Content uploaded by Mohammad Javed Ansari
Author content
All content in this area was uploaded by Mohammad Javed Ansari on Dec 16, 2013
Content may be subject to copyright.
REVIEW ARTICLE
Honey and Cardiovascular Risk Factors, in Normal Individuals
and in Patients with Diabetes Mellitus or Dyslipidemia
Noori Al-Waili,
1
Khelod Salom,
1
Ahmad Al-Ghamdi,
2
Mohammad Javed Ansari,
2
Ali Al-Waili,
1
and Thia Al-Waili
1
1
Waili Foundation for Science, Queens, New York, USA.
2
Unit of Bee Research, Department of Plant Protection,
College of Food and Agricultural Sciences, King Saud University, Riyadh, Saudi Arabia.
ABSTRACT Diabetes mellitus, hypercholesteremia, hypertension (HTN), and obesity are well-known risk factors
for cardiovascular diseases (CVD). Various medications are currently in use for management of these comorbidities.
Undesirablesideeffectsareunavoidableandtheultimateandideal goal is hardly achieved. Honey and other bee products
are widely used in traditional medicine for management of many diseases. Others and the authors have found potent
biological activities of these products. Honey is now reintroduced in modern medicine as part of wound and burn man-
agement. Honey has antioxidant, anti-inflammatory, and antimicrobial activities. More studies are exploring other aspects
of honey activity such as its effect on blood sugar, body weight, lipid profile, C-reactive protein, nitric oxide, proin-
flammatory prostaglandins, and homocysteine. Growing evidence and scientific data support the use of honey in patients
with diabetes, HTN, dyslipidemia, obesity, and CVD. This review discusses clinical and preclinical studies on potential
influence of honey on diabetes mellitus and cardiovascular risk factors, and emphasizes the importance of conducting more
clinical and controlled studies.
KEY WORDS: cholesterol C-reactive protein glucose honey insulin obesity triacylglycerol
INTRODUCTION
Cardiovascular diseases (CVD) are associated with
hypercholesterolemia, hypertension (HTN) and diabe-
tes mellitus (DM). Atherosclerosis, which is due to endothelial
dysfunction, is the main cause of CVD. Cardiovascular dis-
orders remain the leading cause of death worldwide.
1
Obese
and diabetic patients have a high risk of dying from com-
plications associated with CVD.
In addition to normal BMI and blood pressure, main-
taining normal levels of serum homocysteine, C-reactive
protein (CRP), lipids, and insulin are essential to maintain a
healthy cardiovascular system. Normal biological activities
of the vasoactive factors, nitric oxide (NO) and prosta-
glandins are important to maintain a healthy heart and blood
vessels.
Humans have used bee products in folk medicine since
ancient times. Ancient religious texts mentioned honey as a
popular remedy. In this regard, the Talmud, the Old and
New Testaments of the Bible, and the Holy Quran (1400
years ago) mentioned honey as a cure for diseases. A large
chapter (SORA) appears in the Holy Quran named BEE
(Al Nahl) and part of it says: ‘‘And thy LORD taught the bee
to build its cells in hills, on trees and in men’s habitations,
then to eat of all the produce of the earth and find with skill
the spacious paths of its LORD, there issues from within
their bodies a drink of varying colors, wherein is healing for
men, verily in this is a sign for those who give thought.’’
The health benefits attributed to bee products are based on
anecdotes or public observations with limited scientific data.
However, during the last few decades, these products have
been subjected for analysis and testing. Others and the au-
thors have published numerous scientific data showing the
medicinal and nutritional values of bee products.
2–6
The
literature shows that honey has antibacterial, antifungal,
antiviral, anti-inflammatory, antihypertensive, antioxidant,
antitumor, cardioprotective, hepatoprotective, and hypo-
glycemic properties.
3,4,6–15
A recent review showed that the
polyphenol content of various types of honey might prevent
CVD by improving coronary vasodilatation, decreasing the
ability of platelets in the blood to clot, and preventing low-
density lipoproteins (LDL) from oxidizing.
16
Therefore,
honey has received renewed interest as an important natural
substance that can be used in new therapies almost free from
side effects that are encountered with the use of synthetic
and chemical medicines.
Manuscript received November 14, 2012. Revision accepted August 22, 2013.
Address correspondence to: Noori Al-Waili, MD, PhD, DGO, CHT, Waili Foundation for
Science, Queens, NY 11418, USA, E-mail: drnoori6@yahoo.com
JOURNAL OF MEDICINAL FOOD
J Med Food 16 (12) 2013, 1063–1078
#Mary Ann Liebert, Inc., and Korean Society of Food Science and Nutrition
DOI: 10.1089/jmf.2012.0285
1063
DISCUSSION
Honey composition
Honey is a carbohydrate-rich syrup produced by bees, from
floral nectars. Color, flavor, and aroma depend on its floral
origin. Aberrantly, honey composition is tightly associated to
its botanical origin, which is closely related to the geograph-
ical area in which it is originated. In this regard, soil and
climate characteristics determine melliferous flora, in addition
to the presence of different minerals in soil.
17
The organoleptic
characteristics of honey are strongly dependent on its botan-
ical origin and to some extent on its geographical origin.
18
Composition of different honeys from many regions of the
world has been studied, including the United Arab Emirates
(U.A.E.), the United States, Algeria, India, Slovenia, Ban-
gladesh, and Malaysia.
19–25
Honey contains 181 bioactive
substances.
26
More than 500 different volatile compounds
were identified in various types of honey.
27
Fructose and
glucose are the major components while disaccharides, tri-
saccharides, and oligosaccharides are present in small quan-
tities. In addition, honey contains protein, enzymes, amins
acids, vitamins, and minerals (Table 1).
20–25,27–42
The physical chemistry characteristics of honey are directly
related to floral origin.
30,31
Approximately 30 nonaromatic
organic acids have been identified.
32
Gluconic acid is the major
organic acid produced by enzymatic glucose oxidase reaction.
The glucose oxidase reaction in honey produces glutamic acid
and hydrogen peroxide from glucose. Invertase converts su-
crose to fructose and glucose.
33
Amylase splits starch chains
yielding dextrins and maltose.
30
Polyphenols are an important
group of compounds present in honey.
34–36
An analytical survey of U.S. honey was reported.
28
This
includes analyses of 490 samples of U.S. floral honey and 14
samples of honeydew honey gathered from 47 of the 50 states
and representing 82 single floral types and 93 blends of known
composition. Floral honey is higher in fructose and dextrose,
lower in disaccharides and higher sugars, and contains much
less acid. The water content of honey varies greatly, ranging
between 13% and 25%. We have analyzed honey collected
from the U.A.E.; the acidity was 13%, and the composition
includes (out of 100 g): fructose 38 g, glucose 30 g, moisture
29 g, vitamin C 2.3 mg, copper 0.098 mg, zinc 0.6 mg, vitamin
E 0.74 mg, vitamin A 0.49 mg, selenium 0.44 mg, chromium
0.007 mg, iron 0.2 mg, cobalt 0.016 mg, calcium 17 mg, glu-
tathione reductase 0.52 mg, and the remainder consist of other
carbohydrates, proteins, and unidentified substances.
25
Electric conductivity, acidity, amino acids, mineral con-
tent, carbohydrate content, and pollen proteins are used to
assess provenience of honey.
39,40,43–45
Seventeen minerals in
Spanish honey have been determined, reporting a relation-
ship between mineral contents and geographical origin.
40
The authenticity of Galician-labeled honey has been con-
firmed by analyzing elemental composition of honey com-
bined with chemometrics modeling techniques.
45
Further, it
was found that NO
-
3
is a potential reliable marker of a
honey’s origin and quality.
42
The acids have been used as
factors for the characterization of both botanical and
geographical origins of honeys.
41
Table 1. The Main Solid Contents of Honey
Groups Members References
Carbohydrates Dextrose and fructose account for about 85% of the solids in honey. Ten
disaccharides present in honey: sucrose, maltose, isomaltose, mal-
tulose, nigerose, turanose, kojibiose, laminaribiose, a, B-trehalose, and
gentiobiose. Ten trisaccharides are present: melezitose, 3-a-isomalto-
sylglucose, maltotriose, l-kestose, panose, isomaltotriose, erlose,
theanderose, centose, and isopanose. Two more complex sugars,
isomaltotetraose and isomaltopentaose, have been determined
25,28,39
Nonaromatic organic acids Butyric, malic, maleic, citric, succinic, fumaric, oxalic, pyroglutamic
acids, and gluconic acid
24,31,32,41
Trace elements and minerals Aluminum, lead, arsenic, lithium, barium, molybdenum, boron, nickel,
bromine, rubidium, cadmium, silicon, chlorine, strontium, sulfur,
florid, vanadium, iodide, zirconium, cobalt, sodium, calcium, potas-
sium, magnesium, phosphorus, zinc, copper, iron, manganese, chro-
mium, and selenium
25,27,32,40,42
Vitamins Thiamin, riboflavin, pyridoxin, vitamin A, niacin, panthothenic acid,
phyllochinon, vitamin E, and ascorbic acid
24,25,27
Amino acids Eighteen essential and nonessential amino acids; proline, glutamic acid,
alanine, phenylalanine, tyrosine, leucine, and isoleucine are the most
common
24,27,28
Enzymes Glucose oxidase, invertase, amylase, catalase, and acid phosphatase 30,33
Polyphenols Phenolic acids, flavonoids, and phenolic acid derivatives; quercetin,
chrysin, galangin, luteolin, kaempferol, and apigenin are the main
flavonoids in honey
20–23,34–36
NO NO end products 37,38,42
NO, nitric oxide.
1064 AL-WAILI ET AL.
Honey and glycemic response
Many studies showed that honey from various origins has
almost similar activity on blood sugar (Table 2).
14,25,46–53
Glycemic index of Malaysian honey and Australian honey
was studied in eight healthy volunteers. The patients re-
ceived 50 g carbohydrate; two varieties of honey or the
reference food. The results showed that the mean area under
curve and glycemic index of the Malaysian and Australian
honeys did not differ from each other but were significantly
less than that after glucose.
46
In Germany, eight various
German honeys differing in their floral source and carbo-
hydrate composition were tested. Ten healthy fasting indi-
viduals received isoglucidic test meals (25 g carbohydrate)
and a 25 g glucose reference. Five of the eight tested sam-
ples of honey showed a low glycemic index below 55. In
addition, the glycemic index and insulinemic index signifi-
cantly correlated with the fructose content of honey varie-
ties.
47
Another study compared the effects of basswood
honey, an identical sugar solution (containing 75 g of glu-
cose), and oral glucose tolerance test solution on serum
glucose, insulin, and C-peptide values in 12 healthy sub-
jects.
48
Serum insulin, C-peptide, and glucose values at
60 min were significantly lower for honey. The area under
the concentration-time profile for glucose response was
lower for honey than the honey-comparable glucose-fruc-
tose solution. Honey had less effect on serum glucose, C-
peptide, and insulin values than the honey-comparable
glucose-fructose solution.
48
In the United States, the glycemic index of a 250 mL
solution serving of clover, buckwheat, cotton, and tupelo
honey providing 50 g carbohydrate were assessed in 12
healthy adults, relative to triplicate feedings of 50 g carbo-
hydrate as a glucose solution.
49
No significant differences in
glycemic index between these varieties of honey were
found, and there was no relationship between glycemic in-
dex and the fructose-to-glucose ratio. Therefore, small dif-
ferences in fructose-to-glucose ratios do not substantially
affect honey glycemic index.
49
In another U.S. study, oral glucose tolerance testing
comparing sucrose, fructose, and honey was conducted in 33
individuals. Fructose showed minimal changes in plasma
glucose level (PGL) while sucrose gave higher PGL
readings than honey, producing significantly greater glucose
intolerance.
50
In Pakistan, oral glucose tolerance test was conducted in
26 healthy individuals with use of natural honey, simulated
honey, or D-glucose (1 g/kg body weight). Glucose response
Table 2. Effects of Honey on Blood Sugar in Normal Individuals
Study Origin of honey
Number
of individuals Results
Robert et al. (2009)
46
Malaysia and Australia 8 Mean AUC/glycemic index of both honeys were
significantly less than that after glucose
Deibert et al. (2010)
47
Germany; eight samples
of honey
10 5/8 samples of honey show a low glycemic index
Mu
¨nstedt et al. (2008)
48
Germany; basswood honey 12 Serum insulin, C-peptide, and glucose values at
60 min were significantly lower for honey. AUC
for glucose response was lower for the honey than
the honey-comparable glucose-fructose solution
Ischayek and Kern. (2006)
49
United States; clover, buck-
wheat, cotton, and tupelo
honey
12 No significant differences in glycemic index between
the honey samples
Shambaugh et al. (1990)
50
United States 33 Sucrose gave higher PGL readings than honey,
producing significantly greater glucose intolerance
Ahmad et al. (2008)
51
Pakistan 26 Glycemic responses were significantly lower in
subjects who consumed natural honey than those
who consumed glucose or artificial honey
Yaghoobi et al. (2008)
52
Iran 38 Honey reduces fasting PGL (4.2%) compared with
sucrose
Al-Waili (2008)
25
United Arab Emirates 10 Honey reduced fasting blood sugar by 5%
Al-Waili (2003)
14
United Arab Emirates 24 Honey inhalation lowers PGL and elevates plasma
insulin and C-peptide
Al-Waili (2004)
53
United Arab Emirates 16 In glucose toleance test, dextrose raised PGL at 1 h
(53%) and 2 h (3%), and lowered PGL after 3 h by
20%. Honey elevated PGL after 1 h by 14% and
decreased it after 3 h by 10%. Elevation of insulin
and C-peptide was significantly higher after dextrose
than after honey. Daily consumption of 75 g of
honey for 15 days reduced fasting PGL by 6%
AUC, area under curve; PGL, plasma glucose level.
HONEY AND CARDIOVASCULAR RISK FACTORS 1065
was significantly lower in the natural honey group compared
with the artificial honey and D-glucose groups.
51
At 60 min,
individuals in D-glucose and simulated honey group ex-
hibited 20% increments in PGL compared with natural honey
group. However, at 180 min, 20% decrease in PGL was ob-
served in the D-glucose group compared with 9.75% reduc-
tion in the honey group. Therefore, glycemic responses were
significantly lower in subjects who consumed natural honey
than those who consumed glucose or artificial honey.
51
Another study from Iran has shown that a regimen of a 30-day
natural honey intake (70 g) in 38 overweight individuals slightly
reduced fasting PGL (4.2%) compared with 70 g of sucrose.
52
In the U.A.E., 10 normal individuals received a normal
diet supplemented with daily consumption of 1.2 g/kg body
weight honey dissolved in 250 mL of water during a 2-
week test period. Honey reduced fasting blood sugar by 5%
after 2 weeks.
25
In 24 normal individuals, 10% dextrose
inhalation caused mild reduction of plasma insulin and C-
peptide and unremarkable changes in PGL. Honey inha-
lation caused lowering of PGL and elevation of plasma
insulin and C-peptide.
14
In eight healthy subjects, effects of
dextrose solution (250 mL of water containing 75 g of
dextrose) or honey solution (250 mL of water containing
75 g of natural honey) on PGL was studied in the U.A.E.
Further, in eight other normal individuals, effects of honey
solution, administered for 15 days, on PGL was studied. It
was found that dextrose raised PGL at 1 h (53%) and 2 h
(3%), and lowered PGL after 3 h by 20%. Honey elevated
PGL after 1 h by 14% and decreased it after 3 h by 10%.
Elevation of insulin and C-peptide was significantly higher
after dextrose than after honey. In addition, daily con-
sumption of 75 g of honey for 15 days reduced fasting PGL
by 6%.
53
In the U.A.E., food restriction with 50% honey feeding in
rats caused greater reduction in fasting blood sugar com-
pared with total food restriction with 50% dextrose feeding.
Similar results were obtained after acute blood loss in rats on
total food restriction with 50% honey feeding compared
with the other groups.
54
In addition, the authors assessed the
effects of four diets on blood variables in rats: a commercial
regular diet as control, total food restriction with honey, a
commercial regular diet with dextrose, or total food re-
striction with dextrose after administrating carbon tetra-
chloride. Honey feeding ameliorated reduction in PGL
observed after carbon tetrachloride toxicity.
55
Intravenous infusion of 40 g of honey collected in the
U.A.E. in healthy sheep caused elevation of PGL for 90min
postinfusion, whereas it decreased PGL at 2 and 3h post-
infusion compared with fasting blood sugar. Dextrose caused
significant elevation of PGL at all time intervals. Similar
results were obtained with the use of 10% dextrose compared
to 80 g of honey. Inhalation of honey caused significant
lowering of PGL during and after inhalation compared with
water inhalation.
56
In the United Kingdom, hyperglycemic effects of glucose,
sucrose, and honey equivalent to 20 g in 12 normal volun-
teers were studied. Honey attenuated the postprandial gly-
cemic response in normal volunteers.
57
Honey and diabetes
Animal experimentation. In Malaysia, honey (0.2, 1.2,
and 2.4 g/kg/day) given by oral gavage for 4 weeks significantly
increased body weight, total antioxidant status, activities of
catalase, glutathione peroxidase, glutathione reductase, gluta-
thione-S-transferase, and superoxide dismutase activity in dia-
betic rats. In addition, honey ameliorated side effects of DM on
kidney rats and significantly reduced fasting blood sugar.
8
Tualang honey significantly reduced elevated malondialdehyde
levels in streptozotocin-induced diabetic rats and restored su-
peroxide dismutase and catalase activities. These results suggest
that hypoglycemic effect of tualang honey might be attributed to
its antioxidative effect on the pancreas.
13
In streptozotocin-in-
duced diabetic rats, it was found that the combination of glib-
enclamide or metformin with honey improved glycemic
control. Glibenclamide or metformin combined with honey
significantly reduced the elevated levels of creatinine, bilirubin,
triacylglycerol, and VLDL.
58
In Pakistan, oral administration of Apis florea (small-bee)
and Apis dorsata (large-bee) honey in a dose of 5 mL/kg did
not produce a significant increase in PGL in normal and
alloxan-diabetic rabbits, whereas the adulterated honey
significantly raised the PGL in normal and hyperglycemic
rabbits.
59
In higher doses of 10 mL/kg and 15 mL/kg body
weight, all the three honeys produced a significant rise in
PGL of normal and alloxan-diabetic rabbits.
59
In this study,
the animals received very high doses of the interventions
and that may be why PGL increased in all groups.
In New Zealand, a study conducted on rats showed that
HbA1c levels were significantly reduced in 10% honey-fed
compared with rats fed 7.9% sucrose or a sugar-free diet.
60
Human experimentation. In the United Kingdom, hy-
perglycemic effects of glucose, sucrose, and honey equivalent
to 20 g in eight patients with type 1 DM, and six patients with
type 2 DM were studied. Honey attenuated postprandial gly-
cemic response in the patients with DM.
57
In Italy, honey,
compared to an isoglucidic amount of bread, had no additional
hyperglycemic effect in 21 type 2 diabetic individuals when
consumed for breakfast.
61
In Greece, the metabolic effects of
honey (alone or combined with other foods) were investigated
in 31 type 2 diabetics. Honey caused a hyperglycemia similar
to that produced by consuming bread in individuals with type 2
diabetes.
62
In India, 30 individuals with a proven parental history of
type 2 DM were subjected to an oral glucose tolerance test
with the use of either honey or glucose. The subjects with
impaired glucose tolerance showed significantly lower PGL
after consumption of honey in comparison with the glucose
tolerance test. In diabetic patients, high degree of tolerance
to honey was recorded too.
63
In Egypt, a case–control cross-sectional study was con-
ducted on 20 children and adolescents with type 1 DM and 10
healthy children and adolescents. Oral glucose tolerance tests
using glucose, sucrose, or honey were conducted measuring
fasting and postprandial serum C-peptide levels. Honey,
compared with sucrose, had a lower glycemic index and in-
cremental index in both diabetic patients and control.
64
1066 AL-WAILI ET AL.
In the U.A.E., the effects of 70 g of dextrose or 90 g of
honey on PGL in seven patients with type 2 DM and the
effects of 30 g of sucrose or 30 g of honey on PGL, plasma
insulin, and plasma C-peptide in five diabetic patients were
studied.
53
Honey compared with dextrose caused a signifi-
cantly lower rise of PGL. Elevation of PGL was greater after
honey than after sucrose at 30 min, and was lower after
honey than it was after sucrose at 60, 120, and 180 min.
Honey caused a greater elevation of insulin than sucrose did
after 30, 120, and 180 min in diabetics.
Sixteen patients with type 2 DM were treated with in-
trapulmonary inhalation of honey. Fasting PGL was esti-
mated in each patient and was re-estimated during 3 h after
honey inhalation, at 30 min intervals. Glucose tolerance
tests were performed in another eight patients with type 2
DM and after 1 week, the procedure was repeated with
inhalation of honey after ingestion of glucose. Honey in-
halation caused lowering of PGL and elevation of plasma
insulin and C-peptide, and significantly reduced random
PGL after 30 min. Fasting PGL was reduced after honey
inhalation at hour three postinhalation, which was sig-
nificant at hour three. Honey inhalation was effective in
reducing PGL, suggesting it could improve glucose toler-
ance and elevate plasma insulin and C-peptide in diabetic
patients.
14
The blood glucose and plasma insulin responses to some
simple carbohydrates (glucose, fructose, and lactose) and
honey were studied in 32 type 2 DM patients. Ingestion of
25 g glucose, fructose, or lactose, or 30 g honey was tested.
Sixty minutes after ingestion of each meal, the increases in
PGL and in plasma insulin were significantly higher after
glucose, fructose, and lactose than after honey.
65
The above studies showed that honey collected from
different regions had almost similar glycemic effect. Honey
compared with dextrose reduced PGL and insulin in normal
subjects. This is important since hyperinsulinemia is a single
independent determinant for coronary artery diseases and it
increases homocysteine in healthy normal weight, over-
weight, and obese premenopausal women.
66
Hyperglycemia
increases circulatory cytokine concentrations by an oxida-
tive mechanism, particularly in subjects with impaired
glucose tolerance.
67
Table 3 summarizes studies conducted
on patients with type 1 and type 2 diabetes.
14,53,57,61–64
Mechanism of action. Honey contains fructose, oligo-
saccharides, minerals, and antioxidants.
19–25
In normal in-
dividuals, a daily consumption of 1.2 g/kg body weight
honey during a 2-week test increased blood vitamin C con-
centration by 47%, b-carotene by 3%, uric acid by 12%, and
glutathione reductase by 7%. Honey increased serum copper
by 33%.
25
Many studies have shown that flavonoids exert diverse
normoglycemic effects and lead to a lower incidence of
complications associated with DM.
68–70
Antioxidants such
as myricetin, fisetin, quercetin, and their glycoside precursor
(isoquercitrin) showed a strong inhibition of the fructose and
glucose transport mediated by GLUT2.
71
These compounds
are all present in beehive products.
72
Zinc lowers PGL by improvement of insulin sensitivity
and copper sulfate significantly decreases PGL.
73,74
Zinc
and copper are important for insulin and glucose metabo-
lism; both minerals were increased with consumption of
honey.
25
We have found that honey reduces prostaglandin levels
and elevates NO.
37,38,75
It has been shown that prostaglandin
E2 is one of the main physiological inhibitors of insulin.
76
Higher levels of NO and various NO donors stimulate in-
sulin secretion.
77
Glycemic carbohydrates present in natural
honey decrease saccharide absorption.
78–79
It has been found
that hydrogen peroxide can effectively mimic the function
of insulin.
80
Oligosaccharides may play a role in the anti-
diabetic effect of honey.
81–83
Oligosaccharides delayed
gastric emptying, slowed rate of digestion, and delayed in-
testinal absorption.
84–87
Infusion of small amounts of fructose induced amplifi-
cation of the counter regulatory response to mild hypo-
glycemia in normal individuals.
88
It has been proposed that
due to presence of fructose in addition to glucose, the
augmentation of hormonal response to hypoglycemia by
using honey might have a place in the prevention of hy-
poglycemia frequently encountered with use of insulin in
patients with diabetes.
25
Fructose could increase hepatic
glucose uptake and glycogen storage, and reduce periph-
eral glycemia and insulin levels; this could be beneficial in
diabetic patients.
89
This suggests that honey might be a
suitable food for diabetics and nondiabetics. However,
fructose consumption causes undesirable effects such as
hyperinsulinemia, induction of insulin resistance, hyper-
triglyceridemia, increased weight gain, hepatic de novo
lipogenesis, and HTN in animal models.
90–94
Honey contains more than 181 bioactive constituents in-
cluding free radical scavenging and antioxidant com-
pounds.
27,95
In addition, honey contains arginine and NO
metabolites and it increases NO production in animals and
human.
37,38
L-Arginine is able to prevent fructose-induced
HTN and hyperinsulinemia.
96
Therefore, we have proposed
that NO might inhibit fructose-induced hyperinsulinemia
after ingestion of honey.
25
Honey compared with dextrose
or sucrose decreased insulin levels in normal subjects. The
mild effect of honey on PGL and plasma insulin and
C-peptide in normal subjects might be due to fructose
content, as fructose does not stimulate insulin secretion from
pancreatic bcells.
97
Fructose reduces hyperglycemia in rodent models of di-
abetes, healthy subjects, and diabetic patients.
98–100
Fructose
prolongs gastric emptying and it lowers food intake.
101–103
A
low or moderate fructose diet resulted in weight loss in
obese subjects.
103
Obese subjects on the moderate fructose
diet lost more weight than those on the low fructose diet.
104
However, some studies have found that fructose feeding
or consumption at high doses is associated with increased
weight gain.
91,94
Fructose increases hepatic glucose phos-
phorylation via activation of glucokinase, and inhibits
glycogenolysis via suppression of phosphorylase.
105,106
Fructose increased hepatic glycogen synthesis in diabetic
and nondiabetic rats.
105,107
HONEY AND CARDIOVASCULAR RISK FACTORS 1067
Honey tastes sweeter than sucrose, so it was suggested
that a pure natural honey in low doses might be recom-
mended as sources of carbohydrates and even as sweetening
agents in place of sucrose to diabetic patients.
25
The effects
of honey or its constituents on gastric emptying, insulin
secretion, rate of intestinal absorption, prostaglandin inhi-
bition, NO production, fructose transporter, antioxidants
level, hepatic glucose uptake, zinc and copper levels, and
food intake, and perhaps the synergistic effect of glucose
on fructose may contribute to the lowering of glucose
levels.
85,101,103,108–109
Honey and lipids
In Iran, 48 patients with type 2 DM received oral natural
honey intake for eight weeks; honey decreased total cho-
lesterol, low-density lipoprotein–cholesterol (LDL-C), and
triacylglycerol, and increased high-density lipoprotein–
cholesterol (HDL-C).
110
Another study showed that 70 g of
natural honey collected in Iran decreased total cholesterol
(3%), LDL-C (5.8%), and triacylglycerol (11%), and in-
creased HDL-C (3.3%) in subjects with normal values and
in patients who were overweight or obese.
52
In New Zealand, rats fed 10% honey increased the HDL-C
significantly compared with rats fed 7.9% sucrose or a sugar-
free diet.
60
In Germany, among patients who had high cho-
lesterol, LDL-C values did not significantly reduce in males
after ingesting a 75-g honey solution for 14 days. However, in
women, these values increased in the sugar solution group,
but not in that fed honey.
111
It was suggested that although
ingesting honey did not reduce LDL-C values, women might
benefit from substituting honey for sugar in their diet.
111
In the United States, a study conducted in rats showed
that honey lowered serum concentrations of triacylglycerol
compared with diets of equal energy densities. However,
there were no significant differences in serum total choles-
terol or HDL-C.
112
In Nigeria, a recent study showed that
consumption of unrefined Nigerian honey significantly im-
proved lipid profiles and the computed CVD predictive in-
dex in male albino rats.
113
The authors found that a single dose of glucose or artifi-
cial honey (consisting of 40 g fructose +35 g glucose in
Table 3. Effects of Various Samples of Honey on Blood Sugar in Patients with Type 1and Type 2Diabetes Mellitus
Study
Origin of honey/method
of administration Number of patients Results
Samanta et al. (1985)
57
United Kingdom; oral 8 type 1 DM Honey attenuated postprandial
glycemic response6 type 2 D
Bornet et al. (1985)
61
Italy; oral 21 type 2 DM Honey, compared to an isoglu-
cidic amount of bread, has no
additional hyperglycemic ef-
fect in 21 type 2 diabetic indi-
viduals when consumed for
breakfast
Katsilambros et al. (1988)
62
Greece; oral 31 type 2 DM Hyperglycemia similar to that
produced by consuming bread
Agrawal et al. (2007)
63
India; oral 30 with impaired glucose
tolerance test or type 2 DM
Significantly lower PGL after
consumption of honey in
comparison to the glucose
tolerance test. In diabetic pa-
tients, the high degree of tol-
erance to honey was recorded
too
Abdulrhman et al. (2011)
64
Egypt; oral 20 children and adolescents
with type 1 DM and 10
healthy children and
adolescents
Honey, compared to sucrose, had
lower glycemic index and in-
cremental index in both dia-
betic patients and control
Al-Waili (2004)
53
United Arab Emirates; oral 12 type 2 DM Honey compared with dextrose
caused a significantly lower
rise of PGL after GTT. Honey
caused greater elevation of
insulin than sucrose did after
30, 120, and 180 min in dia-
betics
Al-Waili (2003)
14
United Arab Emirates; inhalation 24 type 2 DM Honey inhalation was effective
in reducing PGL; it could
improve glucose tolerance test
and elevate plasma insulin and
C-peptide in diabetic patients
DM, diabetes mellitus; GTT, glucose tolerance test.
1068 AL-WAILI ET AL.
250 mL water) increased cholesterol and triacylglycerol;
this effect was not observed with natural honey collected in
the U.A.E.
53
In this regard, daily consumption of 75 g honey
for 15 days decreased total cholesterol (8%), LDL-C (11%),
and CRP (75%) in normal and hyperlipidemic subjects.
Natural honey decreased total cholesterol and LDL-C in
healthy and hyperlipidemic subjects while artificial honey
increased lipids because of the presence of fructose. It was
proposed that the difference between the effects of artificial
and natural honeys on lipids might be due to the presence
of certain substances in natural honey that are able to re-
duce blood lipids in healthy and hyperlipidemic subjects.
51
Fructose potentiates postprandial lipidemia in both diabetic
and nondiabetic subjects and very high intake of sucrose or
fructose increased fasting triacylglycerol.
114,115
In patients with hypercholesterolemia, the formation
of the F2-isoprostane 8-epi-PGF2ais enhanced, which is
suppressed by vitamin E supplementation.
116
It has been
reported that high doses of B complex vitamin may be useful
in lowering blood cholesterol and triacylglycerole levels.
Vitamin E reduces atherosclerosis plaque, coronary ar-
tery diseases, and myocardial infarction.
117
Many studies
showed that ascorbic acid deficiency involved in the de-
velopment of hypercholesterolemia and atherosclerosis.
118
Antioxidants can modulate the activity and/or the protein
levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase
(the rate-limiting enzyme of cholesterol biosynthetic path-
way).
119
Polyphenols derived from tea were shown to have
antioxidative, antithrombogenic, anti-inflammatory, hypo-
tensive, and hypocholesterolemic properties.
120
Further,
polyphenols have vasodilating effects, and they can improve
the lipid profile and lessen the oxidation of LDL.
121
The
effects of honey on lipid profile might be related to NO, an-
tioxidants, vitamin E, prostaglandins, and antioxidant prop-
erties.
116–123
However, the exact mechanisms through which
honey exerts its effect on lipid values are not well identified.
Honey and blood pressure
It is well known that HTN is one of the major risk factors
for cardiovascular and renal diseases. Most of patients fail to
maintain goal blood pressure despite using various antihy-
pertensive modalities.
Administration of Malaysian tualang honey for 3 weeks
in streptozitocine-induced diabetic spontaneously hyperten-
sive rats resulted in reduction in systolic blood pressure.
124
This effect was mediated via amelioration of oxidative stress
in the kidney.
125
The authors found that systolic and dia-
stolic blood pressure was reduced by honey inhalation in
hypertensive patients; significant changes were obtained at
60 and 120 min after inhalation.
14
Oxidative stress and free radicals are involved in the
pathogenesis and/or maintenance of elevated blood pressure
in HTN.
126–129
In addition, there is strong evidence of a
close relationship between NO deficiency and development
of HTN.
130
Further, chronic NO inhibition with L-nitro-ar-
ginine methyl ester, an antagonist for L-arginine, causes
salt-sensitive HTN and the development of renal injury.
131
Therefore, honey might mitigate HTN by its antioxidant
constituents and its ability to increase NO. Further studies
are needed to explore the exact mechanism of action.
Honey and CRP
CRP is an acute phase protein that is produced by hepa-
tocytes in response to inflammatory cytokines in the body.
CRP serves as a biomarker of CVD risk and inflammation.
Increased levels of CRP are correlated with cardiac risk
factors such as type 2 diabetes mellitus, obesity, and
smoking.
132,133
CRP functions as a pro-atherosclerotic
factor too.
134
In the previous study, oral ingestion of honey
reduced CRP.
53
Further, daily ingestion of 70 g of natural
honey caused 3.2% reduction in CRP in subjects with nor-
mal values and in patients with elevated variables in obese
and overweight individuals.
52
However, in the United
States, a study conducted in rats showed that there were no
significant differences in CRP in rats fed honey or diets of
equal energy densities.
113
It has been shown that antioxidants and vitamin E reduce
the concentration of CRP.
135,136
An increased intake of
foods rich in polyphenolic compounds is inversely associ-
ated with CRP concentrations.
132,133,137–138
Honey contains
many antioxidants. Therefore, honey might reduce CRP by
its antioxidant properties.
Honey and NO
NO is a gaseous signaling molecule, which plays an im-
portant role in a variety of human biological processes. It is
synthesized by NO synthase; neuronal, inducible and en-
dothelial. NO plays an important role in vasodilation via the
relaxation of vascular smooth muscle, in increasing circu-
lation in the body and in the protection against the onset and
progression of CVD. The cardioprotective roles of NO in-
clude regulation of blood pressure and vascular tone,
vasodilatation, prevention of smooth muscle cell prolifera-
tion, inhibition of platelet aggregation, and leukocyte acti-
vation.
139–141
Patients with atherosclerosis, DM, or HTN
show impaired NO pathways.
142
We have found that honey contains NO end products.
37
In addition, honey increases NO end products in various
biological fluids such as urine, saliva, and plasma.
38
In-
travenous honey increased NO end product in plasma and
urine.
38
Tualang honey inhibited UVB-induced inflammatory
cytokines and inducible NO synthase protein expression.
Intravenous honey reduced cytokine (tumor necrosis
factor-a, and interleukins 1band 10) and NO levels
and increased heme oxygenase-1 levels in rats with LPS-
induced endotoxemia.
143
In inflammatory processes, it was found that honey in-
hibits NO and prostaglandins.
143–146
In this situation, honey
might inhibit inducible harmful NO. Inhibition of inducible
nitric oxide synthase (iNOS) activity produces a marked
anti-inflammatory effect in acute and chronic inflamma-
tion.
147
Further, the anti-inflammatory effect of honey might
be due to the presence of polyphenolic compounds.
148,149
HONEY AND CARDIOVASCULAR RISK FACTORS 1069
Polyphenolic compounds have potent antioxidative activi-
ties that might scavenge iNO.
150
In this regard, it has been demonstrated that many plant
polyphenolic compounds could modulate NO levels and/or
actions.
151,152
Therefore, honey could prevent or ameliorate
CVD with upregulation of NO. More studies are required to
explore this important field.
Honey and prostaglandins
It is well documented that prostaglandins are mediators of
inflammation and pain. Prostaglandins reduce immunity and
play a critical role in cancer development.
153,154
The main vasoactive factors released by endothelial
cells are NO and prostaglandins.
155,156
PGI2 and PGD2
are vasodilators, whereas PGH2, PGF2a, and thromboxane
A2 are vasoconstrictors and platelet aggregation indu-
cers.
157–159
PGE2 can induce vasodilation or vasocon-
striction.
160,161
Interaction between PGF2aand its receptor
triggers potent vasoconstriction.
162,163
PGF2apromotes
cardiac hypertrophy.
164
Studies have shown that serum
levels of 8-iso-PGF2-aincreased in obesity, DM, arthritis,
and CVD.
165,166
Thromboxane A2 elicits platelet aggre-
gation and vascular smooth muscle contraction.
167
The
production of thromboxane A2 is increased in patients with
unstable angina, infarction, cerebral vasospasm, and
pregnancy-induced HTN.
168,169
Gelam honey was also shown to depress production of
PGE2 and NO on exudates of rat’s paw induced with car-
rageenan and lipopolysaccharide.
145
It was found that tua-
lang honey inhibited UVB-induced COX-2 expression and
PGE2 production.
146
The authors have reported for the first time that oral honey
could reduce plasma and urinary PGE2, PGF2-a, and
thromboxane B2.
75
Its inhibitory effect was increased with
time. The site of actions could be either at COX-1 or
COX-2, or both. In addition, it was found that artificial
honey made of glucose and fructose, increased prostaglan-
din concentrations.
170
Hydrogen peroxide induces PGE2 production by forming
ROS that oxidizes phospholipids in the membrane.
171
Gelam and Nenas monofloral honeys showed significant
anti-inflammatory effects on inflammation induced-HT29
cells by decreasing the level of PGE2 of cells as effective
as indomethacin.
172
Polyphenols can reduce serum 8-Iso
PGF2a.
173
Therefore, natural honey might contain raw ma-
terials that are capable of inhibiting prostaglandin synthe-
sis.
75
Obviously, it appears that honey has anti-inflammatory
properties that make it a suitable nutrient to be used in acute
or chronic inflammatory conditions.
75
Honey and homocysteine
Homocysteine, an amino acid that is produced in the
human body, impairs the generation and decreases bio-
availability of NO. Individuals with lower homocysteine
have lower rate of CVD.
174
Homocysteine is an important
risk factor for cancer and CVD and increases in its con-
centrations are associated with an increased risk for ne-
phropathy and proliferative retinopathy.
175,176
Honey
decreases homocysteine level by 8% in normal subjects after
15 days of consumption. Vitamin C protects LDL-C from
homocysteine-mediated oxidation.
177
In healthy and dia-
betic subjects homocysteine inhibited platelet NO produc-
tion.
178
We found that honey increased the NO
concentration and antioxidant levels in humans.
24,37,38,75,174
This might explain, in part, the hypohomocysteinemic ef-
fects of honey.
Honey and obesity
Obesity is a global epidemic.
179
It is associated with
CVD, type 2 DM, HTN, cancer, and sleep apnea. Obesity
is an independent risk factor for CVD.
180
Abnormal endo-
thelial function as a results of decreased NO is found in
obesity.
181
HTN is more common in obese than in lean in-
dividuals.
182
A strong correlation was demonstrated be-
tween obesity and IL-6 and CRP levels. In general, obesity
is a low-grade systemic inflammation. Diet modulation,
physical activity, pharmacotherapy, and surgery are re-
commended as part of the management of obesity.
183
Weight
loss improves or prevents many of the obesity-related risk
factors for CVD.
183
In the United States, a study conducted in rats showed that
honey lowered serum concentrations of leptin and reduced
weight gain and adiposity compared with diets of equal
energy densities.
112
In New Zealand, a study was conducted
in rats to determine whether 10% honey and 7.9% sucrose
would have differential effects on weight gain during 52
weeks feeding. Overall weight gain and body fat levels were
significantly higher in sucrose-fed rats than those fed honey
or a sugar-free diet.
60
In New Zealand, despite a similar food
intake, the percentage weight gain was significantly lower in
honey-fed rats than those fed sucrose or mixed sugars.
184
In the University of Wyoming, Laramie, a double-blind,
randomly assigned study evaluated whether the meal-
induced responses of ghrelin and peptide YY (3–36) and/or
meal-induced thermogenesis differ following a honey-
versus a sucrose-containing meal. It was found that honey
delayed the postprandial ghrelin response, enhanced the
total peptide YY response, and blunted the glucose response
compared with consumption of the sucrose-containing
meal.
185
In Iran, daily ingestion of 70 g of natural honey
caused reduction in body weight (1.3%), body fat (1.1%) in
overweight and obese individuals.
52
Honey does not cause a significant reduction in PGL 3 h
after consumption compared with sucrose or D-glucose.
51,53
This might reduce hunger and food intake.
Antioxidative agents
In animal models and clinical studies, DM, hypercho-
lesterolemia, or HTN are associated with increased vascular
free radicals generation.
186–190
CVD is a disease of oxidative
damage and inflammation, which results in elevation of
proinflammatory mediators and low NO bioavailability.
Increased free radicals cause a functional inactivation NO
due to the reaction with superoxide anion. A cross-sectional
1070 AL-WAILI ET AL.
study performed on 71 patients clinically diagnosed with
CVD showed a significant reduction in antioxidant status
(enzymatic and nonenzymatic) with a concomitant increase
in the concentrations of lipid peroxidation products.
191
Polyphenols and flavonoids inhibit LDL oxidation and
platelet aggregation; reduce atherosclerotic lesion formation;
reduce blood pressure; improve endothelial function; and de-
crease vascular cell adhesion molecule expression, iNO gen-
eration, and inflammatory responses.
192–204
Flavonoid intake
reduces risk of CVD.
205
Flavonoids have antithrombotic, anti-
ischemic, antioxidant, and vasorelaxant properties.
206
They
are scavengers of superoxide anions, singlet oxygen, and
lipid peroxy-radicals and they prevent LDL-C oxida-
tion.
190,207,208
The beneficial effect of polyphenols on CVD is
attributed to modulation of NO bioavailability to the endo-
thelium.
209,210
b-carotenoids have anti-inflammatory activity in the vascu-
lature and this might explain the protective effects of carotenoid-
rich diets against CVD risk.
211
b-carotene affect endothelial
response to TNF-aand reduce nitro-oxidative stress.
211
Improvement of endothelial function and the antihyperten-
sive effects of quercetin might be mediated by enhanced eNOS
activity and decreased NADPH oxidase-mediated superoxide
anion generation associated with reduced p47 expression.
212
Various types of honey contain many antioxidants and
antioxidant enzymes including vitamins E and C, ascorbic
acid, phenolic acids, flavonoids, carotenoid derivatives,
organic acids, Maillard reaction products, glucose oxidase,
catalase, and glutathione perioxidase.
213–216
The polyphenols in honey are caffeic acid, caffeic acid
phenyl ester, chrysin, galangin, quercetin, acacetin, kaemp-
ferol, pinocembrin, pinobanksin, and apigenin.
217
Natural
honey protects normal rats from the incidence of epinephrine-
induced cardiac disorders and vasomotor dysfunction.
218
The beneficial effect of honey on CVD might be attrib-
uted to its antioxidative and anti-inflammatory properties,
increment of NO production, and improvement of blood
sugar and blood pressure (Table 4).
24,37,38,51,53,68–71,73–76,78–
83,98–107,110,124–133,135–139,177,178,184
CONCLUSION
Natural honey has many biological activities besides its
antimicrobial activity (Figure 1). Honey ingestion increases
blood vitamin C level, b-carotene, uric acid, glutathione
reductase, copper, zinc, NO end products, and decreases
PGL, CRP, homocysteine, and plasma prostaglandin E2,
F2-a, and thromboxane B2 concentrations. Moreover, honey
Table 4. Effects of Honey on Common Cardiovascular Risk Factors
Variables Effect of honey Possible mechanism of action
Blood sugar Reduces blood sugar in normal indi-
viduals and in patients with diabetes
Flavonoids and antioxidants
68–71
Increases copper and zinc
73,74
Inhibition of prostaglandin
75,76
Elevation of NO
37,38
Glycemic carbohydrates
78,79
Hydrogen peroxide
80
Oligosaccharides
81–83
Fructose
98–107
HTN Lowers blood pressure Antioxidant constituents and increment of NO
24,110
Lipid profile Decreases total cholesterol, LDL-cho-
lesterol, and triacylglycerol, and in-
creases HDL-cholesterol in healthy
and hyperlipidemic subjects
Antioxidants, polyphenols, and vitamin content, elevation
of NO, and suppression of prostaglandins
124–131
CRP Decreases CRP Antioxidants, polyphenols, and vitamin E content
132,133,135–139
Homocysteine Decreases homocysteine Vitamin C content
177
NO production
178
Body weight Decreases body weight in normal,
overweight and obese individuals
Honey delays the postprandial ghrelin response, enhances the
total PYY response, and blunts the glucose response
184
Honey reduces hunger and food intake
51,53
CRP, C-reactive protein; HDL, high-density lipoprotein; HTN, hypertension; LDL, low-density lipoprotein; PYY, peptide YY.
FIG. 1. Biological effects of honey on blood glucose, lipids and
inflammatory markers.
HONEY AND CARDIOVASCULAR RISK FACTORS 1071
improves lipid profiles and modulates C-peptide and insulin
secretion. Honey has powerful antioxidative activity and its
ingestion increases antioxidative materials. Honey appears
to have many effects on various metabolic parameters. Its
contents and effects on metabolic parameters might result in
beneficial effects seen in patients with DM, HTN, and CVD.
From studies reviews, honey appears to be a powerful nat-
ural biological syrup that may be recommended to be used in
healthy individuals, and in patients with DM, HTN, and CVD.
ACKNOWLEDGMENT
The authors are thankful to National Plan for Science and
Technology (NPST) program of King Saud University,
Project No. 11-AGR1748-02 for financial support.
AUTHOR DISCLOSURE STATEMENT
The authors declared that there is no conflict of interest
regarding the publication of this article.
REFERENCES
1. WHO: Cardiovascular diseases (CVDs). www.who.int/mediacentre/
factsheets/fs317/en/index.html (accessed March 2013).
2. Al-Waili N, Salom K: Effects of topical honey on post-operative
wound infections due to gram positive and gram negative bac-
teria following caesarean sections and hysterectomies. Eur J Med
Res 1999;4:126–130.
3. Al-Waili NS, Salom K, Butler G, Al Ghamdi AA: Honey and
microbial infections: a review supporting the use of honey for
microbial control. J Med Food 2011;14:1079–1096.
4. Al-Waili N, Salom K, Al-Ghamdi A: Honey for wound healing,
ulcers, and burns; data supporting its use in clinical practice.
ScientificWorldJournal 2011;11:766–787.
5. Othman N: Honey and cancer: sustainable inverse relationship
particularly for developing nations-a review. Evid Based
Complement Alternat Med 2012;2012:41040.
6. Parmar J, Hunjan P, Brown A, Telfer M: Honey dressing use for
the management of split thickness skin graft donor sites: a
technical note. Br J Oral Maxillofac Surg 2013;1:e40–e41.
7. Erejuwa O, Sulaiman SA, Wahab MS: Hepatoprotective effect
of tualang honey supplementation in streptozotocin-induced
diabetic rats. Int J Appl Res Nat Prod 2012;4:37–41.
8. Erejuwa O, Gurtu S, Sulaiman SA: Hypoglycemic and antiox-
idant effects of honey supplementation in streptozotocin-induced
diabetic rats. Int J Vitam Nutr Res 2010;80:74–82.
9. Erejuwa O, Sulaiman SA, Wahab MS: Antioxidant protective
effect of glibenclamide and metformin in combination with
honey in pancreas of streptozotocin-induced diabetic rats. Int J
Mol Sci 2010;11:2056–2066.
10. Erejuwa O, Sulaiman SA, Wahab MS: Comparison of antioxi-
dant effects of honey, glibenclamide, metformin, and their
combinations in the kidneys of streptozotocin-induced diabetic
rats. Int J Mol Sci 2011;12:829–843.
11. Erejuwa O, Sulaiman SA, Wahab MS: Antioxidant protection of
Malaysian tualang honey in pancreas of normal and streptozotocin-
induced diabetic rats. Ann Endocrinol (Paris) 2010;71:291–296.
12. Beretta G, Orioli M, Facino RM: Antioxidant and radical
scavenging activity of honey in endothelial cell cultures
(EA.hy926). Planta Med 2007;73:1182–1189.
13. Beretta G, Granata P, Ferrero M: Standardization of antioxidant
properties of honey by a combination of spectrophotometric/
fluorimetric assays and chemometrics. Anal Chim Acta 2005;
533:185–191.
14. Al-Waili N: Intrapulmonary administration of natural honey
solution, hyperosmolar dextrose or hypoosmolar distill water to
normal individuals and to patients with type-2 diabetes mellitus
or hypertension: their effects on blood glucose level, plasma
insulin and C-peptide, blood pressure and peaked expiratory
flow rate. Eur J Med Res 2003;8:295–303.
15. AL-Waili N, Al-Ghamdi A, Ansari M, Al-Attal Y, Salom K:
Synergistic effects of honey and propolis toward drug multi-
resistant Staphylococcus aureus, Escherichia coli and Candida
albicans isolates in single and polymicrobial cultures. Int J Med
Res 2012;9:793–800.
16. Khalil MI, Sulaiman SA: The potential role of honey and its
polyphenols in preventing heart diseases: a review. Afr J Tradit
Complement Altern Med 2010;7:315–321.
17. Buldini L, Cavalli S, Mevoli A, Sharma J: Ion chromatographic
and voltammetric determination of heavy and transition metals
in honey. Food Chem 2001;73:487–495.
18. Mun
˜oz E, Palmero S: Determination of heavy metals in honey
by potentiometric stripping analysis and using a continuous flow
methodology. Food Chem 2006;94:478–483.
19. Ouchemoukh S, Louaileche H, Schweizer P: Physicochemical
characteristics and pollen spectrum of some Algerian honeys.
Food Control 2007;18:52–58.
20. Saxena S, Gautam S, Sharma A: Physical, biochemical and
antioxidant properties of Indian honeys. Food Chem 2010;118:
391–397.
21. Bertoncelj J, Dobers
ˇek U, Jamnik M, Golob T: Evaluation of
the phenolic content, antioxidant activity, and colour of Slo-
venian honey. Food Chem 2007;105:822–828.
22. Aljadi A, Kamaruddin M: Evaluation of the phenolic contents
and antioxidant capacities of two Malaysian floral honeys. Food
Chem 2004;85:513–518.
23. Islam A, Islam N, Moniruzzaman M: Physicochemical and
antioxidant properties of Bangladeshi honeys stored for more
than one year. BMC Complement Altern Med 2012;12:177.
24. Anklam E: A review of the analytical methods to determine the
geographical and botanical origin of honey. Food Chem 1998;
63:549–562.
25. Al-Waili NS: Effects of daily consumption of honey solution on
hematological indices and blood levels of minerals and enzymes
in normal individuals. J Med Food 2003;6:135–140.
26. Ensminger A, Ensminger M, Konlande J, Robson J: Food and
Nutrition Encyclopedia. Pegus Press, Clovis, CA, USA, 1983.
27. Bogdanov S, Jurendic T, Sieber R, Gallmann P: Honey for
nutrition and health: a review. J Am Coll Nutr 2008;27:677–689.
28. Riethop M, Subers M, Kushnir I: Composition of American
Honeys. U.S. Department of Agriculture Technical Bulletin
1261, Washington, DC, 1962; p. 124.
29. Baroni V, Chiabrando A, Costa C, Fagundez A, Wunderlin A: De-
velopment of a competitive ELISA for the evaluation of sunflower
pollen in honey samples. J Agric Food Chem 2004;52:7222–7226.
30. White J, Doner L: Honey Composition and properties.
www.beesource.com/resources/usda/honey-composition-and
-properties (accessed October 2013).
31. Nagai T, Inoue R, Kanamori N, Suzuki N, Nagashima T:
Characterization of honey from different floral sources. Its
1072 AL-WAILI ET AL.
functional properties and effects of honey species on storage of
meat. Food Chem 2006;97:256–262.
32. Baroni V, Nores L, Dı
´az P, Chiabrando A, Fassano P, Costa C,
Wunderlin A: Determination of volatile organic compound
patterns characteristic of five unifloral honey by solid-phase
microextraction-gas chromatography-mass spectrometry cou-
pled to chemometrics. J Agric Food Chem 2006;54:7235–7241.
33. Baroni V, Chiabrando A, Costa C, Wunderlin A: Assessment of
the floral origin of honey by SDS–PAGE immunoblot tech-
niques. J Agric Food Chem 2002;50:1362–1367.
34. Al-Mamary M, Al-Meeri A, Al-Habori M: Antioxidant activi-
ties and total phenolics of different types of honey. Nutr Res
2002;22:1041–1047.
35. Gheldof N, Engeseth NJ: Antioxidant capacity of honeys from
various floral sources based on the determination of oxygen
radical absorbance capacity and inhibition of in vitro lipoprotein
oxidation in human serum samples. J Agric Food Chem 2002;
50:3050–3055.
36. Toma
´s-Barbera
´n A, Martos I, Ferreres F, Radovic S, Anklam E:
HPLC flavonoid profiles as markers for the botanical origin of
European unifloral honeys. J Sci Food Agric 2001;81:485–496.
37. Al-Waili NS, Boni NS: Honey increased saliva, plasma, and
urine content of total nitrite concentrations in normal individ-
uals. J Med Food 2004;7:377–380.
38. Al-Waili NS: Identification of nitric oxide metabolites in vari-
ous honeys: effects of intravenous honey on plasma and urinary
nitric oxide metabolites concentrations. J Med Food 2003;6:
359–364.
39. Nozal J, Bernal L, Toribio L, Alamo M, Diego C, Tapia J: The
use of carbohydrate profiles and chemometrics in the charac-
terization of natural honeys of identical geographical origin.
J Agric Food Chem 2005;53:3095–3100.
40. Ferna
´ndez-Torres R, Pe
´rez-Bernal L, Bello-Lo
´pez A, Callejo
´n-
Mocho
´n M, Jime
´nez-Sa
´nchez C, Guirau
´m-Pe
´rez A: Mineral
content and botanical origin of Spanish honeys. Talanta 2005;
65:686–691.
41. Ruoff K, Luginbuhl W, Kunzli R, Bogdanov S, Bosset O, Von
Der Ohe K, Von Der Ohe W, Amado R: Authentication of the
botanical and geographical origin of honey by front-face
fluorescence spectroscopy. J Agric Food Chem 2006;54:
6858–6866.
42. Beretta G, Gelmini F, Lodi V, Piazzalunga A, Maffei Facino R:
Profile of nitric oxide (NO) metabolites (nitrate, nitrite and N-
nitroso groups) in honeys of different botanical origins: nitrate
accumulation as index of origin, quality and of therapeutic
opportunities. J Pharm Biomed Anal 2010;53:343–349.
43. Bogdanov S: Honey quality, methods of analysis, and interna-
tional regulatory standards: review of the work of the inter-
national honey commission. Mitt Gebiete Lebensm Hyg 1999;
90:108–125.
44. Korta E, Bakkali A, Berrueta A, Gallo B, Vicente F: Study of an
accelerated solvent extraction procedure for the determination
of acaricide residues in honey by high-performance liquid
chromatography-diode array detector. J Food Prot 2002;65:
161–166.
45. Grembecka M, Szefer P: Evaluation of honeys and bee products
quality based on their mineral composition using multivariate
techniques. Environ Monit Assess 2013;185:4033–4047.
46. Robert S, Ismail A: Two varieties of honey that are available in
Malaysia gave intermediate glycemic index values when tested
among healthy individuals Biomed Pap. Med Fac Univ Palacky
Olomouc Czech Repub 2009;153:145–147.
47. Deibert P, Ko
¨nig D, Kloock B, Groenefeld M, Berg A: Gly-
caemic and insulinaemic properties of some German honey
varieties. Eur J Clin Nutr 2010;64:762–764.
48. Mu
¨nstedt K, Sheybani B, Hauenschild A, Bru
¨ggmann D, Bretzel
RG, Winter D: Effects of basswood honey, honey-comparable
glucose-fructose solution, and oral glucose tolerance test solution
on serum insulin, glucose, and C-peptide concentrations in
healthy subjects. JMedFood2008;11:424–428.
49. Ischayek JI, Kern M: US honeys varying in glucose and fructose
content elicit similar glycemic indexes. J Am Diet Assoc
2006;106:1260–1262.
50. Shambaugh P, Worthington V, Herbert J: Differential effects of
honey, sucrose, and fructose on blood sugar levels. J Manip-
ulative Physiol Ther 1990;13:322–325.
51. Ahmad A, Azim M, Mesaik M, Khan R: Natural honey
modulates physiological glycemic response compared to
simulated honey and D-glucose. JFoodSci2008;73:H165–
H167.
52. Yaghoobi N, Al-Waili N, Ghayour-Mobarhan M, Parizadeh S,
Abasalti Z, Yaghoobi Z, Yaghoobi F, Esmaeili H, Kazemi-
Bajestani S, Aghasizadeh R, Saloom K, Ferns G: Natural honey
and cardiovascular risk factors; effects on blood glucose, cho-
lesterol, triacylglycerole, CRP, and body weight compared with
sucrose. ScientificWorldJournal 2008;8:463–469.
53. Al-Waili N: Natural honey lowers plasma glucose, C-reactive
protein, homocysteine, and blood lipids in healthy, diabetic, and
hyperlipidemic subjects: comparison with dextrose and sucrose.
J Med Food 2004;7:100–107.
54. Al-Waili NS, Saloom KY, Akmal M, Al-Waili F, Al-Waili TN,
Al-Waili AN, Ali A: Honey ameliorates influence of hemor-
rhage and food restriction on renal and hepatic functions, and
hematological and biochemical variables. Int J Food Sci Nutr
2006;57:353–362.
55. Al-Waili NS, Salom KY, Al-Waili TN, Al-Waili AN, Akmal M,
Al-Waili FS, Al-Waili HN: Influence of various diet regimens
on deterioration of hepatic function and hematological param-
eters following carbon tetrachloride: a potential protective role
of natural honey. Nat Prod Res 2006;20:1258–1264.
56. Al-Waili NS: Intravenous and intrapulmonary administration of
honey solution to healthy sheep: effects on blood sugar, renal
and liver function tests, bone marrow function, lipid profile, and
carbon tetrachloride-induced liver injury. J Med Food 2003;6:
231–247.
57. Samanta A, Burden AC, Jones GR: Plasma glucose responses to
glucose, sucrose, and honey in patients with diabetes mellitus:
an analysis of glycaemic and peak incremental indices. Diabet
Med 1985;2:371–373.
58. Erejuwa O, Sulaiman SA, Wahab MS, Sirajudeen KN, Salleh
MS, Gurtu S: Glibenclamide or metformin combined with
honey improves glycemic control in streptozotocin-induced
diabetic rats. Int J Biol Sci 2011;7:244–252.
59. Akhtar MS, Khan MS: Glycaemic responses to three different
honeys given to normal and alloxan-diabetic rabbits. J Pak Med
Assoc 1989;39:107–113.
60. Chepulis L, Starkey N: The long-term effects of feeding honey
compared with sucrose and a sugar-free diet on weight gain,
lipid profiles, and DEXA measurements in rats. J Food Sci
2008;73:H1–H7.
HONEY AND CARDIOVASCULAR RISK FACTORS 1073
61. Bornet F, Haardt M, Costagliola D, Blayo A, Slama G: Sucrose
or honey at breakfast have no additional acute hyperglicaemic
effect over an isoglucidic amount of bread in Type 2 diabetic
patients. Diabetologia 1985;28:213–217.
62. Katsilambros N, Philippides P, Touliatou A, Georgakopoulus
K, Kofotzouli L, Frangaki D, Siskoudis P, Marangos M,
Sfikakis P: Metabolic effects of honey (alone or combined
with other foods) in type II diabetics. Acta Diabetol Lat 1988;
25:197–203.
63. Agrawal OP, Pachauri A, Yadav H, Urmila J, Goswamy HM,
Chapperwal A, Bisen PS, Prasad GB: Subjects with impaired
glucose tolerance exhibit a high degree of tolerance to honey.
J Med Food 2007;10:473–872.
64. Abdulrhman M, El-Hefnawy M, Hussein R, El-Goud AA: The
glycemic and peak incremental indices of honey, sucrose and
glucose in patients with type 1 diabetes mellitus: effects on
C-peptide level-a pilot study. Acta Diabetol 2011;48:89–94.
65. Ionescu-Tı
ˆrgovisxte C, Popa E, Sı
ˆntu E, Mihalache N, ChetxaD,
Mincu I: Blood glucose and plasma insulin responses to various
carbohydrates in type 2 (non-insulin-dependent) diabetes. Dia-
betologia 1983;24:80–84.
66. Baltali M, Kokmaz M, Kiziltan H: Association between post-
prandial hyperinsulinemia and coronary artery among non-diabetic
women: a case control study. Int J Cardiol 2003;88:215–221.
67. Wang X, Andrae L, Engeseth N: Inflammatory cytokine con-
centrations are acutely increased by hyperglycemia in humans:
role of oxidative stress. Circulation 2002;15:2067–2072.
68. Lee Y, Lee S, Lee H, Kim B, Ohuchi K, Shin KH: Inhibitory
effects of isorhamnetin-3-O-beta-D-glucoside from Salicornia
herbacea on rat lens aldose reductase and sorbitol accumulation
in streptozotocin-induced diabetic rat tissues. Biol Pharm Bull
2005;28:916–918.
69. Fang X, Gao J, Zhu D: Kaempferol and quercetin isolated from
Euonymus alatus improve glucose uptake of 3T3-L1 cells
without adipogenesis activity. Life Sci 2008;82:615–622.
70. Kobori M, Masumoto S, AkimotoY, Takahashi Y: Dietary
quercetin alleviates diabetic symptoms and reduces streptozo-
tocin-induced disturbance of hepatic gene expression in mice.
Mol Nutr Food Res 2009;53:859–868.
71. Kwon O, Eck P, Chen S, Corpe C, Lee J, Kruhlak M, Levine M:
Inhibition of the intestinal glucose transporter GLUT2 by fla-
vonoids. FASEB J 2007;21:366–377.
72. Viuda-Martos M, Ruiz-Navajas Y, Ferna
´ndez- Lo
´pez J, Pe
´rez-
Alvarez J: Functional properties of honey, propolis, and royal
jelly. J Food Sci 2008;73:R117–R124.
73. Song M, Hwang I, Rosenthal M, Harris D, Yamaguchi D, Yi I,
Go V: Antidiabetic action of arachidonic acid and zinc in ge-
netically diabetic Goto-Kakizaki rats. Metabolism 2003;52:7–12.
74. Sitasawad S, Deshpande M, Katdare M, Tirth S, Parab P:
Beneficial effect of supplementation with copper sulfate on STZ-
diabetic mice (IDDM). Diabetes Res Clin Pract 2001;52:72–84.
75. Al-Waili NS, Boni NS: Natural honey lowers plasma prosta-
glandin concentrations in normal individuals. J Med Food 2003;
6:129–133.
76. Cheng H, Straub G, Sharp G: Protein acylation in the inhibition
of insulin secretion by norepinephrine, somatostatin, galanin, and
PGE2. Am J Physiol Endocrinol Metabol 2003;285:E287–E294.
77. Smukler S, Tang L, Wheeler M, Salapatek A: Exogenous nitric
oxide and endogenous glucose-stimulated b-cell nitric oxide
augment insulin release. Diabetes 2002;51:3450–3460.
78. Southgate D: Digestion and metabolism of sugars. Am J Clin
Nutr 1995;62:203S–211S.
79. Vosloo M: Some factors affecting the digestion of glycaemic
carbohydrates and the blood glucose response. J Fam Ecol
Consum Sci 2005;33:1–9.
80. Hayes G, Lockwood H: Role of insulin receptor phosphoryla-
tion in the insulinomimetic effects of hydrogen peroxide. Proc
Nat Acad Sci USA 1987;84:8115–8119.
81. Erejuwa O, Sulaiman SA, Wahab MS: Oligosaccharides might
contribute to the antidiabetic effect of honey: a review of the
literature. Molecules 2012;17:248–266.
82. Sanz ML, Gonzalez M, Lorenzo C: Carbohydrate composition
and physicochemical properties of artisanal honeys from Ma-
drid (Spain): occurrence of Echium sp. honey. J Sci Food Agric
2004;84:1577–1584.
83. Munstedt K, Bohme M, Hauenschild A: Consumption of rapeseed
honey leads to higher serum fructose levels compared with ana-
logue glucose/fructose solutions. Eur J Clin Nutr 2011;65:77–80.
84. Kashimura J, Nagai Y: Inhibitory effect of palatinose on glu-
cose absorption in everted rat gut. J Nutr Sci Vitaminol (Tokyo)
2007;53:87–89.
85. Lina BA, Jonker D, Kozianowski G: Isomaltulose (Palatinose):
a review of biological and toxicological studies. Food Chem
Toxicol 2002;40:1375–1381.
86. Cani PD, Neyrinck AM, Fava F: Selective increases of bifido-
bacteria in gut microflora improve high-fat-diet-induced dia-
betes in mice through a mechanism associated with
endotoxaemia. Diabetologia 2007;50:2374–2383.
87. Wei Y, Bizeau M, Pagliassotti MJ: An acute increase in fructose
concentration increases hepatic glucose-6-phosphatase mRNA
via mechanisms that are independent of glycogen synthase ki-
nase-3 in rats. J Nutr 2004;134:545–551.
88. Gabriely H, Hawkins M, Vilcu C: Fructose amplifies counter-
regulatory responses to hypoglycemia in humans. Diabetes
2002;51:893–900.
89. Watford M: Small amounts of dietary fructose dramatically
increase hepatic glucose uptake. Nutr Rev 2002;60:253–257.
90. Martinez F, Rizza R, Romero J: High fructose feeding elicit
insulin resistance, hypertension and hyperinsulinemia in normal
dogs. Hypertension 1994;23:456–463.
91. Meirelles CJ, Oliveira LA, Jordao AA: Metabolic effects of the
ingestion of different fructose sources in rats. Exp Clin En-
docrinol Diabetes 2011;119:218–220.
92. Malik V, Schulze M, Hu F: Intake of sugar-sweetened bever-
ages and weight gain: a systematic review. Am J Clin Nutr
2006;84:274–288.
93. Huynh M, Luiken JJ, Coumans W: Dietary fructose during the
suckling period increases body weight and fatty acid uptake into
skeletal muscle in adult rats. Obesity (Silver Spring) 2008;16:
1755–1762.
94. Bocarsly ME, Powell ES, Avena NM: High-fructose corn syrup
causes characteristics of obesity in rats: increased body weight,
body fat and triglyceride levels. Pharmacol Biochem Behav
2010;97:101–106.
95. Gheldof N, Wang XH, Engeseth NJ: Identification and quanti-
fication of antioxidant components of honeys from various floral
sources. J Agric Food Chem 2002;50:5870–5877.
96. Tay A, Ozcelikay A, Altan V: Effects of L-arginine on blood
pressure and metabolic changes in fructose-hypertensive rats.
Am J Hypertens 2002;15:72–77.
1074 AL-WAILI ET AL.
97. Elliott S, Keim N, Stern J: Fructose, weight gain and the insulin
resistance syndrome. Am J Clin Nutr 2002;76:911–922.
98. Vaisman N, Niv E, Izkhakov Y: Catalytic amounts of fructose
may improve glucose tolerance in subjects with uncontrolled
non-insulin-dependent diabetes. Clin Nutr 2006;25:617–621.
99. Stanhope K, Griffen S, Bremer A: Metabolic responses to
prolonged consumption of glucose- and fructose-sweetened
beverages are not associated with postprandial or 24-h glucose
and insulin excursions. Am J Clin Nutr 2011;94:112–119.
100. Kwon S, Kim YJ, Kim MK: Effect of fructose or sucrose
feeding with different levels on oral glucose tolerance test in
normal and type 2 diabetic rats. Nutr Res Pract 2008;
2:252–258.
101. Moran TH, McHugh PR: Distinctions among three sugars in
their effects on gastric emptying and satiety. Am J Physiol
1981;241:R25–R30.
102. Kellett GL, Brot-Laroche E, Mace OJ: Sugar absorption in the
intestine: the role of GLUT2. Annu Rev Nutr 2008;28:35–54.
103. Thibault L: Dietary carbohydrates: effects on self-selection,
plasma glucose and insulin, and brain indoleaminergic systems
in rat. Appetite 1994;23:275–286.
104. Madero M, Arriaga JC, Jalal D: The effect of two energy-
restricted diets, a low-fructose diet versus a moderate natural
fructose diet, on weight loss and metabolic syndrome parame-
ters: a randomized controlled trial. Metabolism 2011;60:1551–
1559.
105. Van Schaftingen E, Davies DR: Fructose administration stim-
ulates glucose phosphorylation in the livers of anesthetized rats.
FASEB J 1991;5:326–330.
106. Youn JH, Kaslow HR, Bergman RN: Fructose effect to suppress
hepatic glycogen degradation. J Biol Chem 1987;262:11470–
11477.
107. Ciudad CJ, Carabaza A, Guinovart JJ: Glycogen synthesis from
glucose and fructose in hepatocytes from diabetic rats. Arch
Biochem Biophys 1988;267:437–447.
108. Riby JE, Fujisawa T, Kretchmer N: Fructose absorption. Am J
Clin Nutr 1993;58:748S–753S.
109. Ushijima K, Riby JE, Fujisawa T: Absorption of fructose by
isolated small intestine of rats is via a specific saturable carrier
in the absence of glucose and by the disaccharidase-related
transport system in the presence of glucose. J Nutr 1995;125:
2156–2164.
110. Bahrami M, Ataie-Jafari A, Hosseini S, Foruzanfar MH, Rah-
mani M, Pajouhi M: Effects of natural honey consumption in
diabetic patients: an 8-week randomized clinical trial. Int J
Food Sci Nutr 2009;60:618–626.
111. Mu
¨nstedt K, Hoffmann S, Hauenschild A, Bu
¨lte M, von Georgi
R, Hackethal A: Effect of honey on serum cholesterol and lipid
values. J Med Food 2009;12:624–628.
112. Nemoseck TM, Carmody EG, Furchner-Evanson A, Gleason M,
Li A, Potter H, Rezende LM, Lane KJ, Kern M: Honey pro-
motes lower weight gain, adiposity, and triglycerides than su-
crose in rats. Nutr Res 2011;31:55–60.
113. Alagwu EA, Okwara JE, Nneli RO, Osim EE: Effect of honey
intake on serum cholesterol, triglycerides and lipoprotein levels
in albino rats and potential benefits on risks of coronary heart
disease. Niger J Physiol Sci 2011;26:161–165.
114. Abraha A, Humphreys S, Clark M: Acute effect of fructose on
postprandial lipaemia in diabetic and non-diabetic subjects. Br J
Nutr 1998;80:169–175.
115. Truswell A: Food carbohydrates and plasma lipids—an update.
Am J Clin Nutr 1994;59(Suppl):710S–718S.
116. Davi G, Alessandrini P, Mezzetti A, Minotti G, Bucciarelli T,
Costantini F, Cipollone F, Bon GB, Ciabattoni G, Patrono C: In
vivo formation of 8-Epi-prostaglandin F2 alpha is increased in
hypercholesterolemia. Arterioscler Thromb Vasc Biol 1997;17:
3230–3235.
117. Saggini A, Anogeianaki A, Angelucci D, Cianchetti E,
D’Alessandro M, Maccauro G, Salini V, Caraffa A, Tete
´S,
Conti F, Tripodi D, Fulcheri M, Frydas S, Shaik-Dasthagir-
isaheb YB: Cholesterol and vitamins: revisited study. J Biol
Regul Homeost Agents 2011;25:505–515.
118. Trapani L, Segatto M, Incerpi S, Pallottini V: 3-Hydroxy-3-
methylglutaryl coenzyme A reductase regulation by antioxidant
compounds: new therapeutic tools for hypercholesterolemia?
Curr Mol Med 2011;11:790–797.
119. Yung LM, Leung FP, Wong WT, Tian XY, Yung LH, Chen ZY,
Yao XQ, Huang Y: Tea polyphenols benefit vascular function.
Inflammopharmacology 2008;16:230–234.
120. Ginter E: Chronic vitamin C deficiency increases the risk of
cardiovascular diseases. Bratisl Lek Listy 2007;108:417–421.
121. Quin
˜ones M, Miguel M, Aleixandre A: The polyphenols, nat-
urally occurring compounds with beneficial effects on cardio-
vascular disease. Nutr Hosp 2012;27:76–89.
122. Stapleton PA, Goodwill AG, James ME, Brock RW, Frisbee JC:
Hypercholesterolemia and microvascular dysfunction: inter-
ventional strategies. J Inflamm (Lond) 2010;7:54.
123. Palombo C, Lubrano V, Sampietro T: Oxidative stress, F2-
isoprostanes and endothelial dysfunction in hypercholester-
olemia. Cardiovasc Res 1999;44:474–476.
124. Erejuwa O, Sulaiman SA, Wahab MSA, Sirajudeen KNS,
Salleh MSM, Gurtu S: Differential responses to blood pressure
and oxidative stress in streptozotocin-induced diabetic Wistar-
Kyoto rats and spontaneously hypertensive rats: effects of
antioxidant (honey) treatment. Int J Mol Sci 2011;12:1888–
1907.
125. Erejuwa O, Sulaiman S, Ab Wahab M, Sirajudeen K, Salleh S,
Gurtu S: Honey supplementation in spontaneously hyperten-
sive rats elicits antihypertensive effect via amelioration of
renal oxidative stress. Oxid Med Cell Longev 2012;2012:
374037.
126. Rodrigo R, Gonza
´lez J, Paoletto F: The role of oxidative stress
in the pathophysiology of hypertension. Hypertens Res 2011;
34:431–440.
127. Ostrow K, Wu S, Aguilar A, Bonner R, Suarez E, De Luca F:
Association between oxidative stress and masked hypertension
in a multi-ethnic population of obese children and adolescents. J
Pediatr 2010;158:628–633.
128. Hirooka Y: Oxidative stress in the cardiovascular center has a
pivotal role in the sympathetic activation in hypertension. Hy-
pertens Res 2011;34:407–412.
129. Banday A, Lokhandwala M: Oxidative stress causes renal an-
giotensin II Type 1 receptor upregulation, Na+/H +exchanger
3 overstimulation, and hypertension. Hypertension 2011;57:
452–459.
130. Carlstro
¨m M, Brown R, Edlund J: Role of nitric oxide defi-
ciency in the development of hypertension in hydronephrotic
animals. Am J Physiol Renal Physiol 2008;294:F362–F370.
131. Zatz R, Baylis C: Chronic nitric oxide inhibition model six
years on. Hypertension 1998;32:958–964.
HONEY AND CARDIOVASCULAR RISK FACTORS 1075
132. Nanri A, Moore M, Kono S: Impact of C-reactive protein on
disease risk and its relation to dietary factors. Asian Pac J
Cancer Prev 2007;8:167.
133. Block G, Jensen C, Dietrich M, Norkus EP, Hudes M, Packer L:
Plasma C-reactive protein concentrations in active and passive
smokers: influence of antioxidant supplementation. J Am Coll
Nutr 2004;23:141–147.
134. Wang CH, Li SH, Weisel RD, Fedak PW, Dumont AS, Szmitko
P, Li RK, Mickle DA, Verma DS: C-reactive protein upregu-
lates angiotensin type 1 receptors in vascular smooth muscle.
Circulation 2003;107:1783–1790.
135. Devaraj S, Jialal I: Alpha tocopherol supplementation decreases
serum C-reactive protein and monocytes interleukin-6 levels in
normal volunteers and type 2 diabetic patients. Free Radic Biol
Med 2000;29:790–792.
136. Patrick L, Uzick M: Cardiovascular disease: C-reactive protein
and the inflammatory disease paradigm: HMG-CoA reductase
inhibitors, alpha-tocopherol, red yeast rice, and olive oil poly-
phenols. A review of the literature. Altern Med Rev 2001;6:
248–271.
137. Chun OK, Chung SJ, Claycombe KJ, Song WO: Serum C-
reactive protein concentrations are inversely associated with
dietary flavonoid intake in U.S. adults. JNutr2008;138:753–760.
138. Qureshi MM, Singer MR, Moore LL: A cross-sectional study of
food group intake and C-reactive protein among children. Nutr
Metab (Lond) 2009;6:40.
139. Naseem KM: The role of nitric oxide in cardiovascular diseases.
Mol Aspects Med 2005;26:33–65.
140. Bodzenta-Lukaszyk A, Gabryelewicz A, Lukaszyk A, Bielawiec
M, Konturek JW, Domschke W: Nitric oxide synthase inhibition
and platelet function. Thromb Res 1994;75:667–672.
141. Chen Y, Mehta J: Variable effects of L-arginine analogs on
L-arginine–nitric oxide pathway in human neutrophils and
platelets may relate to different nitric oxide synthase isoforms.
J Pharmacol Exp Ther 1996;276:253–257.
142. World Health Organization physical status: the use and inter-
pretation of anthropometry. WHO, Geneva, 1995.
143. Kassim M, Yusoff KM, Ong G, Sekaran S, Yusof MY, Mansor
M: Gelam honey inhibits lipopolysaccharide-induced en-
dotoxemia in rats through the induction of heme oxygenase-1
and the inhibition of cytokines, nitric oxide, and high-mobility
group protein B1. Fitoterapia 2012;83:1054–1059.
144. Kassim M, Achoui M, Mansor M, Yusoff KM: The inhibitory
effects of Gelam honey and its extracts on nitric oxide and pros-
taglandin E(2) in inflammatory tissues. Fitoterapia 2010;81:
1196–1201.
145. Ahmad I, Jimenez H, Yaacob NS, Yusuf N: Tualang honey
protects keratinocytes from ultraviolet radiation-induced in-
flammation and DNA damage. Photochem Photobiol 2012;88:
1198–1204.
146. Owoyele BV, Adenekan OT, Soladoye AO: Effects of honey on
inflammation and nitric oxide production in Wistar rats. Zhong
Xi Yi Jie He Xue Bao 2011;9:447–452.
147. Foyet HS, Nana P, Chounfack E, Asongalem EA, Dimo T,
Kamtchouing P: Protective effect of Acanthus montanus in
carrageenan-induced models of local inflammation: inhibitory
effect on nitric oxide (NO) production. Pharmacologyonline
2008;2:161–169.
148. Busserolles J, Gueux E, Rock E, Mazur A, Rayssiguier Y:
Substituting honey for refined carbohydrates protects rats from
hypertriglyceridemic and prooxidative effects of fructose.
J Nutr 2002;132:3379–3382.
149. Soler C, Gil MI, Garcia-Viguera C, Thomas-Barberan FA:
Flavonoid patterns of French honeys with different floral origin.
Apidologie 1995;26:53–60.
150. van Acker SA, Tromp MN, Haenen GR, van der Vijgh WJ, Bast
A: Flavonoids as scavengers of nitric oxide radical. Biochem
Biophys Res Commun 1995;214:755–759.
151. Achike FI, Kwan CY: Nitric oxide, human diseases and the
herbal products that affect the nitric oxide signalling pathway.
Clin Exp Pharmacol Physiol 2003;30:605–615.
152. de Nigris F, Balestrieri ML, Williams-Ignarro S, D’Armiento
FP, Fiorito C, Ignarro LJ, Napoli C: The influence of pome-
granate fruit extract in comparison to regular pomegranate
juice and seed oil on nitric oxide and arterial function in obese
Zucker rats. Nitric Oxide 2007;17:50–54.
153. Fischer S: Is cyclooxygenase-2 important in skin carcinogene-
sis? J Environ Pathol Toxicol Oncol 2002;21:183–191.
154. Al-Waili NS, Saloom KY, Al-Waili T, Al-Waili A, Al-Waili H:
Modulation of prostaglandin activity, part 1: prostaglandin
inhibition in the management of nonrheumatologic diseases:
immunologic and hematologic aspects. Adv Ther 2007;24:
189–222.
155. Brandes RP, Fleming I, Busse R: Endothelial aging. Cardiovasc
Res 2005;66:286–294.
156. Ferrari AU, Radaelli A, Centola M: Aging and the cardiovas-
cular system. J Appl Physiol 2003;95:2591–2597.
157. Bunting S, Gryglewski S, Moncada S, Vane JR: Arterial walls
generate from prostaglandin endoperoxides a substance (pros-
taglandin X) which relaxes strips of mesenteric and coeliac
arteries and inhibits platelet aggregation. Prostaglandins 1976;
12:897–913.
158. Gluais P, Vanhoutte PM, Fe
´le
´tou M: Mechanisms underlying
ATP-induced endothelium-dependent contractions in the SHR
aorta. Eur J Pharmacol 2007;556:107–114.
159. Hirao A, Kondo K, Inui N, Umemura K, Ohashi K, Watanabe
H: Cyclooxygenase-dependent vasoconstricting factor(s) in
remodelled rat femoral arteries. Cardiovasc Res 2008;79:
161–168.
160. Gluais P, Lonchampt M, Morrow JD, Vanhoutte PM, Feletou
M: Acetylcholine-induced endothelium-dependent contractions
in the SHR aorta: the Janus face of prostacyclin. Br J Pharmacol
2005;146:834–845
161. Nakano J, McCloy RB, Prancan AV: Circulatory and pulmo-
nary airway responses to different mixtures of prostaglandins
E2 and F2ain dogs. Eur J Pharmacol 1973;24:61–66.
162. Hata A, Breyer R: Pharmacology and signaling of prostaglandin
receptors: multiple roles in inflammation and immune modu-
lation. Pharmacol Ther 2004;103:147–166.
163. Wong S, Leung C: Cyclooxygenase-2- derived prostaglandin
F2amediates endothelium-dependent contractions in the aorta
of hamsters with increased impact during aging. Circ Res
2009;104:228–235.
164. Lai J, Jin H, Yang R: Prostaglandin F2ainduces cardiac myo-
cyte hypertrophy in vitro and cardiac growth in vivo. Am J
Physiol 1996;271:H2197–H2208.
165. Szuldrzynski K, Zalewski J, Machnik A, Zmudka K: Elevated
levels of 8-iso-prostaglandin F2alpha in acute coronary syn-
dromes are associated with systemic and local platelet activa-
tion. Pol Arch Med Wewn 2010;120:19–24.
1076 AL-WAILI ET AL.
166. LeLeiko RM, Vaccari CS, Sola S, Merchant N, Nagamia SH,
Thoenes M, Khan BV: Usefulness of elevations in serum cho-
line and free F2)-isoprostane to predict 30-day cardiovascular
outcomes in patients with acute coronary syndrome. Am J
Cardiol 2009;104:638–643.
167. Matz RL, Andriantsitohaina R: Age-related endothelial
dysfunction: potential implications for ph49. Nakahata N.
Thromboxane A2: physiology/pathophysiology, cellular signal
transduction and pharmacology. Pharmacol Ther 2008;118:18–35.
168. Fitzgerald DJ, Roy L, Catella F, Fitzderald GA: Platelet acti-
vation in unstable coronary disease. N Engl J Med 1986;315:
983–989.
169. Fitzgerald DJ, Rocki W, Murray R, Mayo G, FitzGerald GA:
Thromboxane A2 synthesis in pregnancy-induced hypertension.
Lancet 1990;335:751–754.
170. Al-Waili NS: Effects of honey on the urinary total nitrite and
prostaglandins concentration. Int Urol Nephrol 2005;37:107–
111.
171. Bigler EJ, Whitton J: Prostacyclin synthase and arachidonate 5-
lipoxygenase polymorphisms and risk of colorectal polyps.
Cancer Epidemiol Biomarkers Prev 2006;15:502–508.
172. Wen CT, Hussein SZ, Abdullah S, Karim NA, Makpol S, Mohd
Yusof YA: Gelam and nenas honeys inhibit proliferation of HT
29 colon cancer cells by inducing DNA damage and apoptosis
while suppressing inflammation. Asian Pac J Cancer Prev
2012;13:1605–1610.
173. Nemzer B, Rodriguez L, Hammond L, DiSilvestro R, Hunter J,
Pietrzkowski Z: Acute reduction of serum 8-iso-PGF2-alpha
and advanced oxidation protein products in vivo by a poly-
phenol-rich beverage; a pilot clinical study with phytochemical
and in vitro antioxidant characterization. Nutr J 2011;10:67.
174. Handy D, Loscalzo J: Homocysteine and atherothrombosis:
diagnosis and treatment. Curr Atheroscler Rep 2003;5:276–283.
175. Oikawa S, Murakami K, Kawanishi S: Oxidative damage to
cellular and isolated DNA by homocysteine: implications for
carcinogenesis. Oncogene 2003;22:3530–3538.
176. Looker H, Fagot-Campagna A, Gunter EW, Pfeiffer CM,
Venkat Narayan KM, Knowler WC, Hanson RL: Homocysteine
as a risk factor for nephropathy and retinopathy in Type 2 di-
abetes. Diabetologia 2003;46:766–772.
177. Alul K, Longo J, Marcotte AL, Campione AL, Moore MK,
Lynch SM: Vitamin C protects low-density lipoprotein from
homocysteine-mediated oxidation. Free Radic Biol Med 2003;
34:881–891.
178. Cassone K, Laurenti O, Desideri G, Bravi MC, De Luca O,
Marinucci MC, De Mattia G, Ferri C: L-Arginine infusion
decreases plasma total homocysteine concentrations through in-
creased nitric oxide production and decreased oxidative status in
type II diabetic patients. Diabetologia 2002;45:1120–1127.
179. WHO: Obesity: Preventing and managing the global epidemic.
[WHO Technical report series No. 894]. World Health Orga-
nization, Geneva, 2000.
180. Poirier P, Eckel RH: The heart and obesity. In: Hurst’s The
Heart (Fuster V, Alexander RW, King S, O’Rourke RA, Ro-
berts R, Wellens HJJ, eds.). McGraw-Hill Companies, New
York, 2000, pp. 2289–2303.
181. Arcaro G, Zamboni M, Rossi L, Turcato E, Covi G, Armellini
F, Bosello O, Lechi A: Body fat distribution predicts the degree
of endothelial dysfunction in uncomplicated obesity. Int J Obes
Relat Metab Disord 1999;23:936–942.
182. Stamler R, Stamler J, Riedlinger WF, Algera G, Roberts RH:
Weight and blood pressure: findings in hypertension screening
of 1 million Americans. JAMA 1978;240:1607–1610.
183. Klein S, Burke LE, Bray GA, Blair S, Allison DB, Pi-
Sunyer X, Hong Y, Eckel RH: American Heart Association
Council on Nutrition, Physical Activity, and Metabolism.
Clinical implications of obesity with specific focus on car-
diovascular disease: a statement for professionals from the
American Heart Association Council on Nutrition, Physical
Activity, and Metabolism: endorsed by the American
College of Cardiology Foundation. Circulation 2004;110:
2952–2967.
184. Chepulis L: The effect of honey compared to sucrose, mixed
sugars, and a sugar-free diet on weight gain in young rats.
J Food Sci 2007;72:S224–S229.
185. Larson-Meyer DE, Willis KS, Willis LM, Austin KJ, Hart AM,
Breton AB, Alexander BM: Effect of honey versus sucrose on
appetite, appetite-regulating hormones, and postmeal thermo-
genesis. J Am Coll Nutr 2010;29:482–493.
186. Guzik TJ, West NE, Black E, McDonald D, Ratnatunga C, Pillai
R Channon K: Vascular superoxide production by NAD(P)H
oxidase: association with endothelial dysfunction and clinical
risk factors. Circ Res 2000;86:E85–E90.
187. Miller F, Gutterman D, Rios C, Heistad D, Davidson B: Su-
peroxide production in vascular smooth muscle contributes to
oxidative stress and impaired relaxation in atherosclerosis. Circ
Res 1999;82:1298–1305.
188. Zalba G, Beaumont FJ, San Jose G, Fortuno A, Fortuno MA,
Etayo JC, Diez J: Vascular NADH/NADPH oxidase is involved
in enhanced superoxide production in spontaneously hyperten-
sive rats. Hypertension 2000;35:1055–1061.
189. Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M,
Skatchkov M, Thaiss F, Stahl RA, Warnholtz A, Meinertz T,
Griendling K, Harrison DG, Forstermann U, Munzel T: Me-
chanisms underlying endothelial dysfunction in diabetes melli-
tus. Circ Res 2001;88:E14–E22.
190. Sorata Y, Takahama U, Kimura M: Protective effect of quer-
cetin and rutin on photosensitized lysis of human erythrocytes
in the presence of hematoporphyrin. Biochem Biophys Acta
1982;799:313–317.
191. Karajibani M, Hashemi M, Montazerifar F, Bolouri A, Dikshit
M: The status of glutathione peroxidase, superoxide dismutase,
vitamins A, C, E and malondialdehyde in patients with car-
diovascular disease in Zahedan, Southeast Iran. J Nutr Sci Vi-
taminol (Tokyo) 2009;55:309–316.
192. Zern TL, Wood RJ, Greene C, West KL, Liu Y, Aggarwal D,
Shachter NS, Fernandez ML: Grape polyphenols exert a car-
dioprotective effect in pre- and postmenopausal women by
lowering plasma lipids and reducing oxidative stress. J Nutr
2005;135:1911–1917.
193. Jeong YJ, Choi YJ, Kwon HM, Kang SW, Park HS, Lee M,
Kang YH: Differential inhibition of oxidized LDL-induced
apoptosis in human endothelial cells treated with different fla-
vonoids. Br J Nutr 2005;93:581–591.
194. Fuhrman B, Volkova N, Coleman R, Aviram M: Grape powder
polyphenols attenuate atherosclerosis development in apolipo-
protein E deficient (E0) mice and reduce macrophage ather-
ogenicity. J Nutr 2005;135:722–728.
195. Hubbard GP, Wolffram S, de Vos R, Bovy A, Gibbins JM,
Lovegrove JA: Ingestion of onion soup high in quercetin in-
HONEY AND CARDIOVASCULAR RISK FACTORS 1077
hibits platelet aggregation and essential components of the
collagen-stimulated platelet activation pathway in man: A pilot
study. Br J Nutr 2006;96:482–488.
196. Ludwig A, Lorenz M, Grimbo N, Steinle F, Meiners S, Bartsch
C, Stangl K, Baumann G, Stangl V: The tea flavonoid epi-
gallocatechin-3-gallate reduces cytokine-induced VCAM-1 ex-
pression and monocyte adhesion to endothelial cells. Biochem
Biophys Res Commun 2004;316:659–665.
197. Hallund J, Bugel S, Tholstrup T, Ferrari M, Talbot D, Hall WL,
Reimann M, Williams CM, Wiinberg N: Soya isoflavone-
enriched cereal bars affect markers of endothelial function in
postmenopausal women. Br J Nutr 2006;95:1120–1126.
198. Taubert D, Roesen R, Lehmann C, Jung N, Schomig E: Effects
of low habitual cocoa intake on blood pressure and bioactive
nitric oxide: a randomized controlled trial. JAMA 2007;298:49–60.
199. Park YK, Kim JS, Kang MH: Concord grape juice supple-
mentation reduces blood pressure in Korean hypertensive men:
Double-blind, placebo controlled intervention trial. Biofactors
2004;22:145–147.
200. Heiss C, Finis D, Kleinbongard P, Hoffmann A, Rassaf T, Kelm
M, Sies H: Sustained increase in flow-mediated dilation after
daily intake of high-flavanol cocoa drink over 1 week. J Car-
diovasc Pharmacol 2007;49:74–80.
201. Schroeter H, Heiss C, Balzer J, Kleinbongard P, Keen CL,
Hollenberg NK, Sies H, Kwik-Uribe C, Schmitz HH, Kelm M:
Epicatechin mediates beneficial effects of flavanol-rich cocoa
on vascular function in humans. Proc Natl Acad Sci USA
2006;103:1024–1029.
202. Pearson DA, Paglieroni TG, Rein D, Wun T, Schramm DD,
Wang JF, Holt RR, Gosselin R, Schmitz HH, Keen CL: The
effects of flavanol-rich cocoa and aspirin on ex vivo platelet
function. Thromb Res 2002;106:191–197.
203. Mathur S, Devaraj S, Grundy SM, Jialal I: Cocoa products
decrease low density lipoprotein oxidative susceptibility but do
not affect biomarkers of inflammation in humans. J Nutr
2002;132:3663–3667.
204. Schramm DD, Karim M, Schrader HR, Holt RR, Kirkpatrick
NJ, Polagruto JA, Ensunsa JL, Schmitz HH, Keen CL: Food
effects on the absorption and pharmacokinetics of cocoa fla-
vanols. Life Sci 2003;73:857–869.
205. Middleton E, Kandaswami C, Theoharides T: The effects of plant
flavonoids on mammalian cells: Implications for inflammation,
heart disease and cancer. Pharmacol Rev 2000;52:673–751.
206. Jendekova L, Kojsova S, Andriantsitohaina R, Pechanova O:
The time-dependent effects of Provinols on brain NO synthase
activity in L-NAME-induced hypertension. Physiol Res
2006;55:S31–S37.
207. De Whalley CV, Rankin SM, Hoult J: Flavonoids inhibit the
oxidative modification of low-density lipoproteins by macro-
phages. Biochem Pharmacol 1990;39:1743–1750.
208. Robak J, Gryglewski R: Flavonoids are scavengers of super-
oxide anion. Biochem Pharmacol 1988;37:83–88.
209. Appeldoorn MM, Venema DP, Peters TH, Koenen ME, Arts IC,
Vincken JP, Gruppen H, Keijer J, Hollman PC: Some phenolic
compounds increase the nitric oxide level in endothelial cells in
vitro. J Agric Food Chem 2009;57:7693–7699.
210. Schmitt CA, Dirsch VM: Modulation of endothelial nitric oxide
by plant-derived products. Nitric Oxide 2009;21:77–91.
211. Di Tomo P, Canali R, Ciavardelli D, Di Silvestre S, De Marco
A, Giardinelli A, Pipino C, Di Pietro N, Virgili F, Pandolfi A: b-
Carotene and lycopene affect endothelial response to TNF-a
reducing nitro-oxidative stress and interaction with monocytes.
Mol Nutr Food Res 2012;56:217–227.
212. Sa
´nchez M, Galisteo M, Vera R, Villar IC, Zarzuelo A, Ta-
margo J, Pe
´rez-Vizcaı
´no F, Duarte J: Quercetin downregulates
NADPH oxidase, increases eNOS activity and prevents endo-
thelial dysfunction in spontaneously hypertensive rats. J Hy-
pertens 2006;24:75–84.
213. D’Arcy B: Antioxidants in Australian floral honeys–Identifica-
tion of health enhancing nutrient components. RIRDC Pub-
lication No. 05/040, 2005.
214. Inoue K, Murayarna S, Seshimo F: Identification of phenolic
compound in manuka honey as specific superoxide anion radi-
cal scavenger using electron spin resonance (ESR) and liquid
chromatography with coulometric array detection. J Sci Food
Agric 2005;85:872–878.
215. Fahey JW, Stephenson K: Pinostrobin from honey and Thai
ginger (Boesenbergia pandurata): a potent flavonoid inducer of
mammalian phase 2 chemoprotective and antioxidant enzymes.
J Agric Food Chem 2002;50:7472–7476.
216. Perez RA, Iglesias MT, Pueyo E, Gonzalez M, de Lorenzo C:
Amino acid composition and antioxidant capacity of Spanish
honeys. J Agric Food Chem 2007;55:360–365.
217. Jaganathan SK, Mandal M: Antiproliferative effects of honey
and of its polyphenols: a review. hindawi publishing corpora-
tion. J Biomed Biotechnol 2009;Article ID 830616, 13 pages.
218. Rakha MK, Nabil ZI, Hussein AA: Cardioactive and vasoactive
effects of natural wild honey against cardiac malperformance
induced by hyperadrenergic activity. J Med Food 2008;11:
91–98.
1078 AL-WAILI ET AL.
