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From the Clinical Research Centers |
Departments of Molecular Physiology and Biophysics (M.C.M., A.D.C., S.N.D.) and Medicine (S.L.M., S.N.D.), and the Diabetes Research and Training Center (A.D.C., S.N.D.), Vanderbilt University, Nashville, Tennessee 37232
Address all correspondence and requests for reprints to: M. C. Moore, Ph.D., 702 Light Hall, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615. E-mail: genie.moore{at}mcmail.vanderbilt.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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20% of total energy intake) to replace other
carbohydrates in the diet has improved metabolic control in individuals
with diabetes, whereas other investigations have found little glycemic
benefit from the use of fructose (for reviews, see Refs. 2
and 3). Even where improvements in glycemic control have
been observed, however, these benefits were offset by increases in
total and low density lipoprotein cholesterol and/or triglycerides in
susceptible individuals (4). Hypertension and insulin
resistance have also been observed (2). Therefore, the use
of large amounts of fructose in the diet on a daily basis may not be
desirable. Evidence from animal models suggests, however, that glycemic
benefits may occur even with the ingestion of very small amounts of
fructose. In conscious dogs receiving an intraduodenal glucose infusion at 8 mg/kg·min, with or without the addition of fructose to the infusate at 0.4 mg/kg·min, the net hepatic fractional glucose extraction was 2-fold greater during the infusion of fructose than during the delivery of glucose alone (5). The increase in the arterial blood glucose concentration during fructose infusion was only half as great as it was in the absence of fructose. Moreover, the enhancement of the liver’s role in glucose disposal and the reduction in the glycemic response were not due to an increase in the insulin response, because the arterial plasma insulin concentration was only about half as high during fructose infusion as it was during the infusion of glucose alone (5).
The effect of catalytic amounts of fructose on glucose tolerance in humans is unknown. Moreover, the effect of small amounts of fructose on serum lipids has not been examined. Therefore, the current study was carried out to determine whether the addition of a small amount of fructose to a standard 75-g glucose tolerance test would reduce the glycemic response in normal humans without adversely affecting circulating triglyceride concentrations (the earliest lipid abnormality observed with ingestion of large amounts of fructose).
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Subjects and Methods |
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Studies were conducted on 11 healthy volunteers (5 men and 6 women; 2 African-American, 3 Asian, and 6 Caucasian; age, 29 ± 2 yr; body mass index, 23.6 ± 0.9 kg/m2). Hemoglobin A1c in these subjects ranged from 4.5–6.4% (normal, 4–6.5%). The subjects were taking no regular medications, and they had normal blood counts, serum electrolytes, and liver and renal function. None of them had first degree relatives with diabetes. All subjects consumed a diet containing at least 200 g carbohydrate daily for a week before study. The studies were approved by the institutional review board of Vanderbilt University Medical Center, and all subjects gave written informed consent before study.
Experimental design
All subjects were studied twice in a single blind, randomized fashion, with the two studies in the same subject 13 ± 2 days apart. The subjects were admitted to the General Clinical Research Center of Vanderbilt University Medical Center the evening before each study and were studied after a 10-h overnight fast. At approximately 0800 h on the day of study, a 20-gauge iv cannula was inserted retrograde into a dorsal vein in one hand. The hand was placed in a thermostatically controlled warmed box, where it remained throughout the study so that arterialized venous blood samples could be obtained (6).
Two basal blood samples, 15 min apart, were drawn before the start of each study. After the second sample was drawn, the subject rapidly (within 1 min) drank a solution containing 75 g glucose [oral glucose tolerance test (OGTT)]. On 1 of the study days (OGTT+F), the subject received 7.5 g fructose (Sigma, St. Louis, MO) in addition to the 75 g glucose, and on the other day the subject received no fructose (OGTT-F). Blood samples were drawn every 15 min for 120 min after ingestion of the carbohydrate.
Analytical methods
Plasma glucose concentrations were measured with the glucose oxidase technique using a Glucose Analyzer II (Beckman Coulter, Inc., Fullerton, CA). Plasma insulin and glucagon (using 30-K antiserum) were measured by RIA (7, 8). Lactate (9) and fructose (10) were measured in blood deproteinized with perchloric acid. Plasma nonesterified fatty acids (NEFA) and triglycerides were measured with enzymatic colorimetric assays (NEFA C, Wako Chemicals, Richmond, VA, and IL Test Triglyceride, Instrumentation Laboratory, Lexington, MA, respectively) on a Monarch 2000 centrifugal analyzer (Instrumentation Laboratory).
Calculations and statistical analysis
Data are the mean ± SE. The trapezoidal rule was used for calculation of areas under the curve (AUC) of substrate and hormone responses. All AUC are incremental (i.e. change from baseline values). Paired Student’s t tests were used for analysis of AUC data. Time-course data were analyzed with repeated measures ANOVA. Data were accepted as significant at P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There were no significant differences in the peak plasma glucose
concentrations during the OGTT-F and the OGTT+F (Fig. 1A
). The AUC of the plasma glucose
response, calculated as the change from basal values in each subject,
was approximately 19% smaller during the OGTT+F than during the OGTT-F
(P < 0.05; Fig. 1B).
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). There was no significant effect of
order of study on the glycemic response (P < 0.3).
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The insulin concentrations did not differ significantly between
the OGTT-F and OGTT+F (AUC, 24,732 ± 4,800 and 27,372 ±
4,572 pmol/L, respectively; Fig. 3A). Of
the nine subjects with a smaller glucose AUC during the OGTT+F than
during the OGTT-F, five had a smaller insulin AUC during the OGTT+F
(OGTT+F minus OGTT-F = -3,372 ± 1,536 pmol/L), and four had
a larger insulin AUC during the OGTT+F (OGTT+F minus OGTT-F =
4,392 ± 1,686 pmol/L). Two subjects had greater insulin and
glucose responses during the OGTT+F than during the OGTT-F. Both of
these subjects exhibited an increase of about 30% in the AUC of the
glucose response, with a 50–100% increase in the AUC of the
insulin response.
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), and the
concentrations declined similarly in both studies (final
concentrations, 40 ± 3 and 41 ± 5 ng/L, respectively;
P = NS vs. basal or between studies). Fructose and lactate
The blood fructose concentrations were nearly twice as great
during the study with fructose as in the one without fructose
(20.7 ± 3.9 and 38.4 ± 3.8 µmol/L in OGTT-F and OGTT+F,
respectively; P < 0.05; Fig. 4A).
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). NEFA and triglycerides
Neither NEFA nor triglyceride concentrations differed at any time
between the two studies (Table 1). During
the postprandial period, NEFA concentrations declined in relation to
basal values during both OGTTs. Triglyceride concentrations declined
significantly from baseline only during the OGTT-F.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This study was not designed to examine the mechanism(s) by which fructose had its effect, but differences in the insulin response during the two OGTT and the stimulation of hepatic glucose uptake secondary to enhanced hepatic glucokinase translocation are two possibilities. If the 120-min postingestion period is considered as a whole, there were no significant differences in the insulin responses between OGTTs. However, there was a tendency for the insulin concentrations to be higher in the OGTT+F vs. the OGTT-F for the first 45 min after carbohydrate ingestion. If a paired t test were used to compare the insulin concentrations at the 30 min point, the concentrations would have been significantly higher during the OGTT+F vs. OGTT-F. Similarly, the AUC of the insulin response during the period between 0 and 45 min was about 25% greater during the OGTT+F than during the OGTT-F (P < 0.05). Higher insulin concentrations would have stimulated glucose uptake by both the liver and insulin-responsive peripheral tissues, reducing the glycemic response. Nevertheless, there were no significant correlations between the insulin responses and the glycemic responses (whether the 0–45 min or the 0–120 min time period is considered). Of the nine subjects who demonstrated an improvement in glucose tolerance with fructose administration, five had a smaller insulin response, and four had a larger insulin response during the OGTT+F than during the OGTT-F. The two subjects who exhibited poorer glucose tolerance during the OGTT+F than during the OGTT-F had insulin responses that were 22–48% larger during the OGTT+F than during the OGTT-F. Thus, there was little evidence that stimulation of insulin secretion was responsible for the smaller glycemic response in most subjects during the OGTT+F.
In regard to the second possible mechanism for the fructose
effect (stimulation of glucokinase translocation), it is known that the
liver is a major contributor to the disposition of enterally delivered
glucose, taking up 20–30% of absorbed glucose in healthy humans and
converting approximately 70% of the glucose to glycogen
(12). Phosphorylation of glucose by glucokinase is a
rate-determining step for hepatic glucose metabolism. In the basal
(unfed) state, glucokinase in the liver is localized primarily in the
nucleus, where it is bound to the glucokinase regulatory protein
(GKRP). When GKRP is bound to fructose-6-phosphate, it is in a
conformation that favors interaction with glucokinase. On the other
hand, fructose-1-phosphate competes with fructose-6-phosphate for
binding to GKRP, and in so doing, releases glucokinase from GKRP
(13). Intraportal fructose infusion for 270 min increased
the hepatic concentration of fructose-1-phosphate to more than 170% of
the basal level in conscious dogs (10). Fructose
administration in animal models stimulates the translocation of
glucokinase (Shiota, M., P. Galassetti, T. L. Jetton, M. A.
Magnuson, and A. D. Cherrington, unpublished observations), and
low dose fructose administration accompanying intraduodenal glucose
infusion in dogs enhances net hepatic glucose uptake and net
hepatic fractional extraction of glucose about 2-fold (5).
The difference between the AUC of the plasma glucose responses during
the OGTT+F and OGTT-F totaled approximately 66 mmol. Blood lactate
concentrations were higher after the OGTT+F than the OGTT-F
(P < 0.05), presumably because of an increase in net
hepatic production of lactate (5). The difference in the
lactate AUC between the two tests totaled about 11 mmol glucose
equivalents, consistent with a stimulation of glycolysis. Fructose is
reported to increase the activities of both pyruvate kinase and
phosphofructokinase, key regulators of glycolytic flux
(14, 15, 16, 17). Thus, the difference in the glucose AUC between
the OGTTs was much greater than the difference in the lactate AUC
(55 mmol). Although the fate of this carbon is unclear, the findings
are consistent with enhancement of NHGU and glycogen storage by
fructose. In the presence of low dose fructose infusion, humans
subjected to a euglycemic hyperinsulinemic clamp exhibit enhanced
glycogen synthase flux and hepatic glycogen storage
(18).
The improvement in glucose tolerance with fructose administration
was greatest in those individuals with the largest glycemic excursion
in response to the OGTT-F. The subjects could be divided into those
with large responses to the OGTT-F (defined as >330 mmol/L) and those
with small responses to the OGTT-F (<330 mmol/L). All 6 subjects with
a glucose AUC greater than 330 mmol/L during the OGTT-F exhibited a
smaller glycemic response during the OGTT+F. On the other hand, only 3
of the 5 subjects with a glucose AUC less than 330 mmol/L during the
OGTT-F had a smaller glycemic response during the OGTT+F, and the
reduction in the glycemic response in those 3 subjects was modest. The
difference in the glucose responses between the 2 subgroups can be seen
more clearly in Fig. 5, which depicts the
time course of the glucose response. None of the 11 subjects had
impaired glucose tolerance or frank diabetes, as defined by the
American Diabetes Association criteria (19). Even in these
individuals with normal glucose tolerance, however, those with the
poorest glucose tolerance benefited the most from the addition of
fructose to the glucose load. These results suggest that individuals
with abnormal glucose tolerance might benefit even more than subjects
with normal glucose tolerance from the addition of fructose to glucose
feedings. The 2 subjects who exhibited an increase in the AUC of the
glucose response during the OGTT+F vs. the OGTT-F were both
Asian males, but we know of no data indicating that there are racial or
gender differences in fructose metabolism. These subjects were similar
in age (22 and 31 yr) and body mass index (22.2 and 23.3
kg/m2) to the balance of the subjects. The third
Asian subject, a woman, demonstrated a 57% decrease in the glucose AUC
during the OGTT+F compared with that during the OGTT-F.
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20% of total energy intake and 0.75 g/kg BW,
respectively) are reported to elevate circulating triglyceride levels
(20, 21). In response to a low dose of fructose,
triglyceride concentrations remained at basal levels. On the other
hand, triglyceride concentrations declined significantly during the
OGTT-F, suggesting that there was a mild stimulation of triglyceride
synthesis in response to fructose (22). In conclusion, the addition of small (catalytic) amounts of fructose to a glucose load improves glucose tolerance in normal humans, with the improvement being most evident in those individuals with the worst (albeit not clinically abnormal) glucose tolerance. The improvement in glucose tolerance cannot be explained on the basis of the insulin response to the carbohydrate loads. These findings may hold promise for the improvement of carbohydrate tolerance in individuals with impaired glucose tolerance and diabetes.
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Acknowledgments |
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Footnotes |
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Received January 24, 2000.
Revised August 25, 2000.
Accepted September 5, 2000.
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