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Laboratory of Experimental Medicine and Physiopathology and Department of Endocrinology (F.F., E.O.B.), and Department of Gastroenterology (J.D.), Hôpital Erasme, University of Brussels, B-1070 Brussels, Belgium; and Institute of Physiology (L.T., P.S.), School of Medicine, University of Lausanne, CH-1005 Lausanne, Switzerland
Address all correspondence and requests for reprints to: F. Féry, Laboratory of Experimental Medicine, Brussels Free University, 808 Route de Lennik, B-1070 Brussels, Belgium. E-mail: ffery{at}ulb.ac.be.
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Abstract |
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Context: Twenty-six normal volunteers were given a constant 3-h intraduodenal infusion of glucose (6 mg·kg–1·min–1) labeled with [2-3H]glucose for glucose absorption measurement. During glucose infusion, 19 subjects received iv SST at doses of 10–100 ng·kg–1·min–1 plus insulin and glucagon, and seven subjects were studied under control conditions. In the controls, glucose was absorbed at a rate that, after a 20-min lag period, equaled the infusion rate.
Results: With all the doses of SST tested, absorption was considerably delayed but equaled the rate of infusion after 3 h. At that time, only 5 ± 2% of the total amount of infused glucose was unabsorbed in the control subjects vs. 36 ± 2% (P < 0.001) in the SST-infused subjects. In the latter, the intraluminal residue was almost totally absorbed within 40 min of the cessation of SST infusion. At the lowest dose of SST tested (10 ng·kg–1·min–1), suppression of insulin secretion was incomplete.
Conclusion: These properties of SST hamper the use of intraduodenal hyperglycemic hyperinsulinemic clamps as a tool for exploring postprandial glucose metabolism.
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Introduction |
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One solution recently employed to circumvent these difficulties is to apply the dual isotope technique to hyperinsulinemic hyper- or euglycemic clamps in which glucose is infused by the intraduodenal route (3, 4). To quantify hepatic (splanchnic) glucose uptake under these conditions, the rate of appearance (Ra) of enteral glucose in the peripheral circulation, measured isotopically, is subtracted from its rate of entry into the splanchnic circulation, which is assumed to be equal to the rate of glucose infusion (3, 4). Recent studies have shown this assumption to be correct under physiological conditions up to infusion rates of 8 mg·kg–1·min–1 (5, 6). However, performing hyperglycemic hyperinsulinemic clamps implies the use of somatostatin (SST) to inhibit endogenous insulin release. For the calculation of hepatic (splanchnic) uptake to be correct, it is therefore essential to make sure that SST does not inhibit intestinal glucose absorption.
Many studies of the effects of SST or its analog octreotide on intestinal carbohydrate absorption, measured in vitro and in vivo, are available for various animal species and for humans. In these studies, different techniques were used, with discrepant results (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19). In a recent study of hepatic uptake of glucose during intraduodenal infusions under clamp conditions, we were afraid that SST might inhibit intestinal absorption, and as a precaution, we discarded its use (4). This possibility of inhibition was explored in the present study, in which we evaluated the effects of a wide range of SST doses on intestinal glucose absorption in normal volunteers, using an original isotope technique recently developed in our laboratory (6).
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Subjects and Methods |
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Twenty-six healthy volunteers participated in the study. Their characteristics were the following: age, 26 ± 1 yr; sex, six females and 20 males; body weight, 70.1 ± 1.7 kg; and height, 177 ± 1 cm. 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. The subjects were divided into a control group and a SST group.
Control group
At 0700 h, after an overnight fast, the subjects (n = 7) reported to the metabolic unit, and a Teflon catheter was inserted into an antecubital vein for infusion of all test substances. They were then taken to the endoscopy room, where a duodenal catheter was placed as follows: esogastroduodenoscopy was performed using a G1F160 gastroscope (Olympus, Tokyo, Japan) to introduce a pigtail 6 French nasoduodenal drainage catheter (Cook Ireland Ltd., Limerick, Ireland) whose tip was placed in the duodenum about 15 cm beyond the pylorus. Correct catheter positioning was confirmed fluoroscopically. The proximal end of the catheter was 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 of iv Midazolam (Dormicum; Hoffmann-La Roche, Grenzach, Germany) and lasted for about 20 min. The subjects were then returned to the metabolic unit. A small catheter was placed in a dorsal hand vein for intermittent blood sampling, and the hand was placed in a temperature-regulated heating pad to allow arterialization of the venous blood. After a resting period of about 1 h, three basal blood samples were collected at 20-min intervals (–40, –20, and 0 min). Next (Fig. 1
), infusion of a 20% glucose solution labeled with [2-3H]glucose (1.1 µCi/min) and containing 150 mmol NaCl/liter to facilitate active intestinal glucose transport (20) was started (time 0) using a peristaltic pump and lasted for 180 min, at a constant infusion rate of 6 mg·kg–1·min–1. No priming dose was used. Before time 0, 3 ml was allowed to flow, to fill the nasoduodenal catheter. Blood samples were obtained at 20-min intervals until 40 min after the end of the infusion for determination of glucose, [2-3H] glucose, 3H2O, insulin, C-peptide, and glucagon. At about 1800 h on the day before the test, the volunteers were injected with 20 µCi of 3H2O to determine total body water volume (TBW) from the 3H2O concentration of a basal blood sample collected the next morning. The tracers were purchased from DuPont NEN Life Science Products (Boston, MA).
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SST group
The effects of various doses of SST on duodenal glucose absorption were tested in 19 subjects, using an experimental protocol identical to that of the control group, except for the following hormones, which were administered iv during the duodenal glucose infusion period (0–180 min): 1) SST 14 (UCB, Brussels, Belgium), which was given at the constant rates of 100 (n = 6), 60 (n = 3), 30 (n = 2), and 10 (n = 8) ng·kg–1·min–1; 2) glucagon (Glucagen; Novo Nordisk, Bagsvaerd, Denmark) administered to all subjects at the constant rate of 250 pg·kg–1·min–1; and 3) insulin (Actrapid HM; Novo Nordisk), which was infused at frequently adjusted rates, so as to obtain glucose excursions as close as possible to those observed in the control group.
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 concentrations contained NaF, and those used to measure the glucagon concentration contained aprotinin. After centrifugation at 4 C, plasma was stored at –20 C until assay. Plasma glucose was assayed by a glucose oxidase method (test combination glucose; Boehringer, Mannheim, Germany). Plasma [2-3H]glucose and 3H2O were measured after deproteinization by the Somogyi method. [2-3H]Glucose was counted by scintillation spectrometry on evaporated filtrates reconstituted with water, and 3H2O was determined as the difference between the tritium counts obtained with and without evaporation. The 3H2O in plasma water was calculated by dividing its concentration in total plasma by 0.93. The levels of plasma insulin (INSI-CTK immunoradiometric analysis; DiaSorin, Saluggia, Italy), C-peptide (C-peptide immunoradiometric analysis; DiaSorin), and glucagon (glucagon RIA kit; Linco Research, St. Charles, MO) were determined by RIA. All measurements were made in duplicate.
Calculations
At each time point, the plasma concentration of exogenous glucose was calculated as the ratio of the [2-3H]glucose concentration over the 2-3H specific activity of infused glucose.
Intestinal absorption
Intestinal absorption was calculated according to an original method described previously (6). The principles of this method are the following: at any time t the cumulative intestinal glucose absorption (GA) is equal to the sum of the cumulative amount of exogenous glucose taken up by the tissues from time 0 to time t (GU) and the extracellular glucose content of exogenous origin at time t (GE).
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 cumulative exogenous glucose uptake (21). Thus,
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Furthermore, it is obvious that
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) are those established in a previous study (6) during a constant iv glucose infusion (see Discussion).
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were also calculated for the successive 20-min periods, from the differences between the values obtained at two consecutive time points. All of the data on glucose fluxes were normalized for a body weight of 70 kg.
Statistical analysis
Data in the text and figures are expressed as means ± SEM. Statistical analysis was performed using the computer program SUPERANOVA (Abacus Concepts, Berkeley, CA). Results were analyzed using a two-factor (group x 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 groups were made by a modified t test with the SE derived from the ANOVA.
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Results |
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Figure 3 (A, B, and D–F) shows the glucose (total and enteral), C-peptide, insulin, and glucagon concentrations prevailing during and after the duodenal glucose infusion in the control group, and in the two groups given the two extreme doses of SST (100 and 10 ng·kg–1·min–1). Figure 3C shows the evolution of the amounts of insulin given to the subjects infused with SST. In the control group, all the concentrations measured except that of glucagon followed a biphasic pattern during glucose infusion, with an initial rise followed by a decline. These concentrations dropped rapidly during the postinfusion period. In the two SST groups, the initial rise in the total and exogenous glucose concentrations was much slower than in the control group despite the very small amounts of insulin delivered during the initial 60 min of glucose administration and the very low levels of insulinemia that ensued. The three groups had comparable levels of total glucose during the last 80 min of infusion, because the mean concentrations over that period amounted to 141 ± 9, 143 ± 8, and 146 ± 12 mg/dl (7.8 ± 0.5, 7.9 ± 0.4, and 8.1 ± 0.7 mmol/liter) for the control, SST 100, and SST 10 groups, respectively (P > 0.05). Suppression of C-peptide levels by SST was more marked with 100 than with 10 ng·kg–1·min–1, SST and the difference was highly significant from the 80th minute on (P 
0.01). After the glucose, SST, insulin, and glucagon infusions were stopped at 180 min, a rebound in total and exogenous glucose, C-peptide, and insulin levels was observed in the SST groups in contrast with the drop observed in the controls. Note that because of the experimental design, the circulating insulin levels in the SST experiments were almost exclusively of exogenous origin from 0–180 min and of endogenous origin from 180–220 min. The postinfusion C-peptide and insulin responses were not significantly different in the SST 10 and SST 100 groups. Glucagon levels were slightly lower than baseline in both SST groups and the controls during the infusion period, but their postinfusion rise was more pronounced in the SST groups.
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The total amount of glucose infused over 3 h, normalized for a body weight of 70 kg, was 75.6 g. As shown in Fig. 4, after a slight initial delay, the cumulative absorption curve in the control group ran parallel, and very close, to the glucose infusion line, and at 180 min, virtually all the administered glucose (72.0 ± 1.6 g) had been absorbed. In the subjects infused with SST, absorption was markedly delayed, and by the end of infusion, it amounted to only 47.2 ± 2.9 and 50.2 ± 2.0 g in the SST 100 and SST 10 groups, respectively. In these subjects, absorption persisted at a high rate during the postinfusion period and tended to catch up with the rate for the control subjects by the end of the experiments, at t = 220 min. The absorption curves for the SST 10 and SST 100 groups were not significantly different at any time point. Individual data regarding the cumulative amounts of enteral glucose absorbed at 1, 2, and 3 h of infusion in all subjects tested (Fig. 5) show that there was no overlap between the control and the SST-treated individuals and that the effect on absorption was independent of the SST dose in the range tested.
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. In the control subjects, the average absorption rate amounted to only 52 ± 3% of the infusion rate during the initial 20-min period but became complete during the following 160 min, because it averaged 100.7 ± 2.4% of the infusion rate during that period. Absorption decreased sharply after glucose infusion stopped and was not significantly different from zero during the last 20 min of the postinfusion period. In the subjects infused with SST, the glucose absorption rate was considerably inhibited at the beginning of the test, rose progressively with time, and became complete at 180 min, when it reached 100.1 ± 3.3% of the infusion rate. In sharp contrast with the control group, intestinal glucose absorption by the SST group rose during the postinfusion period, when it reached 19.0 ± 0.8 g from the 180th to the 220th minute vs. 3.5 ± 0.5 g for the same period in the controls (P < 0.001).
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Discussion |
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As mentioned above in the section Calculations, the cumulative absorption of intraduodenally infused glucose containing [2-3H]glucose was obtained at all time points by adding the cumulative amount of glucose taken up by the tissues (as determined by the 3H2O generation) to the exogenous glucose pool. The latter was calculated as the product of the exogenous glucose concentration by its effective distribution volume Veff. The Veff values used at the different time points were those determined in previous experiments for which we used a constant iv glucose infusion labeled with [2-3H]glucose and delivered at the rate of 6 mg·kg–1·min–1, the rate used in the present study. Because in these iv experiments, the rate of glucose entry was a known parameter, the successive Veff values could be calculated at the different time points by dividing the difference between the cumulative amount of glucose infused and that of glucose taken up, by the exogenous glucose concentration (equation 2 in Ref. 6). As shown in Fig. 2, the Veff curve increased with time during these iv glucose experiments until it reached a plateau after about 140 min. This saturation-type curve was interpreted as indicating that during its continuous flow from the plasma water to the cells, the infused glucose gradually gained access to the most remote parts of the interstitial fluid, which have a slow exchange rate with the more central parts of that compartment, and with cell water.
The accuracy of the Veff curve derived from these iv studies was based on at least three assumptions. The first was that the [2-3H]glucose taken up by the tissues was immediately phosphorylated and the 3H transferred to water, so that the 3H2O formation reflected tissue uptake. The second assumption was that the metabolic 3H2O generated at the intracellular sites, where phosphorylation to glucose-6-phosphate and further isomerization to fructose-6-phosphate take place, was in rapid exchange with TBW. The only in vivo experiments that may provide indirect information on the rate of this exchange are those examining the rate of equilibration of an iv bolus of isotopically labeled water with TBW. It has been shown that the degree of equilibration reaches about 67–69% after a few minutes (22), 87–90% after 30 min (22, 23), and about 100% after 1 h (22, 23, 24). To our knowledge, there are no available data on the rapidity of the reverse process we are dealing with here, i.e. the rate of equilibration with TBW of labeled water generated inside the cells. Both the above assumptions seem to have been reasonably well validated by the studies of Rossetti et al. (21) who showed, in humans, using [2-3H]glucose labeling, that the rate of infused glucose uptake is accurately reflected by 3H2O production. Furthermore, it should be noted that any distortion of the Veff abacus resulting from slower-than-expected 3H2O diffusion from the intracellular to the extracellular fluid would have occurred in both the iv and intraduodenal experiments and therefore would have had little impact on absorption measurements. The third assumption was that the Veff abacus derived from the iv experiments (Fig. 2) was applicable to the intraduodenal experiments for determination of absorption. At least two aspects of this question deserve comment. The first is related to the fact that the method requires the use of [3H]glucose labeled in position 2. Some 3H was probably lost in the futile cycling between glucose and glucose-6-phosphate in the liver. However, because the 3H lost in this cycle is recovered as 3H2O, this loss should not have affected the calculation of intestinal absorption (equations 1–3). The second aspect concerns the differences we observed between the glucose and insulin concentrations in iv and intraduodenal studies performed at identical infusion rates (6). The fact that the present intraduodenal studies confirmed the results of previous investigations (5) showing that duodenal glucose absorption is both rapid and complete suggests that the differences between the glucose and insulin concentrations recorded for iv and intraduodenal infusion (and by extension those existing between the control and the SST experiments of the present study) have no significant impact on Veff or on absorption measurements.
Although the above three assumptions on which our method was based seem reasonably well validated, we admit that some inaccuracies may exist in the determination of intestinal glucose absorption and in the comparison between the two experimental conditions tested.
Despite these reservations, it remains obvious that SST markedly delays the absorption of glucose infused intraduodenally at a rate of 6 mg·kg–1·min–1, which is close to the rate prevailing during a standard oral glucose tolerance test.
Our control experiments without SST showed that after a lag period of about 20 min, glucose was rapidly and almost completely absorbed (Figs. 4 and 6) so that of the approximately 75 g infused in 3 h, only approximately 4 g remained in the intestinal lumen at the end of the infusion (Fig. 4). This small residue was totally absorbed during the initial 20 min of the postinfusion period, during which glycemia rapidly returned to its baseline level.
In the SST experiments, the absorption rate was initially inhibited by about 60%, but rose continuously with time during glucose infusion. To understand this process, it should be noted that unlike the conventional multiple-lumen catheter technique (25), which measures absorption by a given intestinal segment, the method used here quantifies absorption by measuring the rate of entry of glucose into the bloodstream, without any knowledge of the length of intestine involved. In the course of the present SST infusions, the increasing amount of unabsorbed glucose probably migrated more and more distally and occupied a continuously increasing surface of intestinal mucosa, until the absorption rate matched the infusion rate. However, because it takes about 3 h to reach equilibrium, a large amount of glucose (
25 g) remained unabsorbed at the end of the glucose infusion. After the SST infusion, the intestine rapidly recovered its absorption capacities thanks to the very short half-life of SST in plasma (26), and most of the unabsorbed glucose entered the bloodstream within the 40 min after infusion, thus accounting for the sharp rise in the glucose concentration that occurred despite the immediate restoration of insulin secretion (Fig. 3). The inhibitory effect of SST on glucose absorption accounted for our inability to obtain glucose concentrations as high as those of the control group during the initial 80 min of the SST experiments, despite very low insulin infusion rates and concentrations.
Discrepancies exist in the literature regarding the effects of SST on carbohydrate absorption. In animal studies, SST has been shown to inhibit or not to affect absorption in rats (7, 14, 19), to inhibit absorption in dogs (16), to have no effects on hamsters (11) or monkeys (17), and to stimulate absorption in minipigs (13). In humans, two important studies have documented an inhibitory effect of SST on glucose absorption using the multiple-lumen catheter technique (25). In one study (9), the authors showed that iv-infused SST had a dose-dependent effect on oral glucose absorption in the proximal 70 cm of intestine after a 75-g oral load, and that the inhibition was still detectable at SST doses as low as approximately 0.7 ng·kg–1·min–1. The decreased absorption effectiveness was compensated by a longer transit time, so that the totally absorbed glucose in the segment studied approached the control value. In the other study (12), the authors tested the effect of a single high dose of SST (133 ng·kg–1·min–1) on the absorption by a 10-cm intestinal segment of increasing amounts of glucose (up to 3 mg·kg–1·min–1). They observed an approximately 30% reduction in the absorption rate, and kinetic analysis revealed that it was mainly the result of a reduced Vmax of glucose transport. These authors ascribed this reduction to a direct action of SST on the intestinal mucosa, rather than on intestinal motility or splanchnic blood flow. Although our experiments were performed with a markedly different methodology, our results are in line with those of these two human studies.
The specific aim of the present study was to evaluate the effects of pharmacological doses of SST on intestinal glucose absorption, in view of its use during intraduodenal glucose clamps. We started with 100 ng·kg–1·min–1, which corresponds to an average dose used to inhibit insulin secretion during iv hyperglycemic hyperinsulinemic clamps. We then tested decreasing SST doses in the hope of finding a dose that would not inhibit absorption but would still inhibit insulin secretion. We found that the lowest dose tested (10 ng·kg–1·min–1) no longer inhibited insulin secretion completely (Fig. 3) but still exerted a maximal inhibitory action on absorption. Consequently, methodological problems seem to prevent the use of SST for performing hyperglycemic hyperinsulinemic clamps with enterally delivered glucose, because at the minimal dose able to control insulin secretion, it cannot be assumed that absorption is complete.
Over the last few years, the group of Rizza and colleagues performed a series of human studies on initial splanchnic uptake of enteral glucose, measured by the dual isotope method in normal (3, 27) and diabetic (27, 28) subjects under hyperglycemic hyperinsulinemic clamp conditions. SST was used at the dose of 60 ng·kg–1·min–1 to suppress endogenous insulin secretion. Intestinal absorption was not measured in these studies, and first-pass splanchnic extraction was computed from the difference between the rate of intraduodenal infusion and the Ra of exogenous glucose in the systemic circulation, implying that absorption was complete despite the infusion of SST. Our present results indicate that at the dose used, SST does markedly impair absorption efficacy. This impairment probably accounts for the observation in the studies by Vella et al. (28) that during a constant enteral glucose infusion with iv SST, the Ra of intestinal glucose rises slowly with time and that it takes more than 180 min to reach a steady state. This pattern is very similar to that observed for glucose absorption in our SST experiments (Fig. 6). Interestingly, our data also show that the average absorption becomes about equal to the infusion rate at 180 min and presumably beyond that time. Therefore, although the Mayo Clinic group seems to have overlooked the possible effects of SST on absorption, their assumption that the absorption rate matched the infusion rate during the last 30 min of a 240-min enteral glucose infusion may be correct. Nevertheless, it remains a hypothesis, because our observations do not necessarily apply to their experimental conditions, which differed from ours, for instance, regarding the site of enteral infusion, the amount of glucose infused, and probably other unknown parameters. On the other hand, even if intraduodenal glucose infusion is maintained long enough to reach a steady absorption rate equal to the rate of infusion, the accumulation of significant amounts of unabsorbed glucose in the gut during the glucose infusion does not allow the clamping of the glucose concentration with the exogenous glucose delivered exclusively by the enteral route. This difficulty can be overcome by performing clamps with dual infusion, comprising a constant infusion of enteral glucose and a variable infusion of iv glucose to maintain glycemia constant (3, 27, 28). However, this procedure does not exactly mimic the physiological postprandial situation.
In this study, we did not explore the mechanisms by which SST inhibits absorption. The inhibition by SST of splanchnic hemodynamics (29) and of intestinal motility (9) (which should prevent optimal contact of the glucose load with the absorbing mucosa) are among the suggested possibilities, but a direct action of SST on the absorptive process itself cannot be excluded. Recent studies by Kellett (30) indicate that at the high intestinal glucose concentrations prevailing after a glucose meal, the main process involved in absorption is facilitated diffusion, which relies on the rapid, glucose-dependent activation and recruitment of the high-Km glucose transporter GLUT-2 from the basolateral membrane to the brush-border membrane of the enterocytes. This regulation involves a protein kinase C-dependent pathway activated by glucose transport through the Na+-glucose cotransporter SGLT-1. This activation might be mediated by a glucose-induced increase in intracellular Ca2+ (30). The essential role of apical membrane GLUT-2 content in sugar absorption was recently confirmed in GLUT-2-null mice (31). To our knowledge, there are no available studies on the effects of SST on this GLUT-2 trafficking process. Because SST reduces intracellular Ca2+ because of its receptor-linked effects on adenylate cyclase and K+ and Ca2+ ion channels (32), it is conceivable that at least part of the inhibitory effect of SST on high-rate intestinal glucose absorption results from the impairment of glucose-induced GLUT-2 translocation.
In summary, the present results indicate that pharmacological doses of SST markedly impair the absorption of intraduodenally administered glucose in humans. The lowest dose tested (10 ng·kg–1·min–1), which still had a maximal inhibitory effect on absorption, did not completely suppress insulin secretion. These properties of SST hamper the use of intraduodenal hyperglycemic hyperinsulinemic clamps as a tool for exploring postprandial glucose metabolism under well-controlled glycemic and insulinemic conditions.
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Acknowledgments |
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Footnotes |
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First Published Online April 12, 2005
Abbreviations: GLUT, Glucose transporter; Ra, rate of appearance; SST, somatostatin; TBW, total body water volume; Veff, effective volume of extracellular glucose space.
Received September 3, 2004.
Accepted April 1, 2005.
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) and subjects infused with SST at doses of 10 (
) and 100 (•) ng·kg–1·min–1. In the SST experiments, insulin was infused at a variable rate, as shown in C. Conversion factors to SI units are 0.05551 for glucose, 6.0 for insulin, and 0.331 for C-peptide.
), 30 (
), and 100 (
) ng·kg–1·min–1.