1 Department of Surgery and 2 Membrane Biology Program, Brigham and Women's Hospital, Harvard Medical School, Boston 02115; and 3 Pediatric Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114
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ABSTRACT |
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Mechanisms underlying the circadian rhythmicity in intestinal sugar absorption remain unclear. To test whether this rhythmicity is caused by changes in Na+-glucose cotransporter 1 (SGLT-1) function, we measured phloridzin-inhibitable sugar fluxes as an index of SGLT-1 activity. Jejunum obtained from rats killed at 6-h intervals during a 12-h light-dark cycle (CT0 is circadian time 0 h, time of light onset) were mounted in Ussing chambers, and 3-O-methylglucose (3-OMG) fluxes were calculated before and after addition of phloridzin. 3-OMG-induced change in short-circuit current and absorptive flux were significantly greater at CT9 than at CT3. This increase was phloridzin inhibitable. Kinetic studies indicated a significant increase in SGLT-1 maximal velocity (Vmax) at CT9. Food intake between CT3 and CT9 was <10% of the daily total, indicating that the increased SGLT-1 activity was anticipatory. Diurnicity of SGLT-1 mRNA was confirmed by Northern blotting. Expression topography analyzed by in situ hybridization revealed more intense labeling along the entire villus axis at CT9 and CT15 compared with CT3 and CT21. We conclude that diurnicity in intestinal sugar absorption is caused by periodicity in SGLT-1 Vmax.
intestinal sugar absorption; Ussing chamber; sodium-glucose cotransporter; in situ hybridization; enzyme kinetics
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INTRODUCTION |
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PLASMA GLUCOSE CONCENTRATION is maintained within a narrow physiological range that exhibits circadian rhythmicity (1, 21). Endocrine mechanisms involved in controlling carbohydrate homeostasis, such as plasma insulin level and glucose tolerance, exhibit striking but largely unexplained diurnicity in both humans (17, 32) and rodents (1, 14, 16, 21). The specific mechanisms responsible for the observed daily shifts in carbohydrate tolerance have not been identified. To provide a better understanding of the pathways regulating carbohydrate homeostasis, we have examined the expression of the intestinal Na+-glucose cotransporter 1 (SGLT-1) because it is responsible for the intestinal absorption of glucose and can be an effector pathway for modulating carbohydrate disposal.
SGLT-1 expression is restricted mainly to the mature villus enterocytes of the small bowel and to the renal epithelium. In the small intestine, the energy-dependent uptake of glucose (and galactose) by apical SGLT-1 combined with its downhill flow via the basolateral GLUT-2 facilitated glucose transporter accounts for the absorption of this sugar. The expression of intestinal glucose transporters shows circadian rhythmicity and is altered in response to the carbohydrate content of the diet. Several studies comparing intestinal sugar absorption during the day versus the night have shown that in rats fed ad libitum and kept under normal physiological conditions with dark nights, sugar uptake is low in daytime and high at night, when these rodents feed (13, 15). This rhythmicity has been shown to be independent of the light cycle but cued by feeding (29, 30). This periodicity is anticipatory because it still occurs during food deprivation (15). Moreover, persistence of this functional rhythm during discontinuous parenteral feeding indicates that use of the intestine is not required (31).
Much of the earlier published work on functional rhythmicity of intestinal glucose absorption was done before the mechanisms involved in intestinal sugar absorption were elucidated and the relevant transporters were identified. Recent work has focused on the diurnal expression rhythm of GLUT-2, GLUT-5 (facilitated fructose transporter), and SGLT-1 at the mRNA and protein levels (6, 23), but physiologically important changes in the SGLT-1 function have not been studied. Although changes in 3-O-methylglucose (3-OMG) absorption have been recognized for many years, it has not been formally shown that SGLT-1 is directly responsible for the temporal changes observed, nor has it been determined whether the changes are caused by rhythmicity in transporter maximal velocity (Vmax) or substrate affinity. To test our hypothesis that the reported diurnicity in intestinal glucose absorption is caused by changes in SGLT-1 function, we measured phloridzin-inhibitable sugar fluxes in the Ussing chamber as an index of SGLT-1 activity and performed kinetic studies. To help further understand the mechanism of SGLT-1 mRNA periodicity, we also mapped the topography of these changes by in situ hybridization.
Our results show that phloridzin-inhibitable periodicity in SGLT-1 activity is responsible for changes in sugar absorption. This change in activity is caused by a significant increase in SGLT-1 Vmax with no change in transporter affinity (Michaelis constant, Km). These changes in transporter activity are anticipatory and are not caused by enzyme induction by the presence of an increased load of nutrients in the intestinal lumen. Northern blot analysis confirmed rhythmicity in SGLT-1 mRNA expression, and in situ hybridization showed that these changes occurred both in enterocytes in the upper villi as well as in the less mature enterocytes in the lower third of the villus. Our studies suggest that diurnal regulation of SGLT-1 occurs by a pathway distinct from the carbohydrate induction pathway (9).
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MATERIALS AND METHODS |
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Animals.
The study protocols were approved by the Harvard Medical Area Standing
Committee on Animals and the Massachusetts General Hospital
Subcommittee on Research Animal Care. Six-week-old female Sprague-Dawley rats (Taconic Farms, Germantown, NY) were acclimatized for at least 5 days to a 12-h photoperiod. Light onset was regarded as
the beginning of the circadian time (0 h; CT0), and rats were killed at
CT3, CT9, CT15, and CT21 (Fig. 1).
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Chemicals. Chemicals were obtained from Sigma (St. Louis, MO). Tritiated 3-OMG ([3H]3-OMG) and 32P-labeled nucleotides were obtained from NEN (Boston, MA).
Transport and kinetic studies.
Rats were anesthetized with an intraperitoneal injection of
pentobarbital sodium (100 mg/kg). Midline laparotomy was performed, and
a 15-cm segment of proximal small intestine, beginning at 5 cm distal
to the ligament of Treitz, was harvested and immediately placed in
ice-cold Ringer solution. The intestine was opened along its mesenteric
border, rinsed free of luminal debris, and divided into two segments.
These segments were stripped of their seromuscular layers under a
magnifying lens and mounted in Lucite Ussing chambers (World Precision
Instruments, Sarasota, FL) with an exposed area of 0.64 cm2. They were bathed on each side with 10 ml of a modified
Ringer solution containing (in mM) 140 Na+, 5.4 K+, 1.3 Ca2+, 1.2 Mg2+, 124 Cl, 2.4 HPO42
, 0.6 H2PO4
, 21 HCO3
, and 5 mM HEPES. pH was adjusted to 7.4 ± 0.01. The solution was
circulated using gas lift with 5% CO2-95% O2.
Temperature was maintained at 37°C with water-jacketed reservoirs.
Ten millimolar fructose was added to the serosal and mucosal chambers.
Transmural potential difference (PD) was measured using calomel
electrodes connected to the bathing solution with Ringer-Agar (2%)
bridges. Tissues were continuously short-circuited with an automatic
voltage clamp (model EVC-4000, World Precision Instruments) except
during 5-s intervals every 5-10 min when the open-circuit PD was
measured. Tissue resistance (R) was calculated from
open-circuit PD and short-circuit current (Isc)
using Ohm's law. After a 40-min period of equilibration, 3-OMG (30 mM,
final chamber concentration) was added to both mucosal and serosal
chambers. The maximal change in Isc
(
Isc) within 20 min of 3-OMG addition was
recorded. Tissues from the same animal were paired together, and at the
time of the addition of 3-OMG, 2 µCi of [3H]3-OMG was
added to the serosal chamber of one tissue and the mucosal chamber of
the other tissue of each pair. If baseline R varied by
>30% between the pair, the tissues were discarded and the results
were not included in the analysis. Thirty minutes later, when
steady-state flux had been reached, two 15-min [3H]3-OMG
fluxes were measured. Phloridzin (100 µM) was then added to both
chambers, and a third 15-min [3H]3-OMG flux was measured.
Response to the addition of 10
8 M vasoactive intestinal
polypeptide (serosal, final chamber concentration) was used at the end
of all experiments to confirm tissue viability. The
radioactivity in each sample was counted using a liquid scintillation counter (1212 Rackbeta, Wallac, Gaithersburg, MD). Mucosal-to-serosal (Jm-s), serosal-to-mucosal
(Js-m), and net (Jnet)
fluxes were calculated. A mean prephloridzin flux was calculated from
the two fluxes measured, and this value was used in further calculations.
Food intake. The food intake of 12 rats, kept in pairs, was recorded over 3 days, and the mean food consumption per rat was calculated for each 24-h cycle and the 6-h period between CT3 and CT9. Percentage of total daily intake eaten between CT3 and CT9 was calculated.
Northern blotting analysis.
After rats were killed by CO2 inhalation, the first 5 cm of
proximal small intestine, beginning 2 cm distal to pylorus, were removed. The first 2 cm were frozen in isopentane and kept in a
80°C freezer for use in the in situ hybridization studies. The
distal 3 cm were flushed with cold phosphate-buffered saline and
everted, and the mucosa was scraped. Mucosa was rapidly frozen in
liquid nitrogen, and RNA was later extracted as previously described
(5). Equal amounts (20 µg) of RNA were electrophoresed on 1% formaldehyde-agarose gels. RNA integrity and quantity were confirmed by ethidium bromide staining. RNA was transferred to Hybond-N
filters (Amersham) and hybridized to a 32P-labeled rat
SGLT-1 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) cDNA as
previously described (20). Blots were washed twice in 2×
SSC, 0.1% SDS (1× SSC is 0.15 M NaCl, 15 mM sodium citrate, pH 7.0)
for 10 min at room temperature, once in 1× SSC, 0.1% SDS for 15 min
at 65°C, and twice in 0.1% SDS for 20 min at 65°C and exposed on
Kodak XAR-5 film at
80°C. Densitometry was performed using NIH
Image software. SGLT-1 hybridization signals were standardized with
GAPDH signals before comparisons. Four rats were studied per time point.
In situ hybridization. Digoxigenin-labeled sense and antisense probes for SGLT-1 were synthesized from linearized expression plasmids containing 2.5 kb of the SGLT-1 sequence and alkali-hydrolyzed to an average length of 500 bp. In situ hybridization was performed on cryosections (15 µm) of fresh frozen tissue from the proximal small intestine (1-2 cm from the pylorus) as we have previously described (2). The hybridization buffer consisted of 50% formamide, 5× SSC, 2% blocking reagent (Roche, Indianapolis, IN), 0.02% SDS, and 0.1% N-laurylsarcosine. The probe concentration was ~100 ng/ml. Sections were immersed in slide mailers in hybridization solution and hybridized at 68°C for 66 h. This step inactivates the endogenous alkaline phosphatases. Sections were washed three times in 2× SSC and for 2 × 30 min in 0.2× SSC at 68°C. The hybridized digoxigenin-labeled probes were visualized with alkaline phosphatase-conjugated anti-digoxigenin Fab fragments (1:5,000, Roche) and BCIP/NBT substrate (Kirkegard and Perry Laboratories). Sections were then rinsed in (mM) 100 Tris, 150 NaCl, 25 EDTA, pH 9.5, and coverslipped with glycerol gelatin medium (Sigma).
Pictures were taken with a digital spot camera attached to a Nikon E600 microscope and imported into Adobe Photoshop (Adobe Systems, Seattle, WA). The exposure settings and sharpness enhancement were identical for each picture.Statistical analysis. Data are presented as means ± SE. Probability of P < 0.05 was taken as significant. P values were estimated using ANOVA with post hoc Tukey intergroup comparison. Computations were performed using a commercially available statistical package (Statistica, version 4.3, StatSoft, Tulsa, OK).
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RESULTS |
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Diurnal variation in baseline Isc and
R.
Baseline Isc were higher during the light cycle
(CT3 and CT9) than during darkness, reaching a significant difference
when CT3 was compared with CT21 (Table
1). Tissue resistance was significantly lower at CT9, when SGLT-1 activity was at its peak, compared with CT3,
when SGLT-1 was least active.
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Diurnal variation in 3-OMG-induced
Isc and fluxes.
At CT9, before the onset of darkness and the start of feeding,
3-OMG-induced
Isc was significantly greater
than at CT3. Jm-s was significantly higher at
CT9 compared with all other time points. 3-OMG
Jnet, however, was significantly higher at CT9
only compared with CT3, consistent with the significant increase in
3-OMG-induced
Isc. There were no significant
differences in Js-m among the four time points
(Table 1).
Effect of phloridzin on 3-OMG fluxes.
Phloridzin, a specific inhibitor of SGLT-1 (7), abolished
the increase in Jm-s and
Jnet observed at CT9. Fluxes in the presence of
phloridzin were not significantly different among the four time points
(Fig. 2).
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Diurnal variation in Vmax.
Kinetic studies demonstrated that the increase in 3-OMG flux was caused
by an increase in SGLT-1 Vmax and not
Km. At CT9, when the 3-OMG flux was at its
maximum, Vmax had increased by a factor of 3. There was no significant difference in Km among the four time points (Table 2; Fig.
3).
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Food intake. The mean daily food intake of each rat was 17.1 ± 0.8 g. Between CT3 and CT9, when maximal increase in 3-OMG flux occurred, rats consumed only 6.6 ± 1.9% (2.4 ± 0.7 g) of their total daily intake. Diurnicity in rat food intake has been documented previously (12).
SGLT-1 mRNA analysis.
To confirm that the SGLT-1 expression rhythm was present in the rats
used in the in situ hybridization studies, RNA extracted from adjacent
distal mucosa was analyzed by Northern blotting. As shown in Fig.
4, and in accord with our previous study
(23), SGLT-1 mRNA levels were increased at CT9 and CT15,
compared with the level at CT3. The increased mRNA levels in mucosal
scrapings at CT9 and CT15 could have been because of increased
transcription within a given subset of villus enterocytes or an
increased fraction of villus cells transcribing SGLT-1. To distinguish
between these possibilities, the villus distribution of SGLT-1 mRNA was
examined using in situ hybridization.
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DISCUSSION |
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Our results show periodicity in intestinal sugar uptake and SGLT-1 function, with the rise to maximal activity occurring just before darkness and the nocturnal increase in feeding. We used phloridzin-inhibitable 3-OMG flux as an index of SGLT-1 activity. 3-OMG is a glucose analog that is transported by SGLT-1 but not metabolized by the enterocyte (19), thus allowing the study of transport function in the absence of confounding alterations in enterocyte metabolism. The abolition of the diurnal increase in sugar uptake by phloridzin provides strong evidence that this glucose cotransporter is responsible for the observed rhythmicity in intestinal sugar absorption. The data show, for the first time, that the changes in SGLT-1 mRNA and protein previously reported (6, 23) are reflected in the physiologically important transporter function. Our kinetic studies showed that the significant increase in Vmax could account for the observed increase in sugar flux. Although the flux Km did show modest temporal changes, we do not believe that cotransporter affinity contributes to the periodicity in sugar fluxes for two reasons. First, the changes did not achieve statistical significance. Second, the cotransporter affinity tended to decrease when the fluxes were highest. Previous reports of diurnicity in SGLT-1 transporter protein, as observed on Western blots, further support this finding (23). Other groups have also found periodicity in other intestinal enzymatic functions, such as sucrase activity, to be caused by changes in Vmax, with no changes in Km (8, 18).
Diet and the presence of food in the intestinal lumen affect intestinal sugar absorptive capacity. However, the animals in our study consumed <10% of their daily total during the interval when the maximum change in SGLT-1 activity was observed (from CT3 to CT9). Thus the observed changes in 3-OMG flux and SGLT-1 Vmax are not brought about by the presence of food in the intestinal lumen per se but occur in anticipation of the bulk of the feeding that occurs early in the dark phase. Presence of anticipatory rhythmicity in intestinal digestive and absorptive functions has been reported before and is supported by the observation that the rhythms persist during starvation (15, 25). The timing of these changes is consistent with our previous work (23), which showed maximal SGLT-1 protein at the CT9 time point (denoted as 1600 h in that study). In addition, other groups have shown the onset of maximal glucose uptake to coincide with the beginning of the feeding time (15, 30).
Our studies have confirmed diurnicity in SGLT-1 mRNA expression. The experiments showed the diurnal peak in mRNA expression and function to coincide, but the design was not sufficiently refined to document any lag time that may exist between the message and the function peaks. We looked at SGLT-1 mRNA localization using in situ hybridization, where studies revealed more intense labeling in villi collected in the afternoon and evening (CT9 and CT15) than in those collected in the morning. It should be noted that the presence of or an increase in the mRNA levels does not necessarily indicate the concurrent presence of SGLT-1 protein or activity in the enterocyte but is an indicator of the cell's commitment to express the transporter. This hybridization pattern demonstrates that mature enterocytes, in the upper third of the intestinal villus, are able to alter the amount of mRNA expressed by the cell on a daily basis. This observation is contrary to what has been previously hypothesized. Dietary factors have long been known to regulate intestinal digestive function in rodents (8) and humans (24). More recently, Ferraris et al. (9-11) and others (22) have confirmed that SGLT-1 transcription, translation, and activity are modified by diet. These investigators proposed a model in which dietary-induced changes take 3-5 days to occur, because only enterocytes exiting the crypt are able to alter SGLT-1 expression and replace the old cells with the previous SGLT-1 expression level along the villus. Other groups have reported acute increases in SGLT-1 activity induced by luminal glucose, although changes in SGLT-1 mRNA expression were not studied (28). However, because sampling in these studies was limited to a single segment of the day, diurnal changes were not detected. Our studies, on the other hand, clearly demonstrate rapid changes in SGLT-1 mRNA expression and function in mature enterocytes. It is likely that there are two distinct and separate pathways regulating SGLT-1 expression and function in intestinal epithelial cells. One pathway utilizes gut luminal signals to induce changes, whereas the other is a daily anticipatory mechanism preparing the intestine for an expected increase in nutrients before exposure to the luminal contents. Two sets of data support this hypothesis. First, isolated loops of rat jejunum show the same circadian rhythm in disaccharidase activity as unligated jejunum, but the overall enzyme activities were not inducible by a carbohydrate-rich diet as was found in the unligated jejunum (27). Second, the circadian changes in intestinal enzyme activities were shown to be independent of the changes induced by dietary protein or carbohydrate (26). Intermediary signals involved in these two distinct pathways are not yet identified. Our earlier work (23) implicates hepatocyte nuclear factor-1 (HNF-1) in regulating diurnal periodicity of SGLT-1 transcription. Whether this factor is involved in dietary regulation of SGLT-1 expression and what signals lie upstream from this nuclear transcription factor remain to be determined.
Intestinal sucrase, lactase, and maltase activities also have circadian periodicity phased to the feeding pattern. Similar to glucose absorption, the rhythm of these enzymes is anticipatory (29). Moreover, this rhythm is independent of the use of the intestine (31). These observations have led investigators to propose the existence of a neuroendocrine mechanism to regulate genes involved in intestinal carbohydrate digestion and absorption (25, 31). Of equal importance, a significant body of work has shown that the insulin level in rats undergoes circadian variation with maximal plasma concentrations late in the afternoon, just before the peak period of food intake (1, 3). Moreover, the nighttime exaggeration of glucose and insulin responses during an oral glucose tolerance test in rats demonstrates that insulin sensitivity itself undergoes a circadian variation (16). Persistence of the periodicity in plasma insulin levels in fasted animals (1), or those given a constant glucose infusion (3), suggests that the serum glucose level is not driving this rhythm. These results suggest the presence of an entrainable neuroendocrine mechanism that not only regulates intestinal sugar absorption but also prepares the whole organism, in part by adjusting the plasma insulin levels, for the expected food intake. The finding that truncal vagotomy abolishes rhythmicity in food intake, insulin secretion, and glucose tolerance in normal rats indicates that the vagus nerve plays an important role in these carbohydrate regulatory mechanisms (21). Because intermittent parenteral nutrition maintains diurnicity in intestinal disaccharidases and glucose absorption, we propose that the hypothesized regulatory neuroendocrine axis has an endocrine/nutritional afferent limb that regulates the efferent output of the vagus nerves. The specific molecular events underlying these two limbs remain to be elucidated.
At CT9, when SGLT-1 was most active, tissue resistance was
significantly lower compared with CT3, when SGLT-1 was least active. Although this is an interesting observation, its basis and significance are presently unclear. During the light cycle, the baseline
Isc was higher than during the dark cycle. This
suggests the presence of a diurnal change in baseline electrolyte
fluxes, including Cl, Na+, and/or
HCO3
. Although we have not yet examined the possible
mechanisms underlying these changes, the phenomenon may be important
and warrants further study.
In summary, we have shown that the periodicity in intestinal sugar absorption is caused by changes in SGLT-1 induction and function. These functional changes are anticipatory and brought about by changes in the SGLT-1 Vmax. Rhythmicity in SGLT-1 mRNA expression was confirmed and shown to be caused by increased mRNA expression by all enterocytes that normally express SGLT-1 rather than a specific subset of villus enterocytes. We propose the presence of an anticipatory pathway regulating intestinal SGLT-1 expression and function. This pathway, unlike others previously described, results in acute and rapid changes in the SGLT-1 induction in mature, as well as immature, enterocytes along the villus axis. Further work on mechanisms involved in this anticipatory control of intestinal absorption and systemic metabolism of sugars could reveal new therapeutic avenues in dealing with intestinal malabsorption syndromes as well as diabetes mellitus.
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ACKNOWLEDGEMENTS |
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The authors gratefully acknowledge the assistance of Lihua Zhang in performing the Northern blot analysis.
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FOOTNOTES |
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This study was supported by National Institutes of Health Grants DK-47326 (S. W. Ashley), HD-31215 (L. L. Levitsky), and DK-54399 (D. B. Rhoads) and by March of Dimes Grant 1-FY99-221 (D. B. Rhoads).
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.
Address for reprint requests and other correspondence: D. B. Rhoads, Massachusetts General Hospital, Pediatric Endocrine Unit, 55 Fruit St., BHX410, Boston, MA 02114 (E-mail: drhoads{at}partners.org).
Received 16 June 2000; accepted in final form 31 August 2000.
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