CRITICAL REVIEW I SYNTH~SECRITIQUE

Regulation o f intestinal glucose transport'

Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIVERSITY OF NEW MEXICO on 11/27/14 For personal use only.

D. J. P H I L ~ TJ. , D. BWTZNER, AND B. B. MEDDHNGS~ d;srstroint~stincBIResearch Group, University of Calgary, Calgary, Aka. , Canada Received January 28, 1992 PHIL~TF B., J., BUTZNER,J. D., and MEDDHNGS, J. B. 1982. Regulation of intestinal glucose transport. Can. J. Physiol. Pharmacol . 70: H 20 1- H 207. The small intestine is capable of adapting nutrient transport in response to numerous stimuli. This review examines several possible mechanisms involved in intestinal adaptation. In some cases, the enhancement of transport is nonspecific, that is, the absorption of many nutrients is affected. Usually, increased transport capacity in these instances can be attributed to an increase in intestinal surface area. Alternatively, some conditions induce specific regulation at the level of the enterocyte that affects the transport of a particular nutrient. Since the absorption of glucose from the intestine is so well characterized, it serves as a useful model for this type of intestinal adaptation. Four potential sites for the specific regulation of glucose transport have k e n described, and each is implicated in different situations. First, mechanisms at the brush-border membrane of the enterocyte are believed to be involved in the upregulation of glucose transport that occurs in streptazotoein-induced diabetes mellitus and alterations in dietary carbohydrate levels. Also, factors that increase the sodium gradient across the enterocyte may increase the rate of glucose transport. It has been suggested that an increase in activity of the basolaterally located Na' -K+ ATPase could be responsible for this phenomena. The rapid increase in glucose uptake seen in hyperglycemia seems to be mediated by an increase in both the number and activity of glucose carriers located at the basolateral membrane. More recently, it was demonstrated that mechanisms at the basolateral membrane also play a role in the chronic increase in glucose transport observed when dietary carbohydrate levels are increased. Finally, alterations in tight-junction permeability enhance glucose absorption from the small intestine. The possible signals that prompt these adaptive responses in the small intestine include glucose itself and humoral as well as enteric nervous interactions. Key words: intestinal transport, glucose transport, intestinal adaptation.

B H I L ~ TD., J., BUTZNER,J. D.,et MEDDHNGS, J. B. 1992. Regulation of intestinal glucose transport. Can. J . Physiol. Phamacol. 7Q : 1208 - 1207. L'intestin grCle peut adapter le transport de nutriments en rCponse h de nombreux stimuli. Cet article examine divers rnCcanismes susceptibles d'gtre irnpliquts dans l'adaptation intestinale. Dans certains cas, l'augmentation du transport n9est pas s@cifique, c'est-h-dire qu'elle influence l'absorption de nombreux nutriments. GCnQalement. dans ces cas, la capacitb accrue du transport peut &re attribuke B une augmentation de la surface intestinale. Par ailleurs, certaines conditions induisent une regulation spkcifique au niveau de 19entCrocytequi influence le transport d'un nutriment particulier. &'absorption de glucose intestinal Chnt bien caraetCrisCe, elle constime un rnodkle utile pour ce type dqadaptation intestinale. On a dkcrit quatre sites potentieis pour la rkgulation spkcifique du transport de glucose, chacun Ctant impliquC dans diverses situations. D'abord, les mCcanismes au niveau de la membrane de h r d u r e en brosse de 19entCrocytesont considCrCs c a m e Ctant impliquCs dans l'augmentation du transport de glucose, observde lors de diabkte sucr6 induit par streptozotocine, et dans les altkrations des taux de glucides alimentaires. De plus, les facteurs qui augmentent le gradient de sodium dans 1'entCrocyte psurraient augmenter le taux de transport de glucose. On a suggCr6 qu'une augmentation de I'activitC de la Na+-K+ ATPase, situke au niveau de la membrane basolatkrale, pourrait etre responsable de ce phCnomkne. L'augmentation rapide de situCe au niveau de la membrane basolatCrale, Plus recemment, on a dCmontrC que les mCcanismes simCs au niveau de la membrane basolatkrale jouent aussi un r6le dans l'augmentation chronique du transport de glucose, qui est observCe lorsque les taux de glucides alimentaires sont accms. Finalement, des altkrations dans la permCabilitC des jonctions lacunaires augmentent %'absorptionde glucose intestinal. Le glucose aimi que les interactions neweuses entQiques et humorales font partie des sigmux qui favoriseraient ces rkponses adaptatives dans l'intestin grsle. Mots cleS : transport intestinal, transport de glucose, adaptation intestinale. [Traduit par la rkdactisn]

Introduction One of the major functions of the small intestine is the efficient absorption of dietary nutrients. For mimals, including man, where dietary intake can vary tremendously in both quantity and quality on a day-to-day basis, some provision must be made to accommodate extremes in dietary fluctuations. While this appears innately reasonable, it is only in recent years that we have come to appreciate the remarkable "This paper has undergone the Journal's usual peer review. 2AuBhor for correspondence at the following address: Department of Medicine, Health Sciences Centre, University of Calgary, 3330 Hospital Drive N. W., Calgary, Alta. Canada T2N 4N 1 . Printed in Canada i ImprirnC au Canada

ability s f the small intestine in adapting ts changing dietary environments. It is of considerable importance to understand the mechanisms h a t underlie these adaptive changes when we eonternplate the alterations in intestinal function that can occur in pathological states. In this review we intend to examine the intestin& alterations that occur in glucose transport in response to a variety af stimuli. Of d l the nutrients that the intestine absorbs, glucose has been studied most extensively and serves as a useful model of intestinal adaptation. It is now apparent that the smdl intestine can alter nutrient absorptive capacity in response to a number of physiological and pathological conditions. These include alterations in type

CAN. J. PHYSIQL. PHARMACOL. VOL. 70, 1992

1202

Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIVERSITY OF NEW MEXICO on 11/27/14 For personal use only.

~ a ' Glucose

thickness sf the unstirred water layer, enhanced mixing of lumind contents during the bulk phase, increased concentrations s f hydrolases, or a general increase in membrane permeability are d l factors that may act to nonspecifically increase the uptake sf glucose from the small intestine (Thomson 1981; Karassv and Diamond 1983; Fedorak 1990; Thornson 1982). While these mechanisms are of obvious importance to the animal as a whole, it has recently become apparent that much finer tuning of nutrient absorption takes place at the level of the enterocyte itself.

Specific. mechanisms

Nonspecific mechanisms

To appreciate the specific rnechanisms that induce increased glucose uptake, the multiple pathways for nutrient absorption must be kept in mind. Figure 1 outlines our present understanding of glucose absorption and the steps where regulation could conceivably occur. Glucose is absorbed from h e intestinal lumen either by traversing the enterocyte (the transcellular route) or by entering between cells (the paracellular route). The transcellular route involves, first, a sodium-dependent carrier on the brush-border membrane (BBM) of the enterscyte, shown as step 1 in Fig. 1. Since glucose can be absorbed against its chemical gradient (i.e., concentrated within the enterscyte), a source of energy is required. The coupling of glucose transport with the absorption of sodium provides this energy. The high inwardly directed sodium gradient, both chemical and electrical, is maintained by the Na+ -K+ ATPase enzyme located at the basolateral membrane (BLM) s f the enterocyte, denoted as step 2 in Fig. 1 . Glucose difhses out of the enterocyte once the intracellular concentration exceeds that of the extracellular space. Since the passage of such a large molecule across the BLM is thermodynamically unfvourable, it is facilitated by a second glucose transporter, which is sodium independent (step 3 in Fig. 1). Finally, glucose can cross the epithelium paracellularly (step 4 in Fig. 1). The tight junctions that exist between enterocytes are now h o w n to be dynamic structures, and factors regulating their opening and closing are of intense interest at this time. ABI of the steps depicted in Fig. 1 are potential sites for the regulation s f nutrient absorption, and data now exist to implicate each in different situations. We shall consider each in turn.

MechaHniisms that act nonspecifically to increase the absorption of glucose from the s m d intestine are induced during pregnancy and lactation or following intestinal resection. During pregnancy and lactation, there is a requirement for increased absorption, whereas following resection, the nutrient requirement remains constant yet diminished intestinal resources exist to meet the need. In these circumstances, the most obvious response is a generalized increase in intestinal absorptive surface area mediated through changes at the gross, microscopic and ultrastructural levels (Karasov and Dimond 1983). The actual length of intestine can increase in both lactation and pregnancy (Craft 1970). Microscopic and ultrastructural changes include an increase in the length and number of villi or rnicrovilli, respectively. Severd studies have indicated that intestinal hypertrophy can account completely for the increase in glucose uptake observed during pregnancy and lactation or after intestinal resection. When transport is normalized to intestinal m s s , glucose uptake appears unchanged or even decreased as compared with controls (Craft 1970; Urban and Hdey 1978; Cripps and Williams 1975). Other mechanisms may affect glucose uptake in a nonspecific way. Changes in

The brush-border membrane In several studies examining nutrient absorption, an increase in the amount of dietary carbohydrate appeared to enhance rates of glucose absorption (Ferraris and Diamond 1986; Karasov et ak. 1983; Diamond and Karasov 1984). In mice fed a high carbohydrate diet, rates of glucose transport increased severalfold as compared with mice on a carbohydrate-free meat diet (Ferraris and Diamond 1986; Karasov et a&.1983; Diamond and Karascsv 1984). This increase in glucose transport was caused by an increase in the maximal rate of glucose transport (Vma,), while the carrier's affinity for glucose (Km) remained unchanged (Karasov et a&. 1983; Diamond and Karasov 1984) when exanin& by kinetic analysis. Fu&emore, the observed increase in transport seemed to be specific for glucose since ( i ) intestinal hypertrophy, as measured by morphometric parameters, did not change, (ik) passive permeability of glucose remained the same; and ( 2 )the absorption of proline, which like glucose is cotranspo~edinto the enterocyte with sodium, was not affected (Karasov et a&. 1983). Thus, it appeared that in response to increased dietary carbohydrate, the smdl intestine specifically enhanced the absorption of glucose.

FIG. 1. Mechanisms of intestinal glucose transport. Depicted are the classical pathways involved in glucose absorption and the possible sites of regulation. These include (1) the sodium-dependent glucose transporter, (2) the basolaterally located Nai - Ki ATPase that provides the driving energy for the transport system, (3) the sodiumindependent glucose transporter located on the basolateral membrane, and (4) the paracellular pathway. Each of these pathways is discussed in the text.

and quantity sf diet, pregnancy and lactation, surgical resection of the intestine, and disease states such as diabetes, thyrotoxicosis, and starvation. In general terns, the adaptive response can occur either at the level of the intestine as a whole or at the enterocyte itself. For the purpose of this review we will refer to the former as nonspecific mechanisms and the latter as specific, since in many cases, alterations at the level s f the enterocyte appear to be nutrient specific. It must be mentioned that such a classification scheme is arbitrary, at best, since multiple processes occur simulttaneously . However, categoriaing the mechanisms in this way provides a convenient basis for discussion.

Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIVERSITY OF NEW MEXICO on 11/27/14 For personal use only.

CRITICAL REVIEW ISYNTHBSE CRITIQUE

A similar response was observed in streptozotocin-induced diabetes mellibs a d , again, the increase in glucose transport could not be accounted for by nonspecific mechanisms (Dude~aet a&. 19%; Fedor& et al. 1987, 1989; Thomson 1981) or any effects of streptozotscin itself (Csaky and Fischer 1981). En both situations, evidence exists that mechanisms at the BBM are the target of this adaptive regulation. The sodiumdependent glucose transporter located within this membrane can be specifically labelled (and inhibited) with the plant glycoside phlorizin, which binds covalently to this membrane protein. In both experimental models, specific binding of [%H]phlorizin to the intact intestinal epithelium revealed a marked increase in the total number of glucose carriers. Furthermore, the magnitude of this increase paralleled the increased rate of glucose transport (Fedorak et a&. 1989; Ferraris and Diamond 1986). Autoradiographic techniques have k e n employed to visualize the distribution of [aH]phlorizin binding sites in the intact ileal epithelium of diabetic and control rats. Both groups had similar carrier density in the tip region of the intestinal villus (Fedorak et a&.1989). However, in diabetic rats, phlorizin binding extended down into the mid and lower villus regions, suggesting that a larger fraction of BBM surface area was committed to glucose absorption in these animals (Fedorak et al. 1989). These findings have been confirmed in recent work where enterocytes from diabetic and control animals were isolated from various locations along the crypt -villus axis. Glucose transport studies were then carried out on BBM vesicles purified from the isolated enterocytes. Increased rates of glucose transport were observed in BBM vesicles purified from enterocytes located in the midvillus Raction of the diabetic animals (Budeja et a&.1990). Some studies have suggested that the activity of nutrient transporters depends upon membrane physical properties (Meddings et al. 1990; Sadowski et a&.1991). Since physical properties of the BBM are altered in diabetes, an attempt was made to relate alterations in membrane fluidity to the emergence of increased BBM glucose transport in the midvillus region of diabetic animals. No apparent relationship, however, was evident (Dudeja et al. 1990). Furthermore, since a change in membrane fluidity would alter other transporters in the midvillus region, it wodd be expected that the absorption of other nutrients would be similarly affected. In both the diabetic model and dietary carbohydrate model, the uptake of other nutrients was unchanged, suggesting a glucose-specific mechanism (Fedorak et al. 1989; Karasov et al. 1983; Diamond and Karasov 1984). Another hypothesis is that streptozotocin-induced diabetes mellitus causes a decrease in the rate at which enterocytes migrate from the crypt region to the villus tip. As the enterocyte migrates up the villus from the crypt it matures and expresses progressively more transport functions (Meddings et al. 1990; Keljo et al. 1985). If migration rates decrease in response to diabetes or changing levels of dietary c a r h hydrate, enterocytes at the midvillus position would be more mature and, consequently, express greater transport capabilities. No data exist at present to confirm or refute this hypothesis. Can the mature enterocyte adapt to changing environmental stimuli or are new enterocytes from the crypts irreversibly 6'programed'' for a particular level of glucose absorption? If preprogramming sf crypt enterocytes is correct, it would provide an explanation for the remarkably short life-span of enterocytes. For example, if adaptation to dietary change took place by altering the "template9' of the enterocyte in the crypt,

1203

it would make little sense to have an enterocyte that lived several months, and accordingly, a rapid turnover of the intestinal epithelium is logical. In fact, very recent data (Ferraris et al. 1992; Ferraris and Diamond 1992) suggest that this scenario is indeed correct. The switch to a high carbohydrate diet initially induced the appearance of increased numbers of BBM glucose transporters in enterocytes located in the crypt region. Gradually, these enterocytes emerged onto the villus after approximately 1 day. When the normal, low carbohydrate diet was reinstated, the basd level sf transporters was restored rapidly in the crypts but took 2 - 3 days to return to normal levels in the villus. These results suggest that the entire change is sensed in the crypt, and the mature villus cell is irreversibly programmed. With the expression, cloning, and cDNA sequencing of the sodium-dependent glucose transporter from the rabbit small intestine, further characterization of this BBM protein was possible (Hediger eb al. 1987). Employing in % ~ B Mhybridization and immunohistochemical techniques, it was determined that transcription of the BBM glucose carrier gene is initiated in enterocytes located at the crypt-villus junction. The level of transcription increases as the cells migrate up the villus. Ewterocytes at the villus tip possess the highest levels of both glucose transporter mRNA and the BBM transporter protein. No significant levels of the BBM glucose transporter protein were found in crypt cells, associated with the BLM, or in the cytoplasm of any cell dong the crypt-villus axis (Hwang et al. 1991; Takata eb a&.1992). These findings indicate that there may be a temporal and (or) spatial set point at which the transcription of the BBM glucose transporter gene is initiated. This point corresponds to the level of maturity or the site at which enterocytes emerge from the crypt region. Then, as the enterocytes migrate up the villus, the glucose carrier protein is synthesized and inserted directly into the BBM in a functiond form (Hwang eta&.1991). The application of these techniques to models of adaptive glucose transport upregulation are just beginning to be realized. In one study, Northern blot analysis demonstrated that chronically diabetic rats exhibited increased levels of BBM glucose transporter mRNA compared with control animals (Miyamoto et al. 1991). Hopefully, further studies will employ in situ hybridization techniques with the BBM glucose transporter gene to clarify the signals responsible for regulation of intestinal BBM glucose transport in other states sf intestinal adaptation. Recently, it was revealed that a single missense mutation in the human BBM glucose transporter gene is responsible for the autosomd recessive glucose-galactose malabsorption syndrome (Turk et a&.1991). Individuals affected with this disease fail to absorb glucose and glacatose from the intestine and consequently develop severe diarrhea and dehydration. This condition is fatd unless these sugars are eliminated from the diet. The identification of this mutation in the genome of afflicted individuals provides further direct evidence that the BBM glucose carrier is the transporter responsible for the uptake of glucose and galactose from the small intestine (Turk et a&. 1991). In addition, this discovery stresses the importance sf further research to Pbally characterize this membrane protein and examine the regulation of its expression in both physiologic and pathologic conditions.

The sodium gradient into the enterocyte It has been suggested that under certain conditions, an increased sodium gradient m y exist across the BBM as the result of an increase in the activity of the basolaterally located

Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIVERSITY OF NEW MEXICO on 11/27/14 For personal use only.

1204

CAN. J. PHYSIOL. PHAWMACOL. VOL. 70, 1992

Nat-K+ ATPase (Hopfer 1975). Thus, a diminished intracellular sodium concentration would stimulate the uptake of any nutrient cotransported into the enterocyte with sodium. The possible mechanisms leading to an increase in activity of the intestinal Na+ -K+ ATPase are unknown. In other systems, however, modulation of Na+ -K+ ATPase activity is responsible for the increased transport of nutrients. In rend proximal ~ . b d epithelium a the mcrophage factor interleukin-l stimulated sodium-dependent glucose and amino acid transport by apparently increasing the activity of Na+ -Kf ATPase (Rohan and Schreiner 1988). Since renal and intestinal epithelium are so dike in terms sf nutrient transport, it seems likely that similar modulation could take place in the small intestine. Once again, it must be stressed that increased uptake by this mechanism would be nonspecific and would likely complement other adaptive mechanisms. The basohterak rnedrapae In 1981, Csaky and Fisher were the first to suggest that mechanisms at the BLM were involved in the rapid upregulation of glucose transport induced by hyperglycemia. They showed that the acute increase in glucose uptake across jejunal sacs of hyperglycemic rats was more sensitive to inhibition by phloretin, a compound that binds the BEM glucose carrier, &an by phlorizin, the inhibitor of BBM glucose transport (Csaky and Fischer 198 1). Since then, others have confirmed this hypothesis (Cheeseman and Maenz 1989; Karasov and Debnam 1987; Maenz and Cheeseman 1986). Furthermore, one study demonstrated that the rate s f glucose uptake in BLM vesicles isolated from hyperglycemic rats was greater than in BBM vesicles (Maenz and Cheeseman 1986). (It is important to point out h a t with regard to BLM vesicle studies, the membrane vesicles are "inside out"; that is, the rate of transport into the vesicles represents the rate of glucose efflux from the enterocyte.) The regulation of glucose transport induced by hyperglycemia is rapid and develops along a particular time course. By using [3H]cytochalasin B, a compound that binds to the BLM glucose carrier, the site density of glucose carriers was quantified at various times following the induction of hyperglycemia. An increase in glucose transport across BLM vesicles was observed within 30 min sf inducing hyperglycemia. Following 2 h of glucose infusion, the maximal rate of glucose transport increased, while binding site density remained unchanged. Six hours of hyperglycemia resulted in a further increase in the rate sf transport as well as an increase in carrier site density. This increase in transporter number, however, did not parallel the increased rate sf transport (Cheeseman and Maenz 1989). These results suggest that, initially, hyperglycemia results in a stimulation of carrier activity, followed by a recruitment of new BLM carriers. Also, since the carrier site density does not directly parallel the increased rate of glucose transport, it is likely that the newly recruited carriers differ from those present in the basd, nolastimulated state. These new carriers may have a higher affinity for glucose, or they may move glucose across the membrane and out of the enterocyte at an increased rate. These results led the investigators to hypothesize that the rapid upregulation of glucose uptake across the BLM induced by hyperglycemia may correspond to a physiological response that codd wcur shortly after the start of a meal to maximize absorption of glucose in the minimum amount of time (Cheeseman and Maenz 1989). Recently it was demonstrated that carbohydrate content in

the diet may also affect the rate sf glucose transport across the BLM. The upregulation of glucose transport induced in this way is, however, m r k d l y different from the very rapid effect caused by induced hyperglycemia. For example, the increase in glucose transport was observed 3 days after initiating the high carbohydrate diet. Also, mdysis of [3H]cytochalasinB binding to the BLM showed a parallel change in the number of glucose-inhibitable binding sites. Consequently, the increase in glucose transport across the BLM in this model appears to involve an increase in the number of glucose carriers in the membrane. In addition, the delayed onset of the response suggests that the new carriers must be synthesized and are not simply inserted into the BLM from a pre-existing pool of carriers within the enterocyte (Cheeseman and Harley 1991). The application of molecular biologicd techniques has led to the identification of two facilitative glucose transporter isoforms in the small intestine, termed GLUT2 and GLUTS (Thorens et ak. 1990; Kayano et a / . 1990). GLUT2 is found not o d y in the intestine but in other tissues, including the liver, pancreas, and kidney (Thorens et ak. 1988). The kinetics sf GLUT2 has been most extensively studied in the liver and pancreas, and in these tissues, this transporter functions as a low-affinity glucose carrier (Thorens et ak. 1990). Because sf this property, the transport of glucose into hepatocytes and pancreatic B-cells by GLUT2 is not rate limiting, increasing linearly as glucose concentrations increase (Mueclder et ak. 1990; Meglasson et ak. 1986). This is in contrast to the facilitative glucose transporter GLUT4 that is present in adipocytes and skeletal muscle cells. In these cells, glucose transport is rate limiting for glucose metabolism. Thus, glucose uptake in adipcytes and myocytes is subject to strict regulation by insulin, which is stimulatory, and by certain counterregulatory factors that oppose insulin's affect (Crofford et gal. 1965; Berger et ak. 1975). The regulation of GLUT2 expression in the small intestine has not been thoroughly examined in models of intestinal adaptation. One study did demonstrate that GLUT2 mRNA levels were increased in rats 30 days after the reduction of diabetes (Miyamoto ct al. 11991). In this study no attempt was made to correlate glucose transport with the increased GLUT2 mRNA levels. An examination of GLUT2 mRNA levels in other models of intestinal adaptation awaits further research. Little is known about GLUTS, although a recent study has demonstrated that it is located on the BBM of the upper third of adult human small intestine rather than the BLM. While these findings suggest that GLUTS is involved in the uptake of sugars from the small intestinal lumen, the role played by GLUTS on glucose uptake from the small intestine is unknown (Davidson et ak. 1992).

The p~racellularroute In addition to the transcellular route of absorption, glucose may also pass from the intestinal lumen to the circulation via the paracelluiar pathway. Structurally, this route involves the tight junction (or zona occludens), which is the site of intimate contact between adjacent enterocytes. The tight junction is associated with a narrow belt of actomyosin that circumferentidly wraps each enterocyte near the apical membrane and adagoins it with its neighbours (Madara 1988). For years, it was believed that the tight junction between enterocytes was a physical barrier to diffusion, impeding the passage of molecules from the lumen to the circulation. Since it was generally agreed that the structure and function of tight junctions were

Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIVERSITY OF NEW MEXICO on 11/27/14 For personal use only.

CRITICAL REVIEW /

"fixed," d l epithelial transport studies were interpreted with this implicit assumption. It wow appears, however, that the tight junction may be a highly dynamic structure subject to regulation. In Ussing chambers, the application of glucose to the mucosal surface of the intestine substantially diminished tight-junction resistance (Asitook et al. 1990). The triggering event appeared to be the activation of the sodium-dependent glucose carrier on the BBM of the enterocytes. This conclusion was based on evidence that both phlorizin and the substitution of sodium with choline in the bathing solutions blocked the glucose-elicited drop in tight-junction resistance (Asitook et al. 1990). It is hypothesized that the activation of the glucose transporter at the BBM stimulates condensation of the perijunctiond ring actomyosin associated with the tight junction, resulting in its contraction. Because of this contraction, the tight junction is opened and permeability between cells increases (Madara et al. 1987). This permits glucose and possibly other molecules to cross the epithelium through the tight junction into the paracellular space by solvent drag (Asitook et ak. 1990). The second messenger triggered by the binding of glucose to the BBM carrier remains to be defined. It has been speculated that the system may resemble that in smooth muscle cells, where phosphorylation of myosin and ultimate contraction is regulated by a calmodulin-dependent b a s e (Madara and Pappenheimer 1987). However, the calmoddin inhibitors W13 and trifluroperazine did not affect the glucose-elicited drop in tight-junction resistance. This suggests that a noncalmodulin-dependent Enase may be involved in regulating myosin phosphorylation (Asitook et al. 1990; Naku et al. 1983). The paracellular route of glucose absorption is thought to be important based on studies suggesting that it accounted for 30%of absorbed glucose when luminal glucose concentrations were relatively high (Asitook et al. 1990). There is some question, however, whether these concentrations are representative of glucose levels in the small intestinal lumen under physiological conditions (Ferraris et al. 1990). Thus, the quantative importance of the paracellular route in glucose absorption may have been overstated.

Signals The preceding discussion has considered the possible mechmisms that exist to upregulate glucose absorption in the small intestine in response to numerous conditions. Somehow, the demand for increased glucose absorption must be translated into a coordinated sign& for the response to occur. The signals responsible for the increase in glucose uptake are unknown, although several possibilities exist. The most direct signal triggering enhanced glucose absorption appears to be glucose itself. Saturation of the glucose carriers at either the BBM or the BLM could stimulate a second messenger system, resulting in enhanced glucose absorption through one of the possible mechanisms discussed previously. It has already been demonstrated that with respect to tight junctions, glucose itself triggers the upregulation of its own absorption (Asitook et al. 1990). Another possibility involves the release of hormones to induce enhanced glucose absorption from the intestine. Hormones and other trsphic factors are certainly involved in the nonspecific upregulation of glucose transport that occurs in response to pregnancy, lactation, and intestinal resection. Evi-

SYNTHBSE

CRITIQUE

1205

dence for this includes the observation that intestinal hypertrophy and the consequent enhanced glucose transport occurs in Thiry-Vella loops (bypassed segments of gut that have no luminal exposure to nutrients) of lactating rats or of rats that have undergone intestinal resection (Hanson et aE. 1977; Elias and Bowling 1973; Williamson and Malt 1981). The list of possible candidates for the above observations includes gastrin, glucagon, insulin, cholecystokinin, secretin, prolactin, and enteroglucagon (Johnson 1976; Rudo and Rosenberg 1973; Caspary 1973; Hughes et al. 1981; Weser et al. 1981; Campbell and Fell 1964; Jacobs et ak. 1981). In addition, trophic factors such as epidermal growth factor and other polypeptide mitogens must be considered (Opleta-Madsen et al. 1991). Humord signals are important in stimulating mechanism that specifically upregulate glucose absorption as well. For instance, plasma insulin levels have been found to play a role in modulating intestinal glucose transport (Westergaard 1989). Furthermore, plasma insulin and glucose levels were experimentally modulated independently or in parallel in order to assess their role as regulators of intestinal glucose transport. Both increases or decreases in plasma insulin concentration, but not glucose concentration, caused a specific increase in the maximal rate of intestinal glucose transport from perfused intestinal loops. Hypoinsulinemia appeared to be a more potent signal, inducing the upregdation of glucose transport more than hyperinsulinemia (Westergaard 1989). This is diametrically opposed to the response in fat and muscle, where hypoinsulinemia causes a decrease in the maximal glucose transport capacity (Karnieli et wl. 1981; Toyoda et al. 1987; Devashr et al. 1972). A more recent study demonstrated that insulin regulates the activity of the BBM glucose transporter (Fujii et ak. 1991). Glucose transport rates in the BBM and phlorizin binding to BBM vesicles were markedly increased in streptozotocin-induceddiabetic rats. Treatment of diabetic rats with insulin not only reduced BBM glucose transport rates to normal but also lowered the amount of phlorizin binding to BBM vesicles. In contrast, lowering blood glucose levels in diabetic rats to control values by starvation did not decrease glucose transport rates or reduce phlorizin binding in the diabetic animals. Hormones other than insulin have also been implicated as possible regulators of intestinal glucose transport. Ileal perfusion of a glucose solution results in the rapid upregulation of glucose absorption in the jejunum with no change in ileal glucose transport (Debnam 1985). Enteroglucagon and neurotensin are two possible hormones mediating this response, since both are lwalized specifically to the lower intestine. Enteroglucagon may be the more likely candidate, since conditions that result in a larger than normd glucose load reaching the ileum prompt increased plasma levels of enteroglucagon (Besterman et al. 1982; Macro et al. 1972; Bloom et al. 1972). This is seen in patients with intestinal resections, gastrectomies, and dumping syndrome. Thus, exposure sf the ileum to glucose may stimulate the release of enteroglucagon, which could then act to enhance glucose absorption in the more proximal small intestine. Also, the observation that glucose absorption is enhanced in animals suffering from proteinenergy malnutrition suggests the existence of some humoral factor (Butzner et al. 1990). Another signal that prompts enhanced glucose uptake could involve the enteric nervous system. It has been proposed that certain epithelial cells in the ileum have a chemoreceptor hnc-

1206

CAN. J. PHYSIOL. BHARMACOL. VOL. 70, 1992

Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIVERSITY OF NEW MEXICO on 11/27/14 For personal use only.

tion and can detect the presence of glucose in the lumen (Newson eb ak. 1982). Through a reflex loop in the enteric nervous system, glucose absorption could be stimulated in the more proximal regions of the small intestine (Debnam 1985). This is supported by evidence that afferent nerve activity originating from the ileum increased markedly when the ileum was perfused with glucose (Hardcastle et ak. 1878).

Conclusions TWOclasses of mechanisms that increase glucose uptake have been identified. First, nonspecific increases in glucose transport occur in certain conditions and are associated with increases in epithelial surface area. Nonspecific mechanisms are stimulated during pregnancy and lactation and following intestinal resection. Secondly. a variety of mechanisms appear to specifically increase the rate of glucose absorption and can involve either the transcellular or the paracellular pathway of glucose absorption. It appears that the upregulation of glucose transport occurring in streptozstocin-induced diabetes mellitus and alterations of dietary carbohydrate levels involve regulation of mechanisms at the site of the BBM. The regulation of glucose transport rate at the BLM is probably important in the rapid response seen in hyperglycernia. Regulation of the paracellular transport of glucose involves alterations in tightjunction permeability, and while the significance of this in overall glucose absorption is unclear, it may have profound implications for events that occur following a meal. The possible signals that trigger the upregulation of glucose absorption are glucose itself and, possibly, humoral and enteric nervous interacticsns. The recent cloning of the sodium-dependent glucose transporter (SGLTI) and the facilitative glucose transporters (GLUT2 and GLUTS) and the subsequent development of specific cDNA probes and antibodies will give researchers powerful new tools to use in the study of the regulation of glucose transport. Asitook, K., earlson, S . , and Madara, J. D. 11990. Effect of phlorizin a d sodium in glucose-elicited alterations in intestinal epithelia. Am. 3. Physiol. 258: C77-C85. Berger, M., Hagg, S. , and Ruderman, N. B. 1975. Glucose rnetabslism in perfkased skeletal muscle. Interactions of insulin and exercise on glucose uptake. Biochern. J. 146: 231 -238. Besteman, N. S., Adrian, T. E., Mallison. C. N . , Christofides, N. D., Sarson, B . L., Pera, A., Lombardo, L., Modigliani, R., and Bloom, S. R. 1982. Gut hormone release after intestinal resection. Gut, 23: $54-861. Bloom, %. R., Royston, C. M. S o , and Thsmson, J. Pa S. 8972. Enteroglucagsn release in the dumping syndrome. Lancet, 2: 789-791. Butzner, J. D., Brockway, B. D., and Meddings, J. B. 1998. Effects of malnutrition on microvillus membrane glucose transport and physical properties. Am. J. Bhysiol. 259: C"d0 -G946. Campbell, R. M., and Fell, B. F. 1964. Gastrointestinal hypertrophy in the lactating rat and its relation to food intake. I. Physiol. (London), I"$: 90 -97. Caspary, W. P. 1973. Effect of insulin and experimental diabetes mellitus on the digestive absorptive function s f the small intestine. Digestion, 9: 248 -263. Cheeseman, C. H., and Harley, B. 1991. Adaptation of glucose transport across rat enterocyte basolateral membrane in response to altered dietary carbohydrate intake. J . Phy siol . (London), 437: 563 -575. Cheeseman, 63. I., and Maem, D. B. 1989. Rapid regulation of D-glucose transport in basolateral membrane of rat jejunum. Am. J. Physiol. 256: C878-G883.

Craft, I. L. 1970. The influence of pregnancy and lactation on the wze~vhologyand absorptive capacity of the rat small intestine. J. Cline Sci. 38: 287-295. Cripps, A. W., and Wiliams, V. 5. 1975. The effect of pregnancy and lactation on food intake, gastrointestinal anatomy and the a b s o ~ t i v ecapacity of the small intestine in the albino rat. Br. J. Nutr. 33: 17-32. Crofford, 0.B., and Reynold, A. E. 1945. Glucose uptake by incubated rat epididymal adipose tissue. Rate limiting steps and site of insulin action. J . Biol. Chem. 240: 3237 -3244. Csaky, T. Z., and Fischer, E. 1981. Intestinal sugar transport in experimental diabetes. Diabetes, 30: 568 -574. Bavidson, N. O., Hausman, A. M. L., Ifkovits, C. A*,Buse, J. B., Gould, G . W., Burant, C. F., and Bell, G. H. 1992. Human intestinal glucose transporter expression and localization of GLUT5. Am. 5. Physiol. 262: C795 -C800. Bebnam, E. S. 1485. Adaptation of hexose uptake by the rat jejunum by the perfklslon of sugars into the distal ileum. Digestion, 31: 25 -30. Devasbr, S. U., and Mueckler, M. M. 1992. The mammalian glucose transporters. Bediatr. Res. 31: H - 13. Diamond, S. M., and h r a s o v , W. H. 1984. Effect s f dietary carbohydrate s n monosaccharide uptake by mouse small intestine in V~PYQ. 3. Physiol. (London), 349: 419 -440. Dudeja, P. K . , WaBi, R. K . , Klitzke, A., and Brasitus, T. A. 19%. Intestinal D-glucosetransport and membrane fluidity along crypt villus axis of streptozocin-induced diabetic rats. Am. J . Physid. 259: G57 1- G577. Elias, E., and Dowling, R. H. 1973. The effect of lactation on intestinal structure and hnctirgsn following by-pass or transposition of the jejunum in the rat-evidence for hormonal stimulation of intestinal mucosal hypeplasia. In Intestinal adaptation. Edited by R. H.Dowling and E. 8. Riecken. Schamuer, Stuttgart, Germany. pp. 93-102. Fedorak, R. N. 1990. Adaptation of small intestinal membrane transpor? processes during diabetes mellitus in rats. Can. J. Physiol. Pharmacol. 68: 630 -635. Fedorak, R. N., Chang, E. B., Madara, J. L., and Field, M. 1987. Intestinal adaptation to diabetes. Altered Na-dependent nutrient absorption in streptozocin-treated chronically diabetic rats. J. Clin. Invest. 79: 1571- 1578. Fdsrak, R. N.,Gesshon, M. D., and Field, M. 1989. Induction of intestinal glucose carriers in streptozoch-treated chronically diabetic rats. Gastroenterology, 96: 37 -44. Ferraris, R. B., and Diamond, J. M. 1986. Use of phlorizin binding to demonstrate induction of intestinal glucose transprters. J. Membr. Biol. 94: 77 - 82. Ferraris, R. P., and Diamond, S . M. 1992. Crypt-villus site s f glucose transporter induction by dietary carbohydrate in mouse intest h e . Am. J. Physiol. 262: G1069-61073. Ferraris, R. B., Yasharpour, S . , Lloyd, K. C. K., Mirzayan, R., and Diamond, 3. M. 1990. Luminal glucose concentrations in the gut under normal conditions. Am. J. Bhysiol. 259: G822 -6837. Ferraris, R. P., Villenas, S. A., Hirayma, B. A., and Diamond, 3. M. 1992. Effect of diet on glucose transporter site density along the intestinal crypt-villus axis. Am. I. Physiol. 262: G1060G1068. Fujii, Y., Kaizuka, M.. Hashida, F., Mamo, J . , Sato, E., Yasuda, H.,Kurokawa, T., and Ishibashi, S. 1991. Insulin regulates Na+/glucose cotransporter activity in rat small intestine. Biochim. Biophys. Acta, 1063: 90-94. Hanson, W. R., Rijke, R. P.,Plaisier, H. M., Vanewuk, W., and Osborne, J. W. 1977. The effect of intestinal resection of ThiryVella fistulae of jejunal and ileal origin in the rat: evidence for a systemic control mechanism of cell renewal. Cell Tissue Kinet. 10: 543 -555. Hardcastle, J., Hardcastle, P. T., and Sanford, P. A. 1978. Effect of actively transport hexoses on afferent nerve discharge from the rat small intestine. 5. Physiol. (London), 285: 71 -84.

Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIVERSITY OF NEW MEXICO on 11/27/14 For personal use only.

CRITICAL REVIEW / S Y N T H ~ S BCRITIQUE

Mediger, M. A., Coady, M. J., Ideda, T. S., and Wright, E. M. 198'7. Expression, cloning and @DNAsequencing of the Na+/glucose co-transporter. Nature (London), 330: 379 - 38 1. Hopfer, U. 19'75. Diabetes mellims: changes in transport properties of isolated microvillus membranes. Broc. Natl. Acad. Sci. U.S. A. 72: 2027 -203 1. Hughes, C. A., Breuer, 8. S., Ducker, D. A., Hatoff, D. E., and Dowling, R. H. 1981. The effect of cholecystokinin and secretin on intestinal and pancreatic structure and function. In Mechanisms of intestinal adaptation. Edited by 3. W. L. Robinson, R. H. Dswling, and E. 8. Riecken. MTP, Lancaster, U.K. pg. 435 -450. Hwang, E., Hirayama, B. A., and Wright, E. M. 1991. Distribution sf the SGLT1 Na+/glucose co-transporter and mRNA along the crypt-villus axis of rabbit small intestine. Biockern. Biophys. Res. C o m u n . 181: 1208-1257. Jacobs, L. R., Polak, S. M., Bloom, S. R., and Dowling, R. H. 1981. Intestinal mucosal and fasting plasma levels of irnmunoreactive enteroglucagon in three models of intestinal adaptation: resection, hypothemic hyperphagia, and lactation in the rat. In Meckanisms of intestinal adaptation. Edited by J. W. L. Robinson, R. H, Rowling, and E. 0. Riecken. MTP, Lancaster, U.K. pp. 231 -240. Johnson, L. R. 1976. The trophic action of gastrointestinal hormones. Gastroenterology, 70: 278 -288. Karasov, W. H., and Debnam, E. %. 1987. Rapid adaptational glucose transport: a brush-border or basolateral phenomenon? Am. J. Bhysiol. 253: 654-G61. h r a s o v , W. H., and Diamond, J. M. 1983. Adaptive regulation of sugar and amino acid transport by the vertebrate intestine. Am. J. Physiol. 245: G 4 3 -G462. Karasov, W. H., Bond, R. S., Solberg, D. H., and Diamond, J. M. 1983. Regulation s f proline and glucose transport in m u s e intestine by dietary substrate levels. Prw. Natl. Acad. Sci. U.S.A. 80: 7674 -7677. Karnieli, E. M., Zarnowski, M. %.,Hissin, P. J., Simpson, 1. A., Salans, L. B., and Cuskrnan, S. W. 1981. Insulin-stimulated translocation of glucose transport systems in the isolated rat adipose cell. J . Biol . @hem. 256: 4772 -4777. Kayano, T., Burant, C. F., Fuhmoto, H.,Gould, G. W., Fan, Y., Eddy, R. L., Byers, M. G., Shows, T. B., Seino, S., and Bell. G . 1. 1990. Human facilitative glucose transporters. J. Biol. Chern. 244: 13 2'76 - 13 282. Keljo, D. J., Macled, R. J., Perdue, M. H.,Butler, D. G., and Hamilton, J. R. 1985. D-Glucose transport in piglet jejunal brush border membranes: insights from a disease model. Am. S. Physiol. 249: G75 1 -G760. Kohan, D. E., and Schreiner, G. F. 1988. Interleukin 1 modulation of renal epithelial glucose and amino acid transport. Am. J. Bhysiol. 254: F879 -F886. Macro, J., Baroja, I. M., Diaz-Fierros. M., Villaneuva, M. L., and Valverde, I. 1972. Relationship between insulin and gut glucagonlike imunoreactivity (GLI) in normal and gastrectomised subjects. J. Clin. Endocrinol. 34: 188 - 191. Madara, J. L, 1988. Tight junction dynamics: is paracellular transport regulated? Cell, 53: 497 -498. Madara, J. L . , and Pappeheimer, %.R. 1987. Structural basis for physiological regulation of paracellular pathways in intestinal epithelia. J. Membr. Biol. 108: 149- 164. Madara, J. L . , Moore, R., and Carlssn, S. 1987. Alterations of intestinal tight junction stmcture and permeability by cytoskeletsn contraction. Am. J. Physiol. 253: C854-C86B. Maenz, D. D., and Cheesemn, C. I. 1986. Effect of hyperglycemia on D - ~ ~ U C O transport S~ across the brush-border and basolateral membranes s f rat small intestine. Biochim. Biophys, Acta, 860: 277 -285. Meddings, J. B., Desouza, Be,Goel, M., and Thiesen, S. 1990.

1207

Glucose transport and microvillus membrane physical properties along the crypt-villus axis of the rabbit. J. Clin. Invest. 85: 1099- 1107. Meglasson, M. D., and Matchinsky, F. M. 1986. Pancreatic islet glucose metabolism and regulation of insulin secretion. Diabetes Metab. Rev. 2: 163-214. Miyamoto, K., Hase, K . , Taketani, Y., Minani, H., Bka, T., Nakabou, Y., and Hagihira, H. 1991. Diabetes and glucose transporter gene expression in rat small intestine. Biochem. Biophys. Res. Commun. 181: 1110-111'7. MuecMer , M . 1990. Family of glucose-transporter genes: implications for glucose homeostasis and diabetes. Diabetes, 39: 6 - 11. Naku, M., Nishikawa, M . , Adelstein, R. S.. and Hidaka, H. 1983. Phsrbol ester induced activation of human platelets is associated with protein kinase C phosphoqlation of myosin light chains. Mature (London), 306: 490 -492. Newson, B., Aklman, H., Dahlstrom, A., and Nyhus, L. M. 1982. Ultrastructural observations in the rat ileal mucosa of possible epithelial "taste cells" and sub-rnarcosal sensory neurons. Acta Physiol. Scand. 114: 161- 164. Opleta-Madsen, K., Hardin, J., and Gall, D. G. 1991. Epidermal growth factor upregulates intestinal electrolyte and nutrient transport. Am. J. Physisl. 260: G807-G814. W o , N. D., and Rosenberg , I. H. 1973. Chronic glucagon administration enhances intestinal transport in the rat. Prsc. Soc. Exp. Bisl. Med. 142: 521 -525. Sadowski, D. C., Gibbs, D. J., and Meddings, J. B. 1991. Proline transport across the intestinal microvillus membrane may be regulated by membrane physical properties. Biochim. Biophys. Acta, 1105: 75-83. Tahta, K., Kaasahara, T., Kashara, M., Ezaki, O . , and Hirans, H. 1992. Imunohistochemical localization of &+-dependent glucose transporter in rat jejunum. Cell Tissue Res. 267: 3 -9. Thomson, A. B. R. 1981. Uptake of glucose into the intestine of diabetic rats. Effects of variations in the effective resistance of the unstirred water layer. Diabetes, 30: 24'7-255. Thomson, A. B. R. 1982. Influence of dietary modifications on uptake of cholesterol, glucose, fatty acids, and alcohols into rabbit intestine. Am. %.elin. Nutr. 35: 556-565. Thsrens, B., Sarkar, H. K., Kaback, H. R., and Eodish, H. IF. 1988. Cloning and functional expression in bacteria of a novel glucose transporter present in liver, intestine, kidney and beta pancreatic islet cell. Cell, 55: 281 -290. Thorens, B., Cheng, Z. Q.,Brown, D., and Lodish, H. F. 1990. Liver glucose transporter: a basolateral protein in hepatocytes and intestine and kidney cells. Am. J. Bhysiol. 259: CP79 -C285. Toyda, N., Elanagan, J. E., and Kono, T. 1987. Reassessment of insulin effects on the V , , , and Km values of hexose transport in isolated rat epididymal adipcytes. J. Bisl. &'hem. 260: 27372745. Turk, E., Zubel, B., Mundles, S., Dyer, J., and Wright, E. M. 1991. Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter. Nabre (London), 358: 354 -356. Urban, E., and Maley , D. P. 1978. Glucose transport by the rat small intestine after extensive small bowel resection. Am. J. Dig. Bis. 23: 531-540. Weser, E., Bell, D., and Tawil, T. 1981. Effects of octapeptidecholecystokinin, secretin, and glucagon on intestinal mucosal growth in parenterally nourished rats. Dig. Dis. Sci. 26:409 -416. Westergaard, H. 1989. Insulin modulates rat intestinal glucose transport: effect ~f hypoinsulinemia and hyperinsulinemia. Am. J. Physiol. 256: G911 -G918. Williamson, R. C, , N., and Malt, R. A. 1981. Humoral modulation of compensatory intestinal hypplasia. In Mechanisms of intestinal adaptations. Edited by J. W. L. Robinson, It* H. Dowling, and E. 8. Riecken. MTP, Lancaster, U.K. pp. 215-224.