1 Laboratory of Experimental Medicine, and Departments of 2 Endocrinology and 3 Gastroenterology, Hôpital Erasme, Brussels Free University, B-1070 Brussels, Belgium
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ABSTRACT |
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To determine whether the route of
glucose administration affects whole body glucose metabolism, 14 healthy volunteers were randomly infused with intraduodenal (id) or
intravenous (iv) glucose at 6 mg · kg1 · min
1 for 180 min. Infused glucose was labeled with [2-3H]glucose in a
first series of paired experiments designed to characterize kinetic
parameters to be used in a second series of experiments in which
[3-3H]- and [U-14C]glucose labeling was
used to characterize the metabolic fate of infused glucose. Experiments
with [2-3H]glucose showed that, after a lag period of
only 20 min, id absorption averaged 105 ± 3% of infusion. During
the final hour of id and iv infusion of [3-3H]glucose,
tissue uptake averaged 98 ± 3 and 107 ± 4% of infusion, respectively, and was equally divided between glycolysis
(3H2O production) and storage
(uptake-glycolysis). Glucose oxidation (14CO2),
total carbohydrate oxidation (indirect calorimetry), and net
carbohydrate balance were also similar, but the thermic effect of
glucose was significantly greater after id infusion. Because insulin
and estimated portal vein glucose levels were similar during the final
80 min of both infusions, our results suggest that hepatic glucose
storage (and therefore muscle storage estimated as whole body minus
liver storage) is not affected by the route of glucose administration.
intestinal glucose absorption; glucose storage; glycolysis; thermic effect of glucose
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INTRODUCTION |
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ORAL GLUCOSE IS KNOWN TO INDUCE a smaller glycemic and a greater insulinemic response than the same dose given intravenously (24, 26). These differences and other potential factors specifically related to the site of entry of glucose (6, 18) might influence its metabolic handling by the organism, especially as regards the relative importance of splanchnic vs. peripheral glucose uptake and storage.
Only a few studies have addressed this question in humans using either hepatic vein catheterization or tracer methodology, with discordant results (7, 28, 29). Among several methodological difficulties encountered when comparing oral and intravenous (iv) glucose metabolism is the difficulty of measuring intestinal absorption without access to the portal vein. Another difficulty is that intestinal absorption is unsteady and poorly predictable, owing to the fluctuations in gastric emptying. For these two reasons it is difficult to obtain a perfect match between an iv infusion and the intestinal absorption of an oral glucose load for comparative studies in the same subject.
To obviate some of these difficulties, the present study aimed at comparing intraduodenal (id) and iv glucose administration in the same individual. Radioisotope techniques were used in a two-step procedure. In a first series of id and iv experiments, we used [2-3H]glucose in the infusate to determine the effective pool volume through which glucose is distributed after intestinal absorption as well as the kinetics of this absorption. After measuring these parameters, we compared, in a second series of experiments, the whole body metabolism of id and iv glucose labeled with [3-3H]- and [U-14C]glucose to measure the rates of tissue uptake, glycolysis, storage, and oxidation of exogenous glucose for the two infusion routes. Total carbohydrate oxidation, net carbohydrate balance, fat oxidation, and energy expenditure were also determined, using indirect calorimetry.
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MATERIALS AND METHODS |
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Protocol
Fourteen healthy male volunteers without history of diabetes participated in the study. Their characteristics were the following: age 27 ± 1 yr, body weight 77 ± 3 kg, and body mass index 22.2 ± 1.6 kg/m2. The nature, purpose, and potential risks of the study were explained to the subjects, and their written, informed consent was obtained before participation. The protocol was approved by the Ethics Committee of the Faculty of Medicine of the University of Brussels. Subjects were divided into two groups, as follows.Group I.
Seven subjects participated in this protocol. They were tested with id
and iv glucose in random order at a 3-wk interval. At about 6:00 PM on
the day before the first experiment, the volunteers were injected with
20 µCi of 3H2O to determine total body water
(TBW) volume from the 3H2O concentration of
basal urine and blood samples collected the next morning. The id test
was performed as follows. After an overnight fast of 12 h, an
esogastroduodenoscopy was performed using a G1F160 gastroscope
(Olympus, Tokyo, Japan) to introduce a "pigtail" 6 French
nasoduodenal drainage catheter (Cook Ireland, Limerick, Ireland), whose
tip was placed in the duodenum ~15 cm beyond the pylorus. Correct
catheter positioning was confirmed fluoroscopically. The proximal end
of the catheter was then passed through the nasal fossae and secured
with tape on the skin next to the nostrils. The whole procedure was
performed under mild sedation with 2-3 mg iv of Midazolam
(Dormicum, Hoffman-La Roche, Grenzach, Germany) and lasted for ~20
min. A small catheter for blood sampling was placed in a dorsal hand
vein in a retrograde fashion. This catheter was kept patent with a slow
saline drip, and the hand was placed in a temperature-regulated heating
pad to allow arterialization of the venous blood. After a resting
period of ~1 h, two basal blood samples were collected at a 20-min
interval. Next, a 20% glucose solution labeled with
[2-3H]glucose (1.1 µCi/min) and containing 150 mmol
NaCl/l to facilitate active intestinal glucose transport
(25) was started and infused at a constant rate of 6 mg · kg1 · min
1 by use of a
peristaltic pump. No priming dose was used. Three milliliters were
allowed to flow before time 0 to fill the nasoduodenal catheter. Blood samples for determination of [3H]glucose,
3H2O, insulin, glucagon, and various substrates
were obtained at 20-min intervals until 40 min after the end of
infusion. Timed urine specimens were obtained before and after the
glucose infusion. The iv infusion test was performed according to the
same protocol, except that the infused glucose did not contain NaCl and
was administered through an indwelling Teflon catheter located in an
antecubital vein.
Group II. Seven subjects participated in this second protocol, which was identical to that of group I except for the following modifications. 1) The infused glucose was labeled with both [3-3H]- (1.1 µCi/min) and [U-14C]glucose (0.03 µCi/min); and 2) samples of expired air were collected in a rubber bag at 20-min intervals during the infusion and postinfusion periods for prompt analysis of 14CO2 specific activity. Respiratory gas exchanges were determined by computerized open-circuit calorimetry (Deltatrac, Datex, Helsinki, Finland) during the basal period and for 15-min periods during the intervals between blood sampling. Subjects were asked to make sure that the meal taken the night before each test was similar in quantity and composition and was ingested at the same hour to ensure comparable nutritional conditions.
All tracers used in both groups were purchased from Du Pont-NEN (Boston, MA)Analytical Procedures
Blood samples were collected in heparinized syringes and transferred to tubes kept on ice. The samples used to measure unlabeled and labeled glucose and lactate concentrations contained NaF, and those used to measure the glucagon concentration contained aprotinin. After centrifugation at 4°C, plasma was stored atCalculations for Group I: Experiments with [2-3H]Glucose
Tissue uptake of exogenous glucose.
Assuming that the glucose taken up by the cells is immediately
phosphorylated to glucose 6-phosphate, which is rapidly and reversibly
converted to fructose 6-phosphate, the formation of 3H2O during infusion of
[2-3H]glucose reflects the exogenous glucose uptake
(30), which was calculated as follows in both id and iv
experiments
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(1) |
Effective glucose space during the course of iv glucose
infusions.
In the iv experiments, the infused glucose enters the bloodstream
directly, and at any time, the amount of glucose not taken up by the
cells is distributed through an effective extracellular glucose space
that can be calculated as
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(2) |
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Intestinal absorption.
Assuming that the time course of Veff was comparable in the
id and iv experiments in a given subject (see DISCUSSION),
cumulative intestinal glucose absorption (GA) at time t (in
g) was calculated as the sum of the extracellular glucose content of
exogenous origin at time t and the cumulative amount of
glucose taken up by the tissues from time 0 to time
t
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(3) |
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Calculations for Group II: Experiments with [3-3H]Glucose
Pathways of glucose metabolism during id and iv glucose infusions. For calculations, we used two items of information obtained in the experiments with group I: 1) the average evolution of Veff with time and 2) the demonstration (see RESULTS) that it takes only ~20 min of constant id infusion for absorption to occur at the rate of infusion. Because in the experiments with group II the 3H label was on carbon-3, the generation of 3H2O allowed the quantification of glycolysis (30).
The cumulative uptake and disposal of exogenous glucose in the id and iv experiments at time t were calculated, in grams, according to the following equations (abbreviations as in Eqs. 1 and 2)
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(4) |
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(5) |
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(6) |
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(7) |
Statistical Analysis
Data were expressed as means ± SE. Statistical analysis was performed using the computer program SUPERANOVA (Abacus Concepts, Berkeley, CA). Results were analyzed using a two-factor (group × time) ANOVA with repeated measures on time, and whenever a difference was detected at a statistically significant level (P < 0.05), simultaneous pairwise comparisons between id and iv tests were made by a modified t-test with the standard error derived from the ANOVA. ![]() |
RESULTS |
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Experiments with [2-3H]Glucose
As shown in Fig. 1A, the radiolabeled glucose concentrations (and therefore the exogenous glucose plasma levels) were significantly lower after id than after iv glucose throughout the infusion period (P = 0.002) and decreased rapidly thereafter in both protocols.
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The curves depicting the 3H2O concentration
(Fig. 1B) and the cumulative uptakes of exogenous glucose
(Eq. 1 and Fig.
2A) were not significantly
different in id and iv experiments (P > 0.05). As
shown in Fig. 2B, noncumulative tissue uptake rose faster in the id studies during the initial 80 min, obviously due to the smaller
increase in the [3H]glucose concentration (Fig.
1A). During the last hour of infusion, the uptake/infusion
ratios were fairly steady and averaged 1.06 ± 0.04 and 1.08 ± 0.04, respectively (not significantly different from 1.00), in id
and iv studies (Fig. 2B).
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Figure 2C shows that the Veff determined from the iv infusion data (Eq. 2) constituted 18 ± 1% of the TBW at t = 20 min and rose gradually to reach a steady-state proportion of 29 ± 3% of the TBW during the last 40 min of infusion. The introduction of the successive individual Veff values in Eq. 3 allowed us to calculate cumulative intestinal glucose absorption in the id experiments (Fig. 2D), which showed that 99 ± 2% of the infused glucose had been absorbed by the end of 180 min of infusion. Splitting up this curve to provide the time course of absorption per 20-min period (Fig. 2E) revealed that the absorption rate amounted to only 52 ± 5% of the infusion rate during the initial 20-min period but that, during the following 160 min, the absorption rate rose quickly to slightly, but not significantly, more than the rate of infusion, with an absorption/infusion ratio averaging 1.05 ± 0.03.
Experiments with [3-3H]Glucose
Table 1 shows that the basal metabolic characteristics of the subjects were comparable at the start of the id and iv infusion tests.
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Substrate and hormone concentrations.
Total and exogenous glucose concentrations exhibited a biphasic pattern
during both iv and id glucose infusion (Fig.
3). However, peak total glucose levels
were lower during id than during iv infusion (153 ± 9 vs.
209 ± 13 mg/dl; P < 0.005) and occurred significantly
earlier (60 ± 7 vs. 80 ± 9 min; P < 0.02)
after the start of infusion. Mean glycemia over 3 h was also
significantly reduced (132 ± 4 vs. 178 ± 11 mg/dl;
P < 0.005). After the 180 min of infusion, the glucose
concentration dropped rapidly, so that plasma glucose fell to below
baseline after 20 and 40 min in both conditions (Fig. 3). Insulin rose
sharply during id glucose infusion, peaked at 40 min, and then declined
slowly. The response to iv glucose was more gradual, peaking only at
~120 min. Average insulin levels were significantly higher with id
glucose over the initial 80 min of infusion (P < 0.005) but were not different thereafter. Lactate concentrations
changed in parallel with glucose concentrations. Peak levels were
slightly, but not significantly, higher after id glucose (1.51 ± 0.06 vs. 1.35 ± 0.11 mmol/l; P > 0.05). Free
fatty acid profiles were similar with both types of infusion (Fig. 3);
an 80% drop was observed during the initial 100 min, followed by
steady levels. Glucagon concentrations (not shown) fell by ~30%
during the initial 100 min under both experimental conditions and
remained steady thereafter until 180 min.
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Glucose fluxes.
The integrated rates of uptake and disposal of exogenous glucose for
the 3-h infusion period are shown in Table
2. Uptake (Eq. 4) was
slightly, but significantly, higher in id than in iv experiments
(74.8 ± 0.9 vs. 70.6 ± 1.0 g/3 h; P < 0.01) on account of the difference in exogenous glucose levels recorded at the end of the infusions (Fig. 3). Whole body metabolic clearance rate was ~45% higher in id studies (83.7 ± 2.7 vs. 57.8 ± 3.9 l/3 h; P < 0.001). Glucose was equally
distributed between glycolysis (Eq. 5) and storage
(Eq. 6) under both experimental conditions (Table 2). The
net carbohydrate balance was very close to isotopically measured
storage under both conditions. Exogenous glucose oxidation (Eq. 7) was similar in id and iv experiments (~12 g/3 h) and
considerably lower than total carbohydrate oxidation.
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Energy expenditure. During id glucose infusion, energy expenditure increased, reached its peak at ~100 min, and then decreased slightly (Fig. 4). A faster fall was observed after the infusion ended. The integrated increment over 180 min amounted to 24 ± 1 kcal. A smaller delayed increase in energy expenditure was also observed after iv glucose, but it did not reach statistical significance (+8 ± 3 kcal over 3 h). The difference between the two integrated incremental values was highly significant (P < 0.005).
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DISCUSSION |
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The lower glycemic and higher insulinemic responses observed after id than after iv glucose confirm the results of many other studies (e.g., Refs. 24 and 26). Because the 3-h glucose entries from endogenous and exogenous sources were comparable in the two experimental protocols, the difference in glucose levels must have been entirely due to the greater whole body metabolic clearance rate observed in the id experiments (Table 2). Note that our experimental design does not permit separate quantification of splanchnic and peripheral glucose uptake. The increased clearance associated with the id administration was at least partly due to the higher insulin response generally attributed to an incretin effect involving gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP1) (8, 22). In the present study, the difference in insulin response to id vs. iv glucose was relatively modest and was observed only during the initial 80 min of infusion (Fig. 3). It has been demonstrated (31) that the incretin effect is much less marked after id than after oral glucose, owing to a lesser stimulation of GLP1 but not of GIP secretion. The slightly higher lactate response observed in our id vs. iv experiments has already been documented and attributed to extra lactate produced by the gut (27).
To our knowledge, this is the first study comparing id and iv glucose metabolism in humans. This comparison was made possible by the demonstration in the first part of the study, using [2-3H]glucose, that glucose absorption from a constant id infusion is both rapid and complete after a lag period of ~20 min (Fig. 2E). The validity of this demonstration rests essentially on three assumptions. The first assumption is that the [2-3H]glucose taken up by the tissues is immediately phosphorylated and the 3H transferred to water, so that the 3H2O formation reflects tissue glucose uptake. The second assumption is that the metabolic 3H2O generated in intracellular water is in rapid exchange with the extracellular water in which measurements are made. Both of these assumptions have been validated previously in humans (30). It is likely that some 3H is lost in the futile cycling between glucose and glucose 6-phosphate in the liver, but there is marked disagreement in the literature regarding the level of activity of this cycle in humans (2, 21). Because the 3H lost in this cycle is recovered as 3H2O, it should not affect the calculation of intestinal absorption (Eq. 3), but it should lead to some overestimation of tissue uptake (Eq. 1) and of Veff (Eq. 2). According to our calculations, Veff accounted for ~18% of TBW at 20 min and rose slowly to ~29% at the end of the infusion, a figure in the accepted normal range for extracellular fluid (9). The initial rise in Veff with time probably reflects the progressive access of infused glucose to more and more remote parts of the interstitial fluid. The third assumption is that the time course of Veff obtained from the iv experiments is also applicable to the id experiments. In favor of the validity of this assumption is the great similarity between the curves describing exogenous glucose tissue uptake in the id experiments with [2-3H]glucose (Fig. 2, top) and [3-3H]glucose (Fig. 4, top) respectively. Indeed, in the latter case, calculations of uptake (Eq. 4) were based on the Veff derived from the iv [2-3H]glucose experiments (Eq. 2).
The authors of several previous studies showed by either hepatic vein catheterization (10, 11) or dual oral-iv tracer glucose techniques (12, 19) that a significant amount of glucose absorbed by the gut is taken up at first pass by the splanchnic tissues and does not appear in the systemic circulation. Our observation that glucose administered id is rapidly and completely absorbed (Fig. 2E) does not contradict these data. In the [2-3H]glucose experiments, intestinal absorption was indeed calculated as the sum of the metabolized glucose (3H2O production) and the pool of [2-3H]glucose present in Veff. Any glucose taken up by the splanchnic bed at first pass will obviously not appear in the systemic circulation, but its absorption from the intestinal lumen will nevertheless be computed in the form of 3H2O originating from its splanchnic (hepatic) metabolism. Unlike the isotope studies in which a peripheral and an oral glucose tracer is used, our experimental design does not allow the quantification of first-pass splanchnic glucose uptake.
The existence of a short lag period before the rate of absorption
becomes equivalent to that of infusion was only to be expected. It
probably corresponds to the time needed for the intraluminal glucose to
cover a sufficiently large area of duodenal mucosa to enable absorption
to keep pace with the load presented. Unfortunately, no data are
available on the maximal duodenal glucose absorption rates measured
over well-defined segments of duodenum in humans with concentrated
glucose solutions. Such information would have permitted estimation of
the approximate length of duodenum participating in the absorption
process under our experimental conditions. Whatever the duodenal length
involved in our studies, the intraluminal glucose not absorbed by the
end of the infusion must have been quite small in view of the fast
decline in exogenous and total glucose concentrations observed after
the infusions ended (Figs. 1 and 3). These conclusions are in agreement
with the data recently published by Livesey et al. (23),
who measured the systemic appearance of intraduodenal glucose in humans
and showed complete and rapid absorption for infusion rates of 8
mg · kg
1 · min
1.
Interestingly, their data suggest that absorption capacities might be
much lower in the more distal part of the intestine.
In the second series of our experiments (group II), designed to quantitate the uptake and pathways of exogenous glucose disposal, we observed that, during the final hour of infusion, when glucose fluxes were reasonably steady, the rates of uptake were comparable under the two experimental conditions and that the uptake was more or less equally divided between glycolysis and storage. A similar pattern was observed for the 3-h infusion period as a whole (Table 2). Because identical values of Veff were used in the calculation of exogenous uptake in id and iv studies (Eq. 4), the possible overestimation of Veff mentioned before should not invalidate the comparison between the two infusion protocols. Note that mean basal carbohydrate and fat oxidations were virtually identical in both of the tests that the subjects underwent (Table 1), indicating a similar degree of metabolic fast. This is important, because the initial nutritional status is a major factor controlling the balance between glycolysis and oxidation on the one hand and storage on the other after oral or iv glucose administration (13, 14).
As mentioned earlier, our experimental design did not allow us to quantitate hepatic and peripheral glucose metabolism separately. In human physiology, it is commonly believed (7), but not universally admitted (27), that orally administered glucose specifically enhances hepatic uptake and storage, in particular because of the higher portal vein levels of insulin and glucose associated with this route of administration. Several possibilities may account for the finding that the site of entry of glucose did not affect the whole body glucose balance under our experimental conditions. 1) Even if the id route of infusion preferentially promotes splanchnic (hepatic) glucose uptake, the effect may be quantitatively too small to be detected at whole body level. 2) Specific enhancement of hepatic uptake and storage after id glucose may have been compensated for by a decrease in peripheral (muscle) storage, with the whole body glucose balance remaining unchanged. In favor of this latter possibility are studies in dogs (1, 16), which compared hepatic uptake of glucose given via the portal or a peripheral vein in normal, conscious animals maintained at basal insulin and glucagon levels and in which it was found that, when glucose is delivered intraportally, hepatic uptake is enhanced at the expense of skeletal muscle uptake and storage (16). These effects were attributed to a "portal signal" triggered by the negative arterial-portal glucose concentration gradient associated with the oral or intraportal delivery of glucose. A similar effect was documented in rats (5). It is not known whether this is also the case in humans, in whom comparable experiments cannot be made in the absence of access to the portal vein. 3) Finally, it is possible that neither hepatic nor peripheral glucose uptake and storage is affected by the route of glucose administration. This possibility is supported by the isotopic experiments performed in humans by Radziuk (28), which showed that the amounts of hepatic glycogen formed by the direct and indirect pathways are not significantly altered by the route of glucose delivery (28, 29). This author pointed out (28) that portal vein glucose levels are probably similar after oral and iv glucose because peripheral glucose levels are higher during iv administration. A simple calculation indicates that this was probably also the case in our study. Indeed, the absolute rate of glucose infusion amounted to ~500 mg/min in group II. Assuming a portal vein blood flow of 1,100 ml/min (17), intestinal glucose absorption should raise the blood level in the portal vein by ~45 mg/dl (~50 mg/dl for plasma), a value close to the difference of ~47 mg/dl observed between peripheral plasma glucose during id and iv infusion (Fig. 3). In addition, because insulin levels were similar in id and iv studies during the final 80 min of infusion (Fig. 3), it is likely that, during that period, the liver was exposed to comparable levels of both glucose and insulin and therefore handled glucose in a similar manner under both conditions. However, this interpretation should be made cautiously, because it does not take into account the possible interference of other potential regulators of hepatic glucose metabolism such as splanchnic blood flow or the portal signal already mentioned.
Exogenous glucose oxidation, calculated from 14CO2 production, did not differ according to the route of administration. Note that this rate of oxidation, even after correction for incomplete recovery of 14CO2 was much lower (~12 g/3 h) than total carbohydrate oxidation, measured by indirect calorimetry (~35 g/3 h). This may indicate either that unlabeled preexisting glycogen continues to be oxidized during the process of exogenous glucose storage (i.e., glycogen turnover) or that the coefficient used for correcting expired 14CO2 production for incomplete recovery was inappropriate, or both. It should be noted that the recovery factor used (32) is supposed to be applied to studies in which the labeled expired CO2 produced by a glucose infusion has reached a steady state thanks to priming of the bicarbonate pool. This was not the case under our experimental conditions, in which a smaller, yet undetermined, recovery factor should probably be used.
The thermic effect of intraduodenal glucose measured over the 3 h of infusion (24 ± 1 kcal) amounted to 8.5 ± 0.5% of the caloric content of the glucose taken up, in agreement with published data (20). This value was significantly higher than after iv glucose, even though the metabolic fluxes in the various pathways were identical. Splanchnic tissues seem to be involved in this difference as shown in a recent study (4); iv and oral (and probably id) glucose elicit extrasplanchnic thermogenic effects of similar magnitude, but during iv infusion, splanchnic O2 consumption is reduced, whereas, during oral (and probably id) administration, it rises proportionally to the splanchnic blood flow.
In conclusion, during constant id infusions of glucose in humans for
180 min at a relatively high rate (6 mg · kg1 · min
1),
intestinal absorption becomes equal to the rate of infusion after a lag
period of ~20 min. Whole body glucose uptake, glycolysis, oxidation,
and storage are comparable to those recorded during equivalent iv
infusions into the peripheral circulation. Because the insulin and
estimated portal vein glucose levels were similar during the final 80 min of both iv and id infusion, our results suggest that hepatic
glucose storage (and therefore muscle glucose storage estimated as
whole body minus liver storage) were not affected by the route of
glucose administration.
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ACKNOWLEDGEMENTS |
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We thank M. A. Neef and the nurses of the Gastroenterology Department for expert technical help, C. Demesmaeker for excellent secretarial assistance, and M. Dreyfus for English correction.
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FOOTNOTES |
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This work was supported by grants from the Fonds de la Recherche Scientifique Médicale Belge (no. 3.4513.00), the Fonds Suzanne et Jean Pirart of the Association Belge du Diabète, and the European Foundation for the Study of Diabetes.
Address for reprint requests and other correspondence: E. O. Balasse, Laboratory of Experimental Medicine, Brussels Free University, 808 Route de Lennik, B-1070 Brussels, Belgium.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 2 November 2000; accepted in final form 8 March 2001.
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