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*
Department of Food Science, Graduate School of Dairy Science Research, Rakuno Gakuen University, Ebetsu 069-8501, Japan,
Department of General Foods, The Hokuren Federation of Agriculture Corporation, Sapporo 060-8651, Japan, and
**
Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume 830, Japan
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-glucosidase from rat intestine. The aim of this study was
to determine whether these nucleosides are sucrase inhibitors in humans
as well as rats. Blood glucose and insulin responses were examined in
23 healthy volunteers (18 males and 5 females) administered sucrose
with inosine and 8 (males) administered sucrose with adenosine. The
initial increase in plasma glucose and serum insulin concentrations at
30 min after loading sucrose (50 g) alone were significantly reduced by
co-administration of inosine (2.5 and 1.0 g) or adenosine (2.5
g). The total increases in the areas under the plasma glucose and serum
insulin concentration curves for 3 h after administration of the
same amount of sucrose with inosine were also significantly less than
those when the volunteers were administered sucrose alone. These
results in humans agree with the findings obtained in our previous
studies in rats. These nucleosides may be used as one of the components
of artificial sweeteners when mixed with sucrose and may be useful as
food additives to suppress increases in blood glucose and insulin.
KEY WORDS: • human volunteers • inosine, adenosine • blood glucose, insulin • -glucosidase inhibitor • diabetes
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Several
water-soluble polysaccharides, guar gum (Jenkins et al. 1977
), pectin (Jenkins et al. 1977
) and konjac
mannan (Ebihara et al. 1981
) decrease postprandial blood
glucose and insulin concentrations when co-administered with
glucose. Guar gum induced lower blood glucose in relation to the
viscosity of the polysaccharide (Jenkins et al. 1978
).
Pullulan (Hiji and Kasaki 1983
, Kurata 1987
) and indigestible dextrin (Wakabayashi et al. 1993
) which are low-viscosity saccharides, also lower blood
glucose and insulin levels in rats administered sucrose and starch in
tolerance tests. Unlike sugars, which can be freely added to a wide
variety of foods, indigestible polysaccharides have limited
applicability, since they are not sweet enough to be used as a
sweetener in drinks, cakes or hard candies.
Administration of -glucosidase inhibitors inhibits the enzyme which
is located in the micro-villus of the small intestine, and reduces
the rapid elevation of blood glucose after meals and the subsequent
rapid increase in insulin levels. Several -glucosidase inhibitors,
such as acarbose (Hotta et al. 1993
, Sachse and Willims 1979
, Tattersall 1993
, Toumilehto 1988
) and voglibose (Matsuo et al. 1992
), have
been applied as oral therapeutic agents for the treatment of
non-insulin-dependent diabetes mellitus. However, these substances are
essentially xenobiotic and cause safety concerns, so use has been
strictly regulated.
We have been investigating several kinds of -glucosidase inhibitors
as components of sweeteners, which act to gradually inhibit
-glucosidase in rat small intestine. In a previous study
(Fukumori et al. 2000
), we found that nucleosides and
their bases inhibited -glucosidase from rat intestine, leading to
delayed digestion of sucrose, so that the inhibitors suppressed rapid
increase in blood glucose and insulin levels of rats. In the present
study, we describe the reduction of blood glucose and insulin levels in
human volunteers administered sucrose with inosine or adenosine.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Healthy volunteers (n = 31), 26 males and 5 females,
aged 20–25 y, participated in the study. They had no history of
gastrointestinal problems and were not presently taking any medication.
All were within normal weight-for-height ranges as determined by
bioelectrical analysis (Segal et al. 1987
). The study
protocol was approved by the ethical committee of the Kurume University
Hospital. Informed consent was obtained from all subjects prior to
their entry into the study.
Administration of test solutions.
Each of the sugar administration tests under the following condition was done with 1-wk intervals. Experiment 1: Twenty-three subjects (18 males and 5 females) administered sucrose (50 g in 500 mL of distilled water) as a control solution and a week later the control solution containing inosine (2.5 or 1.0 g). Experiment 2: Eight subjects (males differed from those in Experiment 1) were administered the same control solution as in Experiment 1 and then the control solution containing adenosine (2.5 or 1.0 g). Inosine of 99% purity and adenosine of 98% purity were obtained from Wako Pure Chemicals, Ltd., Osaka, Japan.
Procedures.
Subjects fasted overnight for 12 h before the test. An indwelling
butterfly needle (21 to 23 gauge) was inserted into an antecubital
vein, and a baseline blood sample was obtained. The needle was
maintained by intermittent irrigation with a diluted solution of
heparinized saline (104 U heparin/L) to allow for repeated
sampling. The subjects were administered a control solution and then
test solutions with an interval week in a randomized, double-blind
fashion. Blood samples were obtained at 30-min intervals for 180 min to
determine plasma glucose and serum insulin concentrations. Samples were
centrifuged and plasma and serum were stored at -20°C until
analyzed. The plasma glucose concentration (mmol/L) was measured by a
glucose oxidase method (Dahlqvist 1961
,
Papadopoulos and Hess 1960
). Serum insulin concentration
(pmol/L) was assayed using an RIA Kit (Soeldner and Slone 1965
).
The total increase in plasma glucose (mmol · L-1 · h) observed for 3 h after administration of sucrose and sucrose with the nucleoside was represented as area calculated from the y coordinate axis (the increase in plasma glucose) and the x coordinate axis (h). The increase in plasma glucose = plasma glucose concentration (mmol · L-1) at 0, 30, 60, 90, 120, 150 or 180 min minus glucose concentration extrapolated from the level points at 0 and 150 min. The increase in serum insulin (pmol · L-1 · h) was also calculated as above.
Statistical analysis.
The data were analyzed using Statistical Analysis System, Stat View 5 for Macintosh (SAS Inc., Cary, NC). The results are expressed as means ± SEM (n = 23, Experiment 1; n = 8, Experiment 2), and significance of differences was calculated by Student’s paired t-test or Welch’s t-test. Differences were considered to be statistically significant at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) or 1.0 g (Fig. 1C
) of inosine was significantly lower
than the control at 30 min. The plasma glucose concentration at 30 min
after administration of sucrose (50 g) with 2.5 g (Fig. 1B
), but not 1 g (Fig. 1D
) of adenosine was
also significantly lower than the control at 30 min. The glucose
concentration at 90, 120 and 150 min after administration of sucrose
with 2.5 g inosine was higher than the control (Fig. 1A)
.
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, left panel) whereas in volunteers administered 2.5 g of adenosine, the total
increase in area under the curve did not differ significantly from the
control value. (Fig. 2
, right panel).
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) and 1.0 g (Fig. 3C
) of inosine were significantly lower
than the control values. The serum insulin concentration at 30 min
after administration of sucrose with 2.5 g (Fig. 3B
) of
adenosine was also significantly lower than the control. Insulin
concentration at 120 and 150 min after administration of sucrose with
2.5 g inosine was higher than the control (Fig. 3A
).
Insulin concentrations after administration of sucrose with 1 g
inosine or 1 g or 2.5 g adenosine did not differ from the
control values from 60–180 min.
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).The total increase in area in the subjects administered 2.5 g of
adenosine was also significantly lower than the control value. (Fig. 4
,
right panel).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The serum glucose and insulin
concentrations in rats following loading of sucrose or soluble starch
were significantly reduced by administration of these compounds. The
decrease in serum glucose and insulin concentrations in rats
administered nucleosides and related substances had no relationship to
changes in gastric emptying (Fukumori et al. 2000
). The
activities of sucrase, maltase, isomaltase and glucoamylase in a crude
preparation from the small intestinal mucosa of the rats were inhibited
by the compounds (Fukumori et al. 2000
). From the above
findings, the suppression in serum glucose and insulin concentrations
was hypothesized to be in response to a reduction in glucose absorption
caused by inhibition of mucosal enzymes that digest sucrose, malto- and
isomalto-oligosaccharides by nucleosides. In the present study, we
tested plasma glucose and serum insulin responses in humans given
sucrose and sucrose with inosine or adenosine. These nucleosides
suppressed the rapid increase in plasma glucose concentrations and
insulin secretion, although inosine appeared to be more effective than
adenosine. We contend that the plasma glucose and serum insulin
concentrations were reduced by the same mechanism we proposed for rats
(Fukumori et al. 2000
).
The drug phenformin (a biguanide) effectively lowers blood glucose
concentrations when administered orally (Hiji and Kasaki 1983
, Hotta 1994
). Phenformin delays the rate of
glucose absorption from the intestine, which results in a decreased
rise in blood glucose concentrations following administration of sugar.
However, phenformin may occasionally cause lacticacidosis
(Berger 1991
, Hermman and Melander 1993
,
Hotta 1994
), which accompanies the increase in lactic
acid, alanine and pyruvic acid in the blood. In a previous study
(Shiomi et al. 1995
), the concentration of lactic acid
in the blood of rats administered sucrose containing adenosine, inosine
or cytosine was not significantly different from that of control rats.
Sulfonylureas also lower blood glucose concentration by stimulating the
release of insulin from pancreatic cells. One of the sulfonylureas,
chloroprotamide, is not usually excreted by elderly people consuming
poor diets or low blood sugar concentrations as a result of kidney
disorders (Hotta 1994
). In a previous study
(Onodera et al. 1996
, Shiomi et al. 1995
), when rats were allowed free access to a diet containing
inosine or adenosine (10, 25 and 50 g/kg of diet) for 7 or 31 d,
no differences in blood glucose or insulin concentrations between the
inosine diet groups and controls were observed. Thus, these nucleosides
are expected to be safe for use as a component of artificial sweeteners
and as food additives to suppress increases in blood glucose and
insulin concentrations.
It is estimated from rat studies (Fukumori et al. 2000
)
that when used in combination with sucrose, nucleosides may mildly
suppress the action of digestive enzymes in the small intestine of
humans, thereby suppressing the rapid increase in blood glucose
concentrations and reducing insulin secretion. The inhibitory action of
the nucleosides in this study was so mild that somewhat large amounts
of the nucleosides can be used at a concentration of 5 g/100 g sucrose,
the same proportion used in the previous study in rats (Fukumori et al. 2000
).
Sweeteners and foods that contain these nucleosides may be useful for the prevention of lifestyle-related diseases such as obesity and diabetes mellitus. This needs to be investigated in a long-term study of high-risk individuals.
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FOOTNOTES |
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Manuscript received December 6, 1999. Revision accepted April 13, 2000.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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