ment of atherosclerotic plaques. given that oxidative stress promotes inflammation and has been linked to atherosclerosis (39) and cancer (40,41), statins have been given considerable attention for promoting
improvements in oxidative biomarkers in conjunc-tion with their lipid-lowering properties.
similar to statins, MoM-3 supplementation has been shown to improve antioxidant status via increasing glutathione peroxidase by 30% (42). supplemental MoM-3 have also been shown to reduce lipid peroxidation by 19% (42), ultraviolet light-induced Dna damage by 70%, and p53 gene expression by 50% (43). MoM-3 consumption also fosters the production of anti-inflammatory signal-ing molecules including trienoic prostaglandins and 5-series leukotrienes while reducing levels of urinary F2-isoprostanes (44). products of omega-6 fatty acid oxidation, F2-isoprostanes are biomarkers for the production of pro-inflammatory dienoic prostaglan-dins (45). MoM-3 promote vasodilation by inhibit-ing thromboxane a2 production and promoting thromboxane a3 and B3 synthesis (45,46). in addi-tion, nomura et al. (47) showed that supplementa-tion with 1.8 g/d epa significantly reduced markers of coagulation including CD62p, CD63, annexin V, as well as platelet and monocyte-derived micropar-ticles, which are prothrombotic. in the same study, epa decreased e-selectin levels, a biomarker of vas-cular damage (47). Finally, MoM-3 have been shown to reduce levels of sdlDl by 21% to 37% (48,49) and remnant-like lipoprotein particles by 21% (50), which, as outlined above, are both athero-sclerotic. 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 table ii, showing that combination MoM-3/statin treatments reduce tg an additional 10% to 30% compared with statin therapy alone (1,51–57). Combination
table i. summary comparison of triglyceride-lowering mechanisms of action between marine-derived omega-3 fatty acids and prescription medications.
hypertriglyceridemia
Functional food and nutraceuticals prescription medication
Marine-derived omega 3 fatty acids: Statins:
↑ ppar-a expression↑ FXr expression↓ lXr expression↓ hnF-4a expression
↓ sreBp 1c↓ tg synthesis↑ tg oxidation
hMg-Coa reductase inhibition
Fibrates:
↑ ppar-a activity↓ hnF-4a activity
↑ tg oxidation↓ tg synthesis
FXr farnesol X receptor; hMg-Coa 3-hydroxy-3-methylgutaryl-coenzyme a; hnF hepatocyte nuclear factor; lXr liver X receptor; ppar peroxisome proliferator-activated receptor; sreBp 1c steroid regulatory element binding protein 1c; tg triglyceride.
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Functional foods as adjuncts to pharmacotherapy 321
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tab
le i
i. s
umm
ary
of s
tudi
es M
oM
-3 a
s a
bene
ficia
l ad
junc
tive
the
rapy
to
stat
in t
hera
py w
hen
trea
ting
hyp
ertr
igly
ceri
dem
ia.
ref
eren
cen
tim
et
reat
men
tp
roto
col
eff
ect
on t
g l
evel
s
Dav
idso
n et
al.
(52)
254
M&
Fh
tg
8 w
kss
iMV
(40
mg/
d)
vege
tabl
e oi
lM
oM
-3 (
4 g/
d)
siM
V (
40 m
g/d)
sub
ject
s re
ceiv
ing
siM
V
8 w
ks w
ere
rand
omly
as
sign
ed t
o ea
ch i
nter
vent
ion
siM
V
pla
cebo
: 2
4%s
iMV
M
oM
-3:
228
%
hon
g et
al.
(54)
40 M&
FC
hD
2 m
os
iMV
(10
–20
mg/
d)
Mo
M-3
(3
g/d)
sub
ject
s tr
eate
d w
ith
siM
V f
or 6
–12
wks
had
M
oM
-3 a
dded
to
thei
r tr
eatm
ent
regi
men
for
2
mo
siM
V
Mo
M-3
: tg
231
%
Mak
i et
al.
(1)
39 M&
FD
Ys
l
6 w
kss
iMV
(20
mg/
d)
corn
oil
siM
V (
20 m
g/d)
M
oM
-3 (
4 g/
d)s
ubje
cts
wer
e ra
ndom
ly a
ssig
ned
to e
ach
trea
tmen
t re
gim
ens
iMV
co
rn o
il: 2
29%
siM
V
Mo
M-3
: 2
44%
nor
doy
et a
l. (5
5)41 M
&F
Ch
la
5 w
kss
iMV
(20
mg/
d)
corn
oil
siM
V (
20 m
g/d)
M
oM
-3 (
4 g/
d)a
fter
5 w
ks o
f s
iMV
the
rapy
, w
ere
assi
gned
to
eit
her
inte
rven
tion
siM
V
corn
oil:
15
%s
iMV
M
oM
-3:
228
%
Dur
ring
ton
et a
l. (5
3)59 M
&F
Ch
Dh
tg
48 w
kss
iMV
10–
20 m
g/d
co
rn o
ils
iMV
M
oM
-3 (
4 g/
d)s
ubje
cts
alre
ady
rece
ivin
g s
iMV
wer
e as
sign
ed
to e
ithe
r in
terv
enti
ons
iMV
co
rn o
il: n
/cs
iMV
M
oM
-3: t
g 2
20%
–30%
Val
divi
elso
et
al.
(56)
8 M&
Ft
iiD
DY
sl
8 w
ksF
lU
V (
80 m
g/d)
Fl
UV
(80
mg/
d)
Mo
M-3
(4
mg/
d)F
ollo
win
g a
6-w
k di
etar
y in
terv
enti
on,
subj
ects
w
ere
pres
crib
ed F
lU
V f
or 8
wks
. aft
er 8
wks
M
oM
-3 w
as c
ombi
ned
wit
h F
lU
V t
hera
py
Fl
UV
: 2
22%
Fl
UV
M
oM
-3:
242
%
Zem
an e
t al
. (5
7)24 M
&F
tii
DD
Ys
l
3 m
op
ra
V (
20 m
g/d)
F
en
oF
iB
(200
mg/
d)
pla
cebo
(ol
ive
oil)
pr
aV
(20
mg/
d)
Fe
no
FiB
(2
00 m
g/d)
M
oM
-3 (
3.6
g/d)
sub
ject
s al
read
y re
ceiv
ing
pr
aV
and
Fe
no
FiB
w
ere
give
n M
oM
-3 t
hera
py a
long
side
the
ir
curr
ent
trea
tmen
t re
gim
en. a
fter
3 m
o su
bjec
ts w
ere
give
n ol
ive
oil
pr
aV
F
en
oF
iB
pla
cebo
: 2
13%
pr
aV
F
en
oF
iB
Mo
M-3
: 228
%
Con
taco
s et
al.
(51)
32 h
l18
wks
pr
aV
(40
mg/
d)p
ra
V (
40 m
g/d)
M
oM
-3 (
4 m
g/d)
sub
ject
s tr
eate
d w
ith
pr
aV
for
6 w
ks h
ad
Mo
M-3
add
ed t
o th
eir
trea
tmen
t re
gim
en
for
an a
ddit
iona
l 12
wks
pr
aV
: 2
13%
pr
aV
M
oM
-3:
242
%
Ch
D
coro
nary
hea
rt d
isea
se;
Ch
la
co
mbi
ned
hype
rlip
idem
ia;
DY
sl
d
yslip
idem
ia;
Fe
no
FiB
fe
nofib
rate
; F
lU
V
fluv
asta
tin;
ht
g
hyp
ertr
igly
ceri
dem
ia;
Mo
M-3
m
arin
e-de
rive
d om
ega-
3 fa
tty
acid
s; n
/c
no
chan
ge;
pr
aV
p
rava
stat
in;
siM
V
sim
vast
atin
; tg
tr
igly
ceri
des;
tii
D
type
ii
diab
etes
.
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therapy has also been shown to further reduce levels of total circulating cholesterol (24% to 230%) (1,52,54,55), VlDl-C (220% to 240%) (1,52,53), VlDl-tg (253%) (56), apoB100 (232%), and apoB48 (236%) (56), as well as increase hDl-C levels (4% to 18%) (1,52,56) 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 micropar-ticles as well as increasing levels of adiponectin (58). adiponectin increases no levels, promoting vasodi-lation (59,60), as well as decreases monocytes from adhesion to endothelial cells (61). 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 (57). recently lovaza® became the first prescription MoM-3 sup-plement 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.
Plant sterols/stanols and hypercholesterolemia
Plant sterols and stanols as treatments for hypercholesterolemia
in 1954, Best et al. (62) 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% (63). 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 (64). 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 (65,66).
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 (table iii). as outlined above, statins inhibit hepatic cholesterol synthesis, while bile acid resins bind bile and inhibit cholesterol reabsorption in the large intestine (67). niacin reduces hepatic lipid synthesis and adipo-cyte lipolysis (68). ezetimibe reduces biliary cho-lesterol absorption by interacting with enterocyte niemann-pick C1-like protein 1 transporters, resulting in an increase in hepatic lDl uptake (67). similar to ezetimibe ps are believed to displace dietary cholesterol from being incorporated into mixed micelles in the small intestine (69) (table iii). absorption of ps into the circulation is poor at 0.1%–1.9% (70) 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 (71) which subsequently pump ps from the enterocytes back into the gastrointestinal lumen (72).
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
table iii. summary comparison of lDl-lowering mechanisms of action between plant sterols and stanols and prescription medications.
hypercholesterolemia
Functional food and nutraceuticals prescription medication
Plant sterols and stanols: Statins:
↑ Displacement of dietary cholesterol
↓ Cholesterol absorption ↓ hMg-Coa reductase activity
Niacin:↓ hepatic cholesterol synthesis↓ adipose tissue lipolysis
↑ lXr ↑ aBCg transporters Cholesterol absorption inhibitors (ezetimibe):
↓ Cholesterol absorption via niemann-pick C1-like protein 1 transporters
↑ hepatic lDl uptake
Bile acid resins:Bind negatively charged bile acid in the gastrointestinal tract
aBCg atp-binding cassette g transporter; hMg-Coa 3-hydroxy-3-methylgutaryl-coenzyme a; lDl low-density lipoprotein; lXr liver X receptor.
}}
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atherosclerotic plaques via nuclear factor kappa-light-chain-enhancer of activated B cells (nFκB) and monocyte chemoattractant protein-1 (MCp-1) path-ways. lDl-cholesterol levels have been shown to increase MCp-1 expression directly as well as indi-rectly via nFκB. endothelial expression of MCp-1 has been implicated for increasing vascular lipid accu-mulation, macrophage recruitment, and atheroscle-rotic plaque growth (73). studies demonstrate that statin treatment decreases atherosclerotic plaque for-mation alongside reduced nFκB and MCp-1 expres-sion (74–76). although not demonstrated in vivo, in vitro experiments show that ps inhibited MCp-1 pro-duction in umbilical venous endothelial cells treated with oxidized lDl (77). 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 addi-tive 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 table iV. studies reveal that when ps are combined with statins, lDl-C levels are reduced an additional 5% to 17%, compared to sta-tins alone (3,65,78–82). ps efficacy is not affected by the type or dose of statin administered, with lDl-C reductions being observed in patients taking simvas-tatin, lovastatin, atorvastatin, pravastatin, fluvastatin, rosuvastatin, and cerivastatin (3,65,78–82). simons et al. (81) 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 (80). 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.
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%) (83). given that ps and ezetimibe both inhibit cholesterol absorption it is possible that the effects of ps on lDl-C were over-shadowed 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 (84). 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 reduc-tions 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, includ-ing polycystic ovary syndrome, type ii diabetes, cardiovascular disease (CVD), hypertension, obesity, and inflammation (85,86). as such, in 1992, rupp et al. (87) emphasized the need for dietary interven-tions that target and subsequently reduce ir. recent insights into the biological effects of non-digestible carbohydrates suggest fibers can signifi-cantly 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 (88). on the other hand, non-vegetarians began to show evidence of ir between 31 and 40 years of age (88). Cross-sectional data from the Framingham offspring Cohort noted an inverse association between cereal fiber intake and ir (89), while a cross-sectional analysis of men and women from the inter99 study showed a relationship between low-fiber consumption and the probability of devel-oping ir (90).
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 (91,92). Moreover, homeostasis-modeling assess-ment, a non-invasive method for measuring ir using fasted blood samples, showed a 33% and 24% reduc-tion in ir after 3 weeks of consuming 3 g/d b-glucan and 4 wks of a fiber-rich (20 g/d) meal replacement beverage, respectively (93,94). similarly, despite no effect on postprandial glycemia, high-fiber bread increased postprandial insulin economy (95). Fur-thermore, using the minimal model index as a mea-sure of ir, 60 g/d resistant starch ingested 24 hrs prior to a fiber-free meal was shown to decrease
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324 C. P. F. Marinangeli & P. J. H. Jones
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tab
le i
V. s
umm
ary
of s
tudi
es s
how
ing
plan
t st
erol
s an
d st
anol
s as
a b
enefi
cial
adj
unct
ive
ther
apy
to s
tati
n th
erap
y fo
r th
e tr
eatm
ent
of h
yper
chol
este
role
mia
.
ref
eren
cen
tim
et
reat
men
tsp
roto
col
eff
ect
on l
Dl
- C
lev
els
sim
ons
et a
l. (8
1)15
2h
Ch
4 w
ksp
lace
bo
cont
rol
mar
gari
nep
lace
bo
ps
(st
erol
)s
tati
n
cont
rol
mar
gari
nes
tati
n
ps
(st
erol
) m
arga
rine
sub
ject
s w
ere
rand
omly
ass
igne
d to
one
int
erve
ntio
n.
the
tes
t st
atin
was
Ce
riV
pla
cebo
co
ntro
l:
2%p
lace
bo
ps
: 2
8%s
tati
n
cont
rol:
232
%s
tati
n
ps
: 2
39%
gol
dber
g et
al.
(65)
26 hl
9 w
kss
tati
n
pla
cebo
sta
tin
p
s t
able
t (s
tano
l) (
1.8
g/d)
sub
ject
s on
sta
ble
stat
in t
reat
men
t fo
r 9
0 d.
sub
ject
s w
ere
rand
omly
ass
igne
d to
one
int
erve
ntio
ns
tati
n
pla
cebo
:
3%s
tati
n
ps
: 2
6%B
lair
et
al.
(3)
146
hl
8 w
kss
tati
n
cont
rol
mar
gari
nes
tati
n
ps
(st
anol
) m
arga
rine
(5.
1 g/
d)s
ubje
cts
on s
tabl
e st
atin
tre
atm
ent
for
90
d (s
iMV
, p
ra
V, a
to
rV
, l
oV
) w
ere
rand
omly
ass
igne
d to
one
in
terv
enti
on
sta
tin
co
ntro
l: 2
7%s
tati
n
ps
: 2
17%
Cas
tro
Cab
ezas
et
al.
(78)
20 hl
6 w
kss
tati
n (8
0 m
g/d)
co
ntro
l m
arga
rine
sta
tin
(80
mg/
d)
ps
(st
anol
)m
arga
rine
(3
g/d)
sub
ject
s re
ceiv
ing
max
imal
dos
e of
at
or
V o
r s
iMV
th
erap
y (8
0 m
g/d)
for
6
mo
wer
e ra
ndom
ly a
ssig
ned
to o
ne i
nter
vent
ion
sta
tin
co
ntro
l: 2
8%s
tati
n
ps
: 2
16%
de J
ong
et a
l. (7
9)54 h
Ch
85 w
kss
tati
n
cont
rol
mar
gari
nes
tati
n
ps
(st
erol
) m
arga
rine
(2.
5 g/
d)s
tati
n
ps
(st
anol
) m
arga
rine
(2.
5 g/
d)
sub
ject
s on
sta
tin
ther
apy
(pr
aV
, s
iMV
, at
or
V,
ro
sU
V,
Fl
UV
) 8
5 w
ks w
ere
rand
omly
ass
igne
d on
e in
terv
enti
on
Con
trol
: n/
cp
s (
ster
ol):
29%
ps
(st
anol
): 2
13%
Ket
omak
i et
al.
(80)
18 Fh
4 w
kss
tati
n
ps
(st
anol
) m
arga
rine
(2
g/d)
sta
tin
p
s (
ster
ol)
mar
gari
ne (
2 g/
d)s
ubje
cts
rece
ivin
g st
atin
tre
atm
ent
(siM
V,
pr
aV
, a
to
rV
, l
oV
) fo
r se
vera
l ye
ars
rece
ived
bot
h in
terv
enti
ons
sta
tin
ps
(st
anol
): 2
15%
sta
tin
p
s (
ster
ol):
214
%
tak
eshi
ta e
t al
. (8
2)61 h
Ch
12 w
kst
g o
ilD
ag
oil
Da
g o
il
ps
(4%
)
sub
ject
s re
ceiv
ing
pr
aV
(10
mg/
d)
4 w
ks w
ere
rand
omly
ass
igne
d to
one
int
erve
ntio
n. s
ubje
cts
repl
aced
the
ir r
egul
ar c
ooki
ng o
il w
ith
a tr
eatm
ent
oil
tg
: n/
cD
ag
: n/
cD
ag
p
s:
25%
at
or
V
ator
vast
atin
; C
er
iV
ceri
vast
atin
; D
ag
d
iacy
lgly
cero
l; h
Ch
h
yper
chol
este
role
mia
; h
l
hyp
erlip
idem
ia;
Fh
fa
mili
al h
yper
chol
este
role
mia
; F
lU
V
fluv
asta
tin;
lD
l-C
lo
w-
dens
ity
lipop
rote
in c
hole
ster
ol;
lo
V
lova
stat
in;
n/c
no
chan
ge;
pr
aV
p
rava
stat
in;
ps
p
lant
ste
rol/s
tano
l; r
os
UV
ro
suva
stat
in;
siM
V
sim
vast
atin
; tg
= t
rigl
ycer
ides
.
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postprandial ir 69%, compared to controls (96). resis-tant starch has also been shown to increase muscle and adipose glucose clearance by 44% and 87%, respectively (91). in another study, lack of effect of 1.5 g/d b-glucan on ir could have been secondary to the low dose administered to subjects (97). an acute dose-dependent study demonstrated that only the maximum dose of 10 g/d b-glucan was able to blunt postprandial insulin responses, despite no effect on postprandial glucose response (98). 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 met-formin stimulates adenosine monophosphate (aMp)- activated protein kinase (aMpK) (99–101), tyrosine kinase phosphorylation at the b-subunit on the insulin receptor (102–104), as well as muscle atypical protein kinase C activation (105). similar to metformin, thiazolidinediones activate aMpK (106) (table V). Moreover, thiazolidinediones target adipose tissue and act as a ppar-g ligand (107), reducing free fatty acid release (108) as well as the expression of ir-related substances such as leptin (109), tumor necro-sis factor (tnF)-a (110,111), and resistin (112). it has also been suggested that thiazolidinediones decrease inhibitory insulin receptor substrate protein
1 serine phosphorylation (113) and increase glucose disposal via higher expression of glucose transporter (glUt)-1 in adipose (114) and skeletal muscle (115).
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 (116). since high levels of circulating non-esterified free fatty acids (neFa) have been linked to ir (117), it has been suggested that sCFa reduce circulating neFa (table V). Conclusive evidence of this phenomenon has yet to be presented in vivo. however, compared to controls, robertson et al. (91) observed a signifi-cant increase in sCFa production in subjects con-suming 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. inter-estingly, robertson et al. also observed an increase in circulating ghrelin after resistant starch (rs) supple-mentation (91) and noted that higher ghrelin levels associate with reduced ir (118–120). rat adipocytes showed an increase in ppar-g expression and lipo-genesis after cells were treated with ghrelin (121). Moreover, recent studies point towards sCFa acting as ligands for adipose g-coupled proteins (gpr). robertson (116) has also suggested that interactions between sCFa and adipose gpr43 could be of importance in decreasing neFa levels while stimulat-ing adipogenesis (122) and adipocyte differentiation (123). adipocyte differentiation has been implicated
table V. summary comparison of insulin resistance-lowering mechanisms of action between fiber and prescription medications.
insulin resistance
Functional food and nutraceuticals prescription medication
Fiber: Metformin:↑ sCFa production ↓ neFa
↑ skeletal muscle glucose uptake↑ adipose glucose uptake↑ Mitochondrial biogenesis↑ adaptive thermogenesis↑ Fat oxidation?↓ adiposity?↑ adipocyte differentiation
aMpK activationMuscle atypical protein kinase C activationphosphorylation of tyrosine kinase at the b-subunit on the
insulin receptor
Thiazolidinediones:aMpK activation↓ inhibitory insulin receptor substrate protein 1 serine
phosphorylation↑ glUt-1 in muscle and adipose tissue
↑ ghrelin ↑ ppar-g↑ lipogenesis
ppar-g ligand ↓ neFa↓ leptin↓ tnF-a↓ resistin
↓ hepatic glucose output
aMpK aMp-activated protein kinase; neFa non-esterified fatty acids; ppar-g peroxisome proliferator receptor gamma; sCFa short-chain fatty acids; tnF-a tumor necrosis factor alpha.
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in decreasing ir, since adipocyte size inversely cor-relates with ir (124,125). sCFa secondary to micro-bial 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. (126) attributed colonic carbohy-drate 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 (127). enhanced skeletal muscle 5’ aMp-activated protein kinase in mice sup-plemented with butyrate was reflected with an increase in adaptive thermogenesis, fat oxidation, mitochon-drial activity, and biogenesis in muscle and brown adipose as well as reduced adiposity (128). 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 medica-tion for treating ir has yet to be explored. it is there-fore worth noting that testing such a combination for potential additive or synergistic effects on adi-pose, 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, suggest-ing 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 (5). 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), b-carotene (0.4 mg), and ps (1.5 mg). the tomato-based sup-plement reduced systolic (sBp) and diastolic blood pressure (DBp) 7% and 6%, respectively (129).
When given the placebo for a second time, blood pressure reverted back to levels observed prior to receiving the tomato-based treatment, strongly sug-gesting that the tomato extract was the efficacious agent (129). in a follow-up study by paran et al. (2), 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 fol-lowed by the treatment. researchers also noted a negative correlation between blood lycopene levels and sBp (2). 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 inde-pendently lowered the risk of Mi, producing an odds ratio of 0.5 (130). a recent investigation into the relationship between lipid-soluble antioxidants and atherosclerosis risk showed a negative correlation between lycopene and carotid intima-media thick-ness in hypertensive patients (131). these data dem-onstrate 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 antago-nists, calcium blockers, b-blockers, and thiazides (table Vi). aCe inhibitors prevent the production of angiotensin ii, a potent vasoconstrictor (132). angiotensin ii receptor antagonists block angio-tensin ii from binding to its receptor in vascular smooth muscle, while calcium blockers decrease car-diac and arteriole muscle contraction. b-Blockers reduce cardiac output, inhibit kidney-mediated renin release, and inhibit vasoconstriction (132). Finally, thiazides are diuretics that inhibit sodium reabsorp-tion in the kidney, promoting diuresis and a decrease in blood volume (132).
researchers hypothesize that high levels of anti-oxidants found in tomato extracts account for their hypotensive properties (2,129) (table Vi). pro-oxi-dation 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 contribu-tors to the production of reactive oxygen species (133). lycopene is considered the most potent anti-oxidant amongst carotenoids (134). Bose et al. (135)
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showed that 200 g/d cooked tomatoes improved anti-oxidant defense systems in hypertensive patients by increasing activities of superoxide dismutase, gluta-thione, glutathione reductase, and glutathione per-oxidase. 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 vaso-dilator (136). Furthermore, mice fed an atheroscle-rotic diet with tomato had reduced lipid peroxide levels and maintained acetylcholine-mediated vasodi-lation compared to mice not receiving tomato (137).
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 (2,136). a study examining the phytochemical content of the Dash diet attributed its hypotensive effects to higher levels of flavonoids and carotenoids, including lycopene (138), indicat-ing high intakes of tomatoes. in general, the anti-oxidant 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 combina-tion of hypotensive medications and tomato extracts for treatment of hypertension. the paran et al. (2) 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 b-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 (139)—thus suggesting that concentrated tomato extract can complement hypotensive medica-tions. 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 dis-tinct 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, indica-tions for treatment, FFn–drug and FFn–food inter-actions, 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 (140) 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
table Vi. summary comparison of blood pressure-lowering mechanisms between lycopene and tomato extracts and prescription medications.
hypertension
Functional food and nutraceuticals prescription medication
Tomato extract and lycopene: ACE inhibitor:↑ antioxidant defenses ↓ angiotensin ii production↑ nitric oxide levels?↓ peroxynitrate formation
↓ Vasoconstriction angiotensin ii receptor antagonistinhibits angiotensin ii from binding to its receptor in vascular
smooth muscle
Calcium blockers:↓ Cardiac and arteriole muscle contraction
b-Blockers:↑ Cardiac output↑ renin release
Thiazides:Diuretics↑ sodium reabsorption
}
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and, as for medications that are available over the counter or with a prescription, FFn must be evaluated on an individual basis regarding efficacy, effective-ness, and ultimately safety. indeed, regulatory agen-cies are beginning to recognize FFn as therapeutic agents. Canada, europe, China, Japan, and the United states have all implemented stringent regula-tory guidelines for health claims surrounding FFn (141–146). however, for FFn to be recognized as treatments for disease, regulatory agencies respon-sible for approving drugs should also bear the respon-sibility 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 depen-dent on how the fish-oil will be utilized. as prescrip-tion fish-oil supplements are indicated as a treatment for htg, over-the-counter supplements and func-tional 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 (147,148).
similar to prescription medications, FFn–food interactions must be thoroughly evaluated by regu-latory agencies. rats fed high doses of lycopene along-side alcohol demonstrated greater levels of hepatic CYp2e1 protein, tnF-a mrna, and histological evidence of hepatic inflammation compared to rats fed lycopene alone (149). 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 medi-cines (150). a recent review has identified over 80 herbal remedies that demonstrate ill effects when taken together with certain prescription medica-tions (151). Further work is required in this area.
the debate surrounding the regulatory aspects and logistics for implementation of FFn into treat-ment 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, effi-cacious adjuncts to pharmacotherapy that deserve attention by the medical community. nonetheless, new efficacious FFn entities must be evaluated by regulatory agencies, establishing dosages, proper uti-lization by physicians and patients, as well as safety to ensure FFn are implemented to treatment guide-lines 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 substanti-ates FFn ability to target molecular processes that foster the development of disease. in the context of Mets, MoM-3 modulate the expression of tran-scription factors that affect tg metabolism. Conse-quently, studies repeatedly show that combination MoM-3/statin therapy is more effective than statins alone for treating htg. MoM-3 also improve over-all 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 strat-egies that utilize both ps and statins are more effec-tive than statins alone for reducing circulating lDl-C levels, a primary target for decreasing athero-genic dyslipidemia. Moreover, Volpe et al. (152) sug-gest that the use of ps may delay the onset or reduce the dosage of prescriptions required for treating hCh. the observation that fiber-fermentation prod-ucts modulate ir at multiple sites of glucose disposal supports the notion that the benefits of fiber con-sumption extend beyond that of gastrointestinal health. although studies that examine fiber/met-formin 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 medica-tion 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.
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Functional foods as adjuncts to pharmacotherapy 329
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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 respon-sible for the content and writing of the paper.
references
Maki KC, McKenney JM, reeves Ms, lubin BC, 1. Dicklin Mr. effects of adding prescription omega-3 acid ethyl esters to simvastatin (20 mg/day) on lipids and lipo-protein particles in men and women with mixed dyslipi-demia. am J Cardiol. 2008;102:429–33.paran e, novack V, engelhard Yn, hazan-halevy i. the 2. effects of natural antioxidants from tomato extract in treated but uncontrolled hypertensive patients. Cardiovasc Drugs ther. 2009;23:145–51.Blair sn, Capuzzi DM, gottlieb so, nguyen t, Morgan JM, 3. Cater nB. incremental reduction of serum total cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to statin therapy. am J Cardiol. 2000;86:46–52.ervin rB. prevalence of metabolic syndrome among adults 4. 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United states, 2003–2006. natl health stat report. 2009;1–8.Cornier Ma, Dabelea D, hernandez tl, lindstrom rC, 5. steig aJ, stob nr, et al. the metabolic syndrome. endocr rev. 2008;29:777–822.grundy sM, Cleeman Ji, Daniels sr, Donato Ka, eckel rh, 6. Franklin Ba, et al. Diagnosis and management of the meta-bolic syndrome: an american heart association/national heart, lung, and Blood institute scientific statement. Cir-culation. 2005;112:2735–52.Jehle aJ. third report of the national Cholesterol edu-7. cation program (nCep) expert panel on Detection, evaluation, and treatment of high Blood Cholesterol in adults (adult treatment panel iii). national institutes of health and national heart, lung, and Blood institute; 2002.senti M, tomas M, Fito M, Weinbrenner t, Covas Mi, sala J, 8. et al. antioxidant paraoxonase 1 activity in the metabolic syndrome. J Clin endocrinol Metab. 2003;88:5422–6.roberts CK, sindhu KK. oxidative stress and metabolic 9. syndrome. life sci. 2009;84:705–12.Chobanian aV, Bakris gl, Black hr, Cushman WC, green la, 10. izzo Jl Jr, et al. the seventh report of the Joint national Committee on prevention, Detection, evaluation, and treat-ment of high Blood pressure: the JnC 7 report. JaMa. 2003;289:2560–72.Kris-etherton pM, harris Ws, appel lJ. Fish consumption, 11. fish oil, omega-3 fatty acids, and cardiovascular disease. arterioscler thromb Vasc Biol. 2003;23:e20–30.
Blonk MC, Bilo hJ, nauta JJ, popp-snijders C, Mulder C, 12. Donker aJ. Dose-response effects of fish-oil supplementation in healthy volunteers. am J Clin nutr. 1990;52: 120–7.Davidson Mh, Maki KC, Kalkowski J, schaefer eJ, torri sa, 13. Drennan KB. effects of docosahexaenoic acid on serum lipo-proteins in patients with combined hyperlipidemia: a randomized, double-blind, placebo-controlled trial. J am Coll nutr. 1997;16:236–43.harris Ws, rothrock DW, Fanning a, inkeles sB, goodnight 14. sh Jr, illingworth Dr, et al. Fish oils in hypertriglyceri-demia: a dose-response study. am J Clin nutr. 1990;51: 399–406.Meyer BJ, hammervold t, rustan aC, howe pr. Dose-15. dependent effects of docosahexaenoic acid supplementation on blood lipids in statin-treated hyperlipidaemic subjects. lipids. 2007;42:109–15.harris Ws. n-3 fatty acids and serum lipoproteins: human 16. studies. am J Clin nutr. 1997;65:1645s–54s.Dyerberg J, Bang ho. haemostatic function and platelet pol-17. yunsaturated fatty acids in eskimos. lancet. 1979;2:433–5.auwerx J, schoonjans K, Fruchart JC, staels B. regulation of 18. triglyceride metabolism by ppars: fibrates and thiazolidinedi-ones have distinct effects. J atheroscler thromb. 1996;3:81–9.staels B, Dallongeville J, auwerx J, schoonjans K, 19. leitersdorf e, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998;98: 2088–93.hertz r, sheena V, Kalderon B, Berman i, Bar-tana J. sup-20. pression of hepatocyte nuclear factor-4alpha by acyl-Coa thioesters of hypolipidemic peroxisome proliferators. Bio-chem pharmacol. 2001;61:1057–62.Davidson Mh. Mechanisms for the hypotriglyceridemic 21. effect of marine omega-3 fatty acids. am J Cardiol. 2006;98: 27i–33i.Kim hJ, takahashi M, ezaki o. Fish oil feeding decreases 22. mature sterol regulatory element-binding protein 1 (sreBp-1) by down-regulation of sreBp-1c mrna in mouse liver. a possible mechanism for down-regulation of lipogenic enzyme mrnas. J Biol Chem. 1999;274:25892–8.lund eK, harvey lJ, ladha s, Clark DC, Johnson it. 23. effects of dietary fish oil supplementation on the phosphol-ipid composition and fluidity of cell membranes from human volunteers. ann nutr Metab. 1999;43:290–300.ge CJ, lu sZ, Chen YD, Wu XF, hu sJ, Ji Y. synergistic 24. effect of amlodipine and atorvastatin on blood pressure, left ventricular remodeling, and C-reactive protein in hyperten-sive patients with primary hypercholesterolemia. heart Vessels. 2008;23:91–5.Mastalerz-Migas a, reksa D, pokorski M, steciwko a, 25. Muszynska a, Bunio a, et al. Comparison of a statin vs. hypolipemic diet on the oxidant status in hemodialyzed patients with chronic renal failure. J physiol pharmacol. 2007;58 suppl 5:363–70.Cangemi r, loffredo l, Carnevale r, pignatelli p, Violi F. 26. statins enhance circulating vitamin e. int J Cardiol. 2008; 123:172–4.Weitberg aB. the antioxidant effect of lovastatin on phago-27. cyte-induced Dna damage: implications for cancer preven-tion. J exp Clin Cancer res. 2007;26:583–6.orem C, orem a, Uydu ha, Celik s, erdol C, Kural BV. 28. the effects of lipid-lowering therapy on low-density lipopro-tein auto-antibodies: relationship with low-density lipopro-tein oxidation and plasma total antioxidant status. Coron artery Dis. 2002;13:65–71.Molcanyiova a, stancakova a, Javorsky M, tkac i. Benefi-29. cial effect of simvastatin treatment on lDl oxidation and
![Page 14: Functional food ingredients as adjunctive therapies to pharmacotherapy for treating disorders of metabolic syndrome](https://reader031.fdocuments.us/reader031/viewer/2022030104/57509f501a28abbf6b18969b/html5/thumbnails/14.jpg)
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rial
Col
lege
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don
on 0
6/03
/14
For
pers
onal
use
onl
y.
antioxidant protection is more pronounced in combined hyperlipidemia than in hypercholesterolemia. pharmacol res. 2006;54:203–7.Muacevic-Katanec D, Bradamante V, poljicanin t, reiner Z, 30. Babic Z, simeon-rudolf V, et al. Clinical study on the effect of simvastatin on paraoxonase activity. arzneimittelforsc-hung. 2007;57:647–53.shin MJ, Chung n, lee Jh, Jang Y, park e, Jeon Ki, et al. 31. effects of simvastatin on plasma antioxidant status and vita-mins in hypercholesterolemic patients. int J Cardiol. 2007;118:173–7.de sotomayor Ma, perez-guerrero C, herrrera MD, 32. Jimenez l, Marin r, Marhuenda e, et al. improvement of age-related endothelial dysfunction by simvastatin: effect on no and CoX pathways. Br J pharmacol. 2005;146:1130–8.Branchi a, Fiorenza aM, torri a, Muzio F, Berra C, 33. Colombo e, et al. effects of low doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol levels in patients with hypercholesterolemia. Clin ther. 2001;23: 851–7.Wierzbicki as, Mikhailidis Dp. Dose-response effects of 34. atorvastatin and simvastatin on high-density lipoprotein cho-lesterol in hypercholesterolaemic patients: a review of five comparative studies. int J Cardiol. 2002;84:53–7.ai M, otokozawa s, asztalos BF, nakajima K, stein e, 35. Jones ph, et al. effects of maximal doses of atorvastatin versus rosuvastatin on small dense low-density lipoprotein cholesterol levels. am J Cardiol. 2008;101:315–8.empen K, geiss hC, lehrke M, otto C, schwandt p, 36. parhofer Kg. effect of atorvastatin on lipid parameters, lDl subtype distribution, hemorrheological parameters and adhesion molecule concentrations in patients with hypertrig-lyceridemia. nutr Metab Cardiovasc Dis. 2003;13:87–92.guerin M, egger p, soudant C, le goff W, van tol a, 37. Dupuis r, et al. Dose-dependent action of atorvastatin in type iiB hyperlipidemia: preferential and progressive reduc-tion of atherogenic apoB-containing lipoprotein subclasses (VlDl-2, iDl, small dense lDl) and stimulation of cel-lular cholesterol efflux. atherosclerosis. 2002;163:287–96.Karalis Dg, ishisaka DY, luo D, ntanios F, Wun CC. 38. effects of increasing doses of atorvastatin on the atherogenic lipid subclasses commonly associated with hypertriglyceri-demia. am J Cardiol. 2007;100:445–9.Wilson pW. evidence of systemic inflammation and estima-39. tion of coronary artery disease risk: a population perspective. am J Med. 2008;121:s15–20.serafini M, Villano D, spera g, pellegrini n. redox mole-40. cules and cancer prevention: the importance of understand-ing the role of the antioxidant network. nutr Cancer. 2006;56:232–40.Federico a, Morgillo F, tuccillo C, Ciardiello F, loguercio C. 41. Chronic inflammation and oxidative stress in human car-cinogenesis. int J Cancer. 2007;121:2381–6.Kesavulu MM, Kameswararao B, apparao C, Kumar eg, 42. harinarayan CV. effect of omega-3 fatty acids on lipid per-oxidation and antioxidant enzyme status in type 2 diabetic patients. Diabetes Metab. 2002;28:20–6.rhodes le, shahbakhti h, azurdia rM, Moison rM, 43. steenwinkel MJ, homburg Mi, et al. effect of eicosapentae-noic acid, an omega-3 polyunsaturated fatty acid, on UVr-related cancer risk in humans. an assessment of early genotoxic markers. Carcinogenesis. 2003;24:919–25.Mori ta, puddey iB, Burke V, Croft KD, Dunstan DW, 44. rivera Jh, et al. effect of omega 3 fatty acids on oxidative stress in humans: gC-Ms measurement of urinary F2-iso-prostane excretion. redox rep. 2000;5:45–6.
schmitz g, ecker J. the opposing effects of n-3 and n-6 fatty 45. acids. prog lipid res. 2008;47:147–55.sametz W, Jeschek M, Juan h, Wintersteiger r. influence of 46. polyunsaturated fatty acids on vasoconstrictions induced by 8-iso-pgF(2alpha) and 8-iso-pge(2). pharmacology. 2000; 60:155–60.nomura s, Kanazawa s, Fukuhara s. effects of eicosapen-47. taenoic acid on platelet activation markers and cell adhesion molecules in hyperlipidemic patients with type 2 diabetes mellitus. J Diabetes Complications. 2003;17:153–9.Kelley Ds, siegel D, Vemuri M, Mackey Be. Docosahexae-48. noic acid supplementation improves fasting and postprandial lipid profiles in hypertriglyceridemic men. am J Clin nutr. 2007;86:324–33.nordoy a, hansen JB, Brox J, svensson B. effects of atorv-49. astatin and omega-3 fatty acids on lDl subfractions and postprandial hyperlipemia in patients with combined hyper-lipemia. nutr Metab Cardiovasc Dis. 2001;11:7–16.Kelley Ds, siegel D, Vemuri M, Chung gh, Mackey Be. 50. Docosahexaenoic acid supplementation decreases remnant-like particle-cholesterol and increases the (n-3) index in hypertriglyceridemic men. J nutr. 2008;138:30–5.Contacos C, Barter pJ, sullivan Dr. effect of pravastatin 51. and omega-3 fatty acids on plasma lipids and lipoproteins in patients with combined hyperlipidemia. arterioscler thromb. 1993;13:1755–62.Davidson Mh, stein ea, Bays he, Maki KC, Doyle rt, 52. shalwitz ra, et al. efficacy and tolerability of adding pre-scription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin ther. 2007;29: 1354–67.Durrington pn, Bhatnagar D, Mackness Mi, Morgan J, 53. Julier K, Khan Ma, et al. an omega-3 polyunsaturated fatty acid concentrate administered for one year decreased trig-lycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. heart. 2001; 85:544–8.hong h, Xu ZM, pang Bs, Cui l, Wei Y, guo WJ, et al. 54. effects of simvastain combined with omega-3 fatty acids on high sensitive C-reactive protein, lipidemia, and fibrinolysis in patients with mixed dyslipidemia. Chin Med sci J. 2004;19: 145–9.nordoy a, Bonaa Kh, nilsen h, Berge rK, hansen JB, 55. ingebretsen oC. effects of simvastatin and omega-3 fatty acids on plasma lipoproteins and lipid peroxidation in patients with combined hyperlipidaemia. J intern Med. 1998;243:163–70.Valdivielso p, rioja J, garcia-arias C, sanchez-Chaparro Ma, 56. gonzalez-santos p. omega 3 fatty acids induce a marked reduction of apolipoprotein B48 when added to fluvastatin in patients with type 2 diabetes and mixed hyperlipidemia: a preliminary report. Cardiovasc Diabetol. 2009;8:1.Zeman M, Zak a, Vecka M, tvrzicka e, pisarikova a, 57. stankova B. n-3 fatty acid supplementation decreases plasma homocysteine in diabetic dyslipidemia treated with statin-fibrate combination. J nutr Biochem. 2006;17: 379–84.nomura s, inami n, shouzu a, omoto s, Kimura Y, 58. takahashi n, et al. the effects of pitavastatin, eicosapentae-noic acid and combined therapy on platelet-derived micro-particles and adiponectin in hyperlipidemic, diabetic patients. platelets. 2009;20:16–22.Chen h, Montagnani M, Funahashi t, shimomura i, Quon MJ. 59. adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem. 2003;278:45021–6.
![Page 15: Functional food ingredients as adjunctive therapies to pharmacotherapy for treating disorders of metabolic syndrome](https://reader031.fdocuments.us/reader031/viewer/2022030104/57509f501a28abbf6b18969b/html5/thumbnails/15.jpg)
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care
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on 0
6/03
/14
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onal
use
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y.
hattori Y, suzuki M, hattori s, Kasai K. globular adiponec-60. tin upregulates nitric oxide production in vascular endothe-lial cells. Diabetologia. 2003;46:1543–9.ouchi n, Kihara s, arita Y, Maeda K, Kuriyama h, 61. okamoto Y, et al. novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation. 1999;100:2473–6.Best MM, Duncan Ch, Van loon eJ, Wathen JD. lowering 62. of serum cholesterol by the administration of a plant sterol. Circulation. 1954;10:201–6.Berger a, Jones pJ, abumweis ss. plant sterols: factors 63. affecting their efficacy and safety as functional food ingredi-ents. lipids health Dis. 2004;3:5.abumweis ss, Barake r, Jones pJ. plant sterols/stanols as 64. cholesterol lowering agents: a meta-analysis of randomized controlled trials. Food nutr res. 2008;52 doi: 10.3402/fnr.v52i0.1811. epub 2008 aug 18.goldberg aC, ostlund re Jr, Bateman Jh, schimmoeller l, 65. Mcpherson tB, spilburg Ca. effect of plant stanol tablets on low-density lipoprotein cholesterol lowering in patients on statin drugs. am J Cardiol. 2006;97:376–9.Mcpherson tB, ostlund re, goldberg aC, Bateman Jh, 66. schimmoeller l, spilburg Ca. phytostanol tablets reduce human lDl-cholesterol. J pharm pharmacol. 2005;57:889–96.hou r, goldberg aC. lowering low-density lipoprotein 67. cholesterol: statins, ezetimibe, bile acid sequestrants, and combinations: comparative efficacy and safety. endocrinol Metab Clin north am. 2009;38:79–97.pandian a, arora a, sperling ls, Khan BV. targeting mul-68. tiple dyslipidemias with fixed combinations–focus on extended release niacin and simvastatin. Vasc health risk Manag. 2008;4:1001–9.Marinangeli Cp, Varady Ka, Jones pJ. plant sterols com-69. bined with exercise for the treatment of hypercholestero-lemia: overview of independent and synergistic mechanisms of action. J nutr Biochem. 2006;17:217–24.ostlund re Jr, Mcgill JB, Zeng CM, Covey DF, stearns J, 70. stenson WF, et al. gastrointestinal absorption and plasma kinetics of soy Delta(5)-phytosterols and phytostanols in humans. am J physiol endocrinol Metab. 2002;282:e911–6.plat J, nichols Ja, Mensink rp. plant sterols and stanols: 71. effects on mixed micellar composition and lXr (target gene) activation. J lipid res. 2005;46:2468–76.plat J, Mensink rp. increased intestinal aBCa1 expression 72. contributes to the decrease in cholesterol absorption after plant stanol consumption. FaseB J. 2002;16:1248–53.shin Ws, szuba a, rockson sg. the role of chemokines in 73. human cardiovascular pathology: enhanced biological insights. atherosclerosis. 2002;160:91–102.Bustos C, hernandez-presa Ma, ortego M, tunon J, ortega l, 74. perez F, et al. hMg-Coa reductase inhibition by atorvasta-tin reduces neointimal inflammation in a rabbit model of atherosclerosis. J am Coll Cardiol. 1998;32:2057–64.lewandowski M, Kornacewicz-Jach Z, Millo B, Zielonka J, 75. Czechowska M, Kaliszczak r, et al. the influence of low dose atorvastatin on inflammatory marker levels in patients with acute coronary syndrome and its potential clinical value. Cardiol J. 2008;15:357–64.ortego M, Bustos C, hernandez-presa Ma, tunon J, Diaz C, 76. hernandez g, et al. atorvastatin reduces nF-kappaB activa-tion and chemokine expression in vascular smooth muscle cells and mononuclear cells. atherosclerosis. 1999; 147: 253–61.Bustos p, Duffau C, pacheco C, Ulloa n. beta-sitosterol 77. modulation of monocyte-endothelial cell interaction: a com-parison to female hormones. Maturitas. 2008;60:202–8.
Castro Cabezas M, de Vries Jh, Van oostrom aJ, iestra J, 78. van staveren Wa. effects of a stanol-enriched diet on plasma cholesterol and triglycerides in patients treated with statins. J am Diet assoc. 2006;106:1564–9.de Jong a, plat J, lutjohann D, Mensink rp. effects of long-79. term plant sterol or stanol ester consumption on lipid and lipoprotein metabolism in subjects on statin treatment. Br J nutr. 2008;100:937–41.Ketomaki a, gylling h, Miettinen ta. non-cholesterol ster-80. ols in serum, lipoproteins, and red cells in statin-treated Fh subjects off and on plant stanol and sterol ester spreads. Clin Chim acta. 2005;353:75–86.simons la. additive effect of plant sterol-ester margarine and 81. cerivastatin in lowering low-density lipoprotein cholesterol in primary hypercholesterolemia. am J Cardiol. 2002;90:737–40.takeshita M, Katsuragi Y, Kusuhara M, higashi K, Miyajima e, 82. Mizuno K, et al. phytosterols dissolved in diacylglycerol oil reinforce the cholesterol-lowering effect of low-dose pravastatin treatment. nutr Metab Cardiovasc Dis. 2008;18: 483–91.Jakulj l, trip MD, sudhop t, von Bergmann K, Kastelein JJ, 83. Vissers Mn. inhibition of cholesterol absorption by the com-bination of dietary plant sterols and ezetimibe: effects on plasma lipid levels. J lipid res. 2005;46:2692–8.nigon F, serfaty-lacrosniere C, Beucler i, Chauvois D, 84. neveu C, giral p, et al. plant sterol-enriched margarine low-ers plasma lDl in hyperlipidemic subjects with low choles-terol intake: effect of fibrate treatment. Clin Chem lab Med. 2001;39:634–40.ginsberg hn. insulin resistance and cardiovascular disease. 85. J Clin invest. 2000;106:453–8.Watson Ke, peters harmel al, Matson g. atherosclerosis 86. in type 2 diabetes mellitus: the role of insulin resistance. J Cardiovasc pharmacol ther. 2003;8:253–60.rupp h. insulin resistance, hyperinsulinemia, and cardio-87. vascular disease. the need for novel dietary prevention strat-egies. Basic res Cardiol. 1992;87:99–105.Valachovicova M, Krajcovicova-Kudlackova M, Blazicek p, 88. Babinska K. no evidence of insulin resistance in normal weight vegetarians. a case control study. eur J nutr. 2006;45:52–4.McKeown nM, Meigs JB, liu s, saltzman e, Wilson pW, 89. Jacques pF. Carbohydrate nutrition, insulin resistance, and the prevalence of the metabolic syndrome in the Framingham offspring Cohort. Diabetes Care. 2004;27: 538–46.lau C, Faerch K, glumer C, tetens i, pedersen o, 90. Carstensen B, et al. Dietary glycemic index, glycemic load, fiber, simple sugars, and insulin resistance: the inter99 study. Diabetes Care. 2005;28:1397–403.robertson MD, Bickerton as, Dennis al, Vidal h, 91. Frayn Kn. insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism. am J Clin nutr. 2005;82:559–67.Weickert Mo, Mohlig M, schofl C, arafat aM, otto B, 92. Viehoff h, et al. Cereal fiber improves whole-body insulin sensitivity in overweight and obese women. Diabetes Care. 2006;29:775–80. liatis s, tsapogas p, Chala e, Dimosthenopoulos C, 93. Kyriakopoulos K, Kapantais e, et al. the consumption of bread enriched with betaglucan reduces lDl-cholesterol and improves insulin resistance in patients with type2 dia-betes. Diabetes Metab. 2009;35:115–20. rave K, roggen K, Dellweg s, heise t, tom Dieck h. 94. improvement of insulin resistance after diet with a whole-grain based dietary product: results of a randomized, con-
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onl
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trolled cross-over study in obese subjects with elevated fasting blood glucose. Br J nutr. 2007;98:929–36. ostman eM, Frid ah, groop lC, Bjorck iM. a dietary 95. exchange of common bread for tailored bread of low gly-caemic index and rich in dietary fibre improved insulin economy in young women with impaired glucose tolerance. eur J Clin nutr. 2006;60:334–41. robertson MD, Currie JM, Morgan lM, Jewell Dp, Frayn 96. Kn. prior short-term consumption of resistant starch enhances postprandial insulin sensitivity in healthy sub-jects. Diabetologia. 2003;46:659–65. Kohl a, gogebakan o, Mohlig M, osterhoff M, isken F, 97. pfeiffer aF, et al. increased interleukin-10 but unchanged insu-lin sensitivity after 4 weeks of (1, 3)(1, 6)-beta-glycan consum-ption in overweight humans. nutr res. 2009;29:248–54. Kim h, stote Ks, Behall KM, spears K, Vinyard B, 98. Conway JM. glucose and insulin responses to whole grain breakfasts varying in soluble fiber, beta-glucan: a dose response study in obese women with increased risk for insu-lin resistance. eur J nutr. 2009;48:170–5. Fryer lg, parbu-patel a, Carling D. the anti-diabetic 99. drugs rosiglitazone and metformin stimulate aMp-acti-vated protein kinase through distinct signaling pathways. J Biol Chem. 2002;277:25226–32. schimmack g, Defronzo ra, Musi n. aMp-activated pro-100. tein kinase: role in metabolism and therapeutic implica-tions. Diabetes obes Metab. 2006;8:591–602. Zhou g, Myers r, li Y, Chen Y, shen X, Fenyk-Melody J, 101. et al. role of aMp-activated protein kinase in mechanism of metformin action. J Clin invest. 2001;108:1167–74. santos rF, nomizo r, oliveira e, Ursich M, Wajchenberg B, 102. reaven gM, et al. erythrocyte insulin receptor tyrosine kinase activity is increased in glyburide-treated patients with type 2 diabetes in good glycaemic control. Diabetes obes Metab. 2000;2:237–41. santos rF, nomizo r, Wajhenberg Bl, reaven gM, azhar s. 103. Changes in insulin receptor tyrosine kinase activity associ-ated with metformin treatment of type 2 diabetes. Diabetes Metab. 1995;21:274–80. stith BJ, goalstone Ml, espinoza r, Mossel C, roberts D, 104. Wiernsperger n. the antidiabetic drug metformin elevates receptor tyrosine kinase activity and inositol 1,4,5-trisphos-phate mass in Xenopus oocytes. endocrinology. 1996; 137: 2990–9. luna V, Casauban l, sajan Mp, gomez-Daspet J, powe Jl, 105. Miura a, et al. Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(po4)3 in muscle of diabetic subjects. Diabetologia. 2006;49:375–82. Fediuc s, pimenta as, gaidhu Mp, Ceddia rB. activation 106. of aMp-activated protein kinase, inhibition of pyruvate dehydrogenase activity, and redistribution of substrate par-titioning mediate the acute insulin-sensitizing effects of troglitazone in skeletal muscle cells. J Cell physiol. 2008;215:392–400. stumvoll M, haring hU. glitazones: clinical effects and 107. molecular mechanisms. ann Med. 2002;34:217–24. oakes nD, thalen pg, Jacinto sM, ljung B. thiazolidin-108. ediones increase plasma-adipose tissue FFa exchange capacity and enhance insulin-mediated control of systemic FFa availability. Diabetes. 2001;50:1158–65. Williams lB, Fawcett rl, Waechter as, Zhang p, Kogon Be, 109. Jones r, et al. leptin production in adipocytes from mor-bidly obese subjects: stimulation by dexamethasone, inhibi-tion with troglitazone, and influence of gender. J Clin endocrinol Metab. 2000;85:2678–84.
Derosa g, salvadeo sa, D’angelo a, Fogari e, ragonesi pD, 110. Ciccarelli l, et al. rosiglitazone therapy improves insulin resistance parameters in overweight and obese diabetic patients intolerant to metformin. arch Med res. 2008; 39:412–9. Wu Zh, Zhao sp, Chu lX, Ye hJ. pioglitazone reduces 111. tumor necrosis factor-alpha serum concentration and mrna expression of adipose tissue in hypercholestero-lemic rabbits. int J Cardiol. 2010;138:151–6. Majuri a, santaniemi M, rautio K, Kunnari a, Vartiainen J, 112. ruokonen a, et al. rosiglitazone treatment increases plasma levels of adiponectin and decreases levels of resistin in over-weight women with pCos: a randomized placebo-controlled study. eur J endocrinol. 2007;156:263–9. Jiang g, Dallas-Yang Q, Biswas s, li Z, Zhang BB. ros-113. iglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (ppargamma), decreases inhibitory ser-ine phosphorylation of irs1 in vitro and in vivo. Biochem J. 2004;377:339–46. tafuri sr. troglitazone enhances differentiation, basal glu-114. cose uptake, and glut1 protein levels in 3t3-l1 adipocytes. endocrinology. 1996;137:4706–12. park Ks, Ciaraldi tp, abrams-Carter l, Mudaliar s, 115. nikoulina se, henry rr. troglitazone regulation of glu-cose metabolism in human skeletal muscle cultures from obese type ii diabetic subjects. J Clin endocrinol Metab. 1998;83:1636–43. robertson MD. Metabolic cross talk between the colon and 116. the periphery: implications for insulin sensitivity. proc nutr soc. 2007;66:351–61. Carpentier a, Mittelman sD, lamarche B, Bergman rn, 117. giacca a, lewis gF. acute enhancement of insulin secre-tion by FFa in humans is lost with prolonged FFa eleva-tion. am J physiol. 1999;276:e1055–66. Barazzoni r, Zanetti M, stulle M, Mucci Mp, pirulli a, 118. Dore F, et al. higher total ghrelin levels are associated with higher insulin-mediated glucose disposal in non-diabetic main-tenance hemodialysis patients. Clin nutr. 2008;27:142–9. liu J, lin h, Cheng p, hu X, lu h. effects of ghrelin on 119. the proliferation and differentiation of 3t3-l1 preadi-pocytes. J huazhong Univ sci technolog Med sci. 2009;29: 227–30. pagotto U, gambineri a, Vicennati V, heiman Ml, tschop M, 120. pasquali r. plasma ghrelin, obesity, and the polycystic ovary syndrome: correlation with insulin resistance and androgen levels. J Clin endocrinol Metab. 2002;87:5625–9. Choi K, roh sg, hong Yh, shrestha YB, hishikawa D, 121. Chen C, et al. the role of ghrelin and growth hormone secretagogues receptor on rat adipogenesis. endocrinology. 2003;144:754–9. ge h, li X, Weiszmann J, Wang p, Baribault h, Chen Jl, 122. et al. activation of g protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. endocrinology. 2008;149: 4519–26. hong Yh, nishimura Y, hishikawa D, tsuzuki h, Miyahara h, 123. gotoh C, et al. acetate and propionate short chain fatty acids stimulate adipogenesis via gpCr43. endocrinology. 2005;146:5092–9. Weyer C, Foley Je, Bogardus C, tataranni pa, pratley re. 124. enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type ii diabetes independent of insu-lin resistance. Diabetologia. 2000;43:1498–506. lonn M, Mehlig K, Bengtsson C, lissner l. adipocyte size 125. predicts incidence of type 2 diabetes in women. FaseB J. 2010.24:326–31.
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thorburn a, Muir J, proietto J. Carbohydrate fermentation 126. decreases hepatic glucose output in healthy subjects. Metabolism. 1993;42:780–5. song YJ, sawamura M, ikeda K, igawa s, Yamori Y. 127. soluble dietary fibre improves insulin sensitivity by increas-ing muscle glUt-4 content in stroke-prone spontaneously hypertensive rats. Clin exp pharmacol physiol. 2000;27: 41–5. gao Z, Yin J, Zhang J, Ward re, Martin rJ, lefevre M, 128. et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes. 2009.;58:1509–17. engelhard Yn, gazer B, paran e. natural antioxidants 129. from tomato extract reduce blood pressure in patients with grade-1 hypertension: a double-blind, placebo-controlled pilot study. am heart J. 2006;151:100. Kohlmeier l, Kark JD, gomez-gracia e, Martin BC, 130. steck se, Kardinaal aF, et al. lycopene and myocardial infarction risk in the eUraMiC study. am J epidemiol. 1997;146:618–26. gianetti J, pedrinelli r, petrucci r, lazzerini g, 131. De Caterina M, Bellomo g, et al. inverse association between carotid intima-media thickness and the antioxidant lyco-pene in atherosclerosis. am heart J. 2002;143:467–74. Canadian pharmacists association. Cps Compendium of 132. pharmaceuticals and specialties. 9th ed. ottawa: Canadian pharmacists association; 2003. Delles C, Miller Wh, Dominiczak aF. targeting reactive 133. oxygen species in hypertension. antioxid redox signal. 2008;10:1061–77. Di Mascio p, Kaiser s, sies h. lycopene as the most effi-134. cient biological carotenoid singlet oxygen quencher. arch Biochem Biophys. 1989;274:532–8. Bose Ks, agrawal BK. effect of lycopene from tomatoes 135. (cooked) on plasma antioxidant enzymes, lipid peroxida-tion rate and lipid profile in grade-i hypertension. ann nutr Metab. 2007;51:477–81. de leeuw pW, Bast a. tomato extract for hypertension? 136. editorial to ‘the effects of natural antioxidants from tomato extract in treated but uncontrolled hypertensive patients’ by e. paran et al. Cardiovasc Drugs ther. 2009;23: 107–8. suganuma h, inakuma t. protective effect of dietary 137. tomato against endothelial dysfunction in hypercholestero-lemic mice. Biosci Biotechnol Biochem. 1999;63:78–82. Most MM. estimated phytochemical content of the 138. dietary approaches to stop hypertension (Dash) diet is
higher than in the Control study Diet. J am Diet assoc. 2004;104:1725–7. law M, Wald n, Morris J. lowering blood pressure to pre-139. vent myocardial infarction and stroke: a new preventive strategy. health technol assess. 2003;7:1–94. Jones pJ, asp ng, silva p. evidence for health claims on 140. foods: how much is enough? introduction and general remarks. J nutr. 2008;138:1189s–91s. asp ng, Bryngelsson s. health claims in europe: new leg-141. islation and passClaiM for substantiation. J nutr. 2008; 138:1210s–5s. hasler CM. health claims in the United states: an aid to 142. the public or a source of confusion? J nutr. 2008;138: 1216s–20s. l’abbe Mr, Dumais l, Chao e, Junkins B. health claims 143. on foods in Canada. J nutr. 2008;138:1221s–7s. tapsell lC. evidence for health claims: a perspective from 144. the australia-new Zealand region. J nutr. 2008;138: 1206s–9s. Yamada K, sato-Mito n, nagata J, Umegaki K. health claim 145. evidence requirements in Japan. J nutr. 2008;138: 1192s–8s. Yang Y. scientific substantiation of functional food health 146. claims in China. J nutr. 2008;138:1199s–205s. gustin DM, rodvold Ka, sosman Ja, Diwadkar- 147. navsariwala V, stacewicz-sapuntzakis M, Viana M, et al. single-dose pharmacokinetic study of lycopene delivered in a well-defined food-based lycopene delivery system (tomato paste-oil mixture) in healthy adult male subjects. Cancer epidemiol Biomarkers prev. 2004;13:850–60. Jonker D, Kuper CF, Fraile n, estrella a, rodriguez 148. otero C. ninety-day oral toxicity study of lycopene from Blakeslea trispora in rats. regul toxicol pharmacol. 2003;37: 396–406. Veeramachaneni s, ausman lM, Choi sW, russell rM, 149. Wang XD. high dose lycopene supplementation increases hepatic cytochrome p4502e1 protein and inflammation in alcohol-fed rats. J nutr. 2008;138:1329–35. Bressler r. grapefruit juice and drug interactions. explor-150. ing mechanisms of this interaction and potential toxicity for certain drugs. geriatrics. 2006;61:12–8. izzo aa. herb-drug interactions: an overview of the clinical 151. evidence. Fundam Clin pharmacol. 2005;19:1–16. Volpe r, niittynen l, Korpela r, sirtori C, Bucci a, Fraone n, 152. et al. effects of yoghurt enriched with plant sterols on serum lipids in patients with moderate hypercholesterolae-mia. Br J nutr. 2001;86:233–9.