Received:Jun. 25, 2011
Accepted:Aug. 24, 2011
Published online:Sep. 9, 2011
Original Article
Effect of Grapefruit Intake on Postprandial Plasma Glucose
Mari Ogura 1,2), Masayuki Yagi 1), Keitaro Nomoto 1), Ryo Miyazaki 1), Masaya Kongoji 3), Show Watanabe 1,4),
Umenoi Hamada 1), Yoshikazu Yonei 1)
1) Anti-Aging Medical Research Center, Graduate School of Life and Medical Sciences, Doshisha University
2) Faculty of Human Life and Science, Doshisha Women’s College of Liberal Arts
3) Kikunodai Clinic
4) Life Science Promotion Foundation
Abstract
Objective: Previous epidemiological surveys of diet indicated a potential relationship between fruit intake and the pathogenesis of
lifestyle-related disease. Recent reports indicate grapefruit (GF) may affect sugar metabolism. The present study measured glucose,
triglyceride and insulin levels in human blood after GF ingestion with and without other foods.
Methods: Twelve healthy, non-smoking female volunteers, non-obese (age 40.5 ± 4.2 years old, BMI 22.0 ± 0.9) were provided
with five different breakfasts on successive days: GF, bread or fried vegetables alone, GF + bread, GF + fried vegetables. In meals
that included GF, the GF was eaten before the bread or fried vegetables. Blood samples were taken after meals to measure plasma
glucose, immuno reactive insulin (IRI), triglyceride and vitamin C.
Results: Plasma glucose following a meal of bread or fried vegetables or a meal of bread and fried vegetables with GF was similar.
Insulin secretion was slower after a meal of GF alone compared to bread alone (p < 0.001) and the area under curve (AUC) of
glucose per carbohydrate intake was lower when GF was eaten prior to bread or fried vegetables than after a single intake of bread
or fried vegetables alone (p < 0.001). The AUC of triglyceride after a prior intake of GF before fried vegetables was slower than that
after an intake of fried vegetables alone (p < 0.05). Blood vitamin C concentration increased after GF intake (p < 0.001).
Conclusion: GF contains saccharides and a variety of dietary elements, including fiber, vitamins, citric acid, naringenin and
bergamottin. It is possible that these compounds may affect sugar and lipid metabolism.
KEY WORDS: grapefruit, sugar metabolism, lipid metabolism, insulin, triglyceride
Introduction
This program found measures of body weight, body mass index
(BMI), blood pressure and blood vessel senility all improved
over time with increased fruit consumption. It has also been
reported that female college athletes increase fruit intake and
decrease confectionery intake following dietary instruction 16).
Grape fruit (GF) (Citrus X paradisi) contains 38 kcal, 89
g water, 9.6 g sugar, 1 g citric acid, 0.6 g dietary fiber, 140 mg
potassium, 36 mg vitamin C and 9 mg magnesium 17) per 100
g fruit. Other components include limonene, furanocoumarins
and flavonoids.
Previous studies identified the potential of GF to favorably
affect metabolic syndrome 18) and lipid metabolism 19). The
present study measured the change of the blood glucose,
triglyceride and insulin following GF consumption by human
volunteers, in combination with other foods.
Many epidemiological surveys of diet have analyzed the
relation between fruit intake and lifestyle-related disease 1). It
has been claimed that fruit consumption reduces blood pressure
2), hypertension risk 3) and the prevalence of cerebral apoplexy 4);
prevents Alzheimer’s disease 5) and gastric cancer 6,7); improves
oral function, i.e., teeth and gum condition in elderly persons8),
glucose tolerance in middle-aged and older women 9) , and
mental outlook in middle-aged and older men and women10).
However, none of these reports clearly tested the protective
efficacy of fruit consumption in an interventional study design.
Excess fruit consumption may lead to excess calorie intake
and, in consequence, cause obesity and hyperuricemia 11) .
Recent surveys of junior high school students 12) and senior
citizens in urban areas 13) found fruit consumption has declined.
In contrast, the consumption of western-style cakes and jellies
by students in women’s colleges has increased 14). The increase
in the consumption of confectionery, which contains high
levels of fructose and corn syrup, leads to increase intake of
isomerized sugar and may cause nutritional problems.
One study of a health program that promoted fruit intake,
found that as fruit intake increased, lipid intake decreased 15).
Anti-Aging Medicine 8 (5) : 60-68, 2011
(c) Japanese Society of Anti-Aging Medicine
60
Prof. Yoshikazu Yonei, M.D., Ph.D.
Anti-Aging Medical Research Center, Graduate School of Life and Medical Sciences Doshisha University
1-3, Tatara Miyakodani, Kyotanabe city, Kyoto Prefecture, 610-0321 JAPAN
Tel: +81-774-65-6382 / Fax: +81-774-65-6394 / E-mail: [email protected]
Effect of Grapefruit Intake on Postprandial Plasma Glucose
Methods
Ethical considerations and conflict of interest
Objective
The study was completed at the Kikunodai Medical Clinic
in compliance with the ethical principles of the Declaration
of Helsinki, the Personal Information Protection Law, and
with reference to the “Ordinance regarding the Good Clinical
Practice” (Ministry of Health and Welfare Ordinance No.
28, March 27, 1997). The study was approved by the thirdparty ethical committee of the Fukushima Health Care Center
(Osaka-city, Osaka) and the ethical committee of Doshisha
University (approval number #0832). We declare there is
no financial or other conf lict of interest in the writing or
publication of this paper.
Twelve healthy, non-obese, non-smoking women, (mean
age 40.5 ± 4.2 years, BMI 22.0 ± 0.9) were chosen from 249
applicants who responded to an Internet advertisement in a
social network service (Marsh Research, Setagaya-ku, Tokyo).
Pregnant and lactating women, persons on medication or
with high blood pressure, diabetes or a medical history of
digestive surgery were excluded. Tests for each participant were
conducted over five consecutive days between December 2010
and January 2011.
Prior written informed consent was obtained from all
subjects. The aims and methods of the study were explained at
meetings conducted at the Kikunodai Medical Clinic (Chofushi, Tokyo).
Data analysis
Statistics were calculated with SPSS (IBM Japan, Minatoku, Tokyo). Differences before and after the trial period were
tested by paired-t (parametric) and Wilcoxon signed rank (nonparametric) tests. Group means were compared by Dunnett’s
test. The results are presented as mean ± standard deviation
and p < 0.05 was assumed to be significant. The safety of the
test product was evaluated by prevalence of adverse effects in
individual subjects.
Fruit samples
GF were provided by Florida Department of Citrus (United
States of America) via Amano and Associates (Minato-ku,
Tokyo). The mean weight of GF used in the trial was 421 ± 2 g.
Bread was provided by Shikishima Bread-Making Inc.(Nagoyacity, Aichi) and fried vegetables was provided by Seiyu (Kita-ku,
Tokyo).
Trial design
Day
Food
intake
Energy content Carbohydrate
(kcal)
(g)
Lipid
(g)
Protein vitamin C
(g)
(mg)
① 12/20
GF
81.9
20.7
0.2
1.9
77
② 12/21
Bread
158.0
29.8
2.2
4.8
0
③ 12/22
GF + bread
237.1
49.8
2.4
6.7
77
④ 12/24
GF + fried
vegetables
297.4
36.0
16.0
5.1
80
Fried
vegetables
202.5
14.6
14.8
2.7
3
⑤
1/5
Result
In all diets, plasma glucose level rose 30 minutes after a
test meal had been ingested (Fig. 1a), but glucose AUC did
not differ between groups (Fig. 1b). In contrast, glucose AUC/
carbohydrate intake for GF + bread and GF + fried vegetables
was less than that for bread or fried vegetables ingested without
GF (Fig. 1c; p < 0.001).
The mean concentration of serum vitamin C increased
from 9.67 ± 2.01 μg/ml prior to GF ingestion to 12.66 ± 2.35 μg/
ml (+30.9%, p < 0.001) after 180 minutes (Fig. 2).
Insulin levels rose after meal ingestion, but the IRI 30
minutes after GF intake was lower than that after intake of
bread or fried vegetables (Fig. 3a; p = 0.001, p = 0.017). The
AUC for IRI after GF intake was lower than that for all other
menus (Fig. 3b; p < 0.05). The AUC of IRI/carbohydrate intake
was lower when the FV was taken with GF than that after
intake of fried vegetables without GF (Fig. 3c; p < 0.001).
Triglyceride level gradually increased 30, 60 and 120
minutes after fried vegetables intake (Fig. 4a), and the
triglyceride AUC was lower when GF was eaten prior to fried
vegetables (Fig. 4b; p = 0.049). Triglyceride AUC/carbohydrate
intake was lower when GF was eaten prior to fried vegetables
(Fig. 4c; p < 0.001).
Each subject was given 15 minutes to ingest the breakfast
menu specified above. The breakfast start-time for each
subject was staggered (5-minute intervals) to allow time for
blood sampling, resulting in a 60-minute difference in the
start and end time of the first and the last subject. On each
sample day, blood samples were taken from each subject at 0,
30, 60, 120 and 180 minutes after the meal, and glucose and
immunoreactive insulin (IRI) were measured. In addition,
vitamin C was measured at 0 and 180 minutes on day-1, and
triglyceride was measured at 0, 30, 60, and 120 minutes on day4 and -5. Biochemical parameters were measured by Mitsubishi
Chemistry Medicine (Minato-ku, Tokyo). Results for values of
glucose, insulin and triglyceride are expressed as ‘area under
curve’ (AUC) and AUC/carbohydrate intake.
Subjects were examined on the first day of the study,
and their height, weight, blood pressure, pulse rate, and body
composition were measured. Body composition was measured
by a bioelectrical impedance analysis body-composition
monitor (Bc-118D, TANITA, Itabashi-ku, Tokyo) 20).
The subjects physical and mental condition was assessed
by the Anti-Aging Quality of Life common questionnaire 20).
During the study period, one participant was excluded from the
study because nettle-rash hives and did not consume the day-4
diet of GF + fried vegetables.
61
Effect of Grapefruit Intake on Postprandial Plasma Glucose
Fig. 1a
Fig. 1b
Fig. 1c
Fig. 1
Change of plasma glucose
a. plasma glucose [mg/dl]; b. area under curve (AUC) of plasma glucose[mg/dl・min];
c. glucose AUC/carbohydrate intake [mg/dl・min/g]. Means ± standard deviation (SD), n = 12.
*** = p < 0.001. GF: grape fruits, FV: fried vegetables.
AUC of each diet compared by Dunnett’s test.
62
Effect of Grapefruit Intake on Postprandial Plasma Glucose
Fig. 2
Vitamin C concentration [µg/ml]
*** = p < 0.001 by paired t-test.
63
Effect of Grapefruit Intake on Postprandial Plasma Glucose
Fig. 3a
Fig. 3b
Fig. 3c
Fig. 3
Change of insulin
a. insulin [μU/ml] ; b. area under curve (AUC) of insulin [μU/ml・min] ;
c. insulin AUC/carbohydrate intake [μU/ml・min/g] . Means ± standard deviation (SD), n = 12.
* p < 0.05, ** p < 0.01, *** p < 0.001,
AUC of each diet compared by Dunnett’s test.
GF. grapefruit, FV. fried vegetable.
64
Effect of Grapefruit Intake on Postprandial Plasma Glucose
Fig. 4a
Fig. 4b
Fig. 4c
Fig. 4
Change of triglyceride
a: triglyceride [mg/dl], b: area under curve (AUC) of triglyceride [mg/dl・min],
c: triglyceride AUC/carbohydrate intake [mg/dl・min/g].
Means ± standard deviation (SD), n = 12. ** p < 0.01, *** p < 0.001,
AUC of each diet compared by Wilcoxon test.
GF: grapefruit, FV: fried vegetable.
65
Effect of Grapefruit Intake on Postprandial Plasma Glucose
Discussion
women who consume less than 200 g fruit per a day 10). There
are gender differences between metabolic responses to dietary
fiber.
Fruit consumption does not influence blood sugar levels
after meals in insulin-dependent diabetes mellitus (IDDM)
patients receiving intensive insulin treatment or non-insulindependent diabetes mellitus (NIDDM) patients, who retain
insulin secretion capacity. However fruits with abundant
sucrose and low fructose, often increase postprandial glucose
in IDDM patients receiving conservative insulin therapy and
NIDDM patients losing insulin secretion capacity 45). In these
latter cases, patients should not consume excessive quantities of
fruit.
The glycemic index (GI) of different fruits is reported as:
grape 76 ± 25%, pineapple 70 ± 47%, persimmon 66 ± 37%,
mandarin orange 59 ± 24%, banana 58 ± 20%, watermelon 57 ±
45%, melon 55 ± 28%, strawberry 46 ± 18%, GF 44 ± 17%, and
apple 41 ± 15% 46). The GI of rice is 72 and, apart from grape,
pineapple and persimmon, fruit has a lower GI value than rice.
Here we found that postprandial blood sugar, IRI and
triglyceride concentrations were affected by GF ingestion. In
particular, plasma glucose AUC and the ratio of plasma glucose
to carbohydrate intake were lower when GF was ingested
prior to bread or fried vegetables. The reason that the AUC
was divided by carbohydrate intake is to reflect the concept of
“glycemic load” 21). “Glycemic load” is the index which divides
“glycemic index” exponent with 100 and applies the number of
grams weight of carbohydrate included in the food. This index
reflects the blood glucose rise after intake of the food more
correspondingly than “glycemic index”.
These results suggest that some constituent of GF exerts
some inf luences on glycolipid metabolism. We speculate
the vitamin C, naringenin (a f lavonoid), bergamottin (a
furanocoumarin), and dietary fiber in GF improved glycolipid
metabolism since previous studies showed the favorable effects
of these molecules on glycolipid metabolism. GF contains
vitamin C abundantly. Vitamin C is known to reduce oxidation
stress and improve insulin resistance, thus exerting a favorable
effect on controlling blood glucose 22,23). Naringenin is a known
antioxidant 24) and is also reported to have antiviral effect 25),
protect against dimethylnitrosamine-induced liver damage 26),
inhibit tumor growth 27), accelerate glucose uptake by skeletal
muscle 28) and improve of lipid metabolism 19).
Naringenin is repor ted to have a similar molecular
structure to estrogen and to bind to estrogen β receptor 29). When
orchidectomized rats were fed GF, urinal deoxypridinoline, which
is increased by orchidectomy, decreased to the original level 30).
As orchidectomy changes bone metabolism by increasing bone
absorption, these data indicate that bone metabolism may be
improved by naringenin supplementation. Naringenin acts like
estrogen and increases bone mineral density.
GF has a higher antioxidant activity than other fruits 31).
As there is no correlation between antioxidant activity and the
concentration of polyphenol, a major antioxidant, the effect
observed following GF intake may be derived from naringenin.
Grapefruit juice contains 7.7 μg/g bergamottin (BG), 8.8
μg/g bergaptol (BT), and 3.7 μg/g 6’,7’-dihydroxybergamottin
(DHB) 32). At these concentrations, 200 ml of grapefruit juice
contains 1.5 mg BG, 1.8 mg BT and 0.75 mg DHB. Bergamottin
interferes with CYP3A4 cytochrome P450 33-38), and is reported
to have anticarcinogenic activity 39,40), anti-tumor cell invasion 41)
and suppress Helicobacter pylori 42). Bergamottin also activates
peroxisome proliferator-activated receptor α (PPARα) or
PPARγ, induces adiponectin secretion and inhibits very lowdensity lipoprotein (VLDL) in adipocytes. In consequence,
bergamottin reduces insulin resistance and can prevent
hyperinsulinemia, type-2 diabetes mellitus (DM), obesity,
visceral fat accumulation, hypertension, hyperlipidemia and
arteriosclerosis 43). A company (Arkray, Kamigyo-ku, Kyoto)
has applied for a patent on bergamottin as a food-supplement
to prevent and remedy lipid metabolism disorder and metabolic
syndrome 43).
Effect of grapefruit on sugar and lipid metabolism
In trials using experimental rats fed cholesterol-rich food,
lipid metabolism is improved by GF intake 47). This finding is
explained by the anti-oxidative action of GF. Grapefruit oil
limited the generation and reduced the activity of glycerol-3phosphate dehydrogenase (GPDH) by 70% in cell cultures of
subcutaneous adipocytes and PPARγ gene expression which
suggests that GF may reduce intracellular fat accumulation 48).
Effect of citric acid on intracellular glucose
High sugar intake may increase intracellular glucose
c o n c e nt r a t io n . I n t u r n , t h i s m ay i n c r e a s e g lyc a t io n
(saccharification) stress and interfere with the tricarboxylic
acid (TCA) cycle in mitochondria 49) . Excessive glucose
in fat cells generates fumaric acid, which may react with
cysteine in proteins. This reaction produces S-(2-succinyl)
cysteine (2SC) 50), which affects proteins, such as cytoskeleton
protein, cytokine, heat shock protein and adiponectin 51). In
the streptozotocin-induced DM rats, oral administration of
citric acid reduced ketone generation and accumulation of
N ε -(carboxyethyl)lysine (CEL) in the crystalline lens, thus
preventing the progress of cataract and renal dysfunction
52). Since citric acid acts at the beginning of the TCA cycle,
elevated levels, such as those arising from GF ingestion, may
modify the deleterious affects of excessive glucose and reduce
glycation stress.
Effect of grapefruit on the vascular system
Grapefruit consumption may decrease coronary vascular
resistance and mean arterial pressure 53). Surveys have found
fruit, vegetable, potassium and vitamin C consumption lower
the risk of hypertension 3). Guidelines for the management of
hypertension (JSH 2009) recommend that a patient’s diet should
include vegetables, fruit, fish or fish oil; patients should restrict
salt intake, maintain standard weight, undertake moderate
aerobic exercise and quit smoking 54).
In a previous study, we examined the effects of GF juice
on arteriosclerosis in genetically modified (ApoE inactivated)
mice. ApoE mice were fed a high cholesterol diet for 21 weeks.
One group (n = 10) was given GF juice and the control group
(n = 10) was given a fructose solution. The development of
atherogenesis in the aortic valve was delayed in the GF group 55).
The evidence from the present and other studies indicate
Effect of dietary fiber on blood insulin levels
We thought that the dietary fiber did a some influence,
with the latest record as the reason whose blood glucose rise
is lenient. Dietary fiber reduces limit blood sugar rise by
preventing enzymes acting on food disaccharides 44) and, in
consequence, avoid the rapid insulin secretion. Fruit intake and
insulin resistance are correlated in middle-aged men. Women
who consume more than 200 g fruit per day have lower blood
sugar and HbA1c levels (measured on an empty stomach) than
66
Effect of Grapefruit Intake on Postprandial Plasma Glucose
Grapefruit safety
that GF ingredients have a composite influence upon glycolipid
metabolism. Dietary fiber reduces the absorption rate of sugar
and lipid 44) . Naringenin and bergamottin promote insulin
function and increase muscle cell glucose uptake 19,28,43). Citric
acid may moderate excessive glucose in the TCA cycle 52).
Other components of GF stimulate the central and sympathetic
nervous system to produce heat 56). Naringenin and bergamottin
stimulate intercellular signals that promote sugar metabolism.
The duration of these affects remain unclear and if the duration
were long, the result of 4th day (GF + fried vegetable) would be
over-estimated by GF intake for two continuous days. This may
be the study limitation and future research will test the duration
of these affects.
Insulin controls blood sugar levels, but other insulinc omp et it ive hor mone s , s uch a s g lucagon , a d r e n a l i n ,
adrenocorticotropic hormone (ACTH), cortisol, or growth
hormone are also involved 57). The present study was limited
as it was not feasible to measure the effect of diet on other
hormones.
Grapefruit peel samples were tested for several biocide
residues. Orthophenylphenol (OPP) was detected at low levels;
diphenyl (DP) was not detected; thiabendazole (TBZ) was
found at 1.4 – 2.0 mg/kg; imazalil (IMZ) was found at average
densities 0.77¬ – 1.4 mg/kg. These biocide levels are below the
maximum acceptable daily intake set by the Ministry of Health,
Labour and Welfare 58).
Acknowledgements
This study was supported by a research grant from Florida
Department of Citrus, United States of America. Part of this
study was presented at the 11th Meeting of Japanese Society of
Anti-Aging Medicine at Kyoto, 2011.
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