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Annu. Rev. Physiol. 1992. 54:911-30 Copyright © 1992 by Annual Reviews

Inc. All

rights reserved

MAMMALIAN FACILITATIVE GLUCOSE TRANSPORTER FAMILY: STRUCTURE AND MOLECULAR REGULATION Jeffrey E. Pessin Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242

Graeme

I. Bell

Howard Hughes Medical Institute and Departments of Biochemistry, Molecular Biolo­ gy, and Medicine, University of Chicago, Chicago, Illinois 60637 KEY WORDS:

insulin, diabetes, adipose, muscle, liver

FACILITATIVE GLUCOSE TRANSPORTERS-MOLECULAR STRUCTURE Except for the active uptake of glucose from the lumen of the small intestine and proximal tubule of the kidney, the" transport of glucose across cell membranes' occurs by facilitated diffusion. Currently, cDNAs encoding five structurally-related proteins with the properties of faCilitative glucose transporters have been isolated and characterized (Table I). The five isoforms have been designated GLUT lIerythrocyte, GLUT2/liver, GLUT3/brain, GLUT4/muscle-fat,andGLUT5/smali intestine (25,52). In addition to these five functional facilitative glucose transporters, an expressed facilitative glu­ cose transporter pseudogene-like sequence (GLUT6) has been identified in human tissues (39). This sequence is part of a ubiquitously expressed mRNA, but does not encode a functional protein. The purification and characteriZation of the human erythrocyte glucose transporter provided the basiS" for th"e isolation of human and rat GLUT1 0006-4278/92/03 154>911$02.00

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Table 1

Mammalian glucose transporters: major sites of expression and physiological functions

Designation

Major sites of expression

Function

A. Sodium-dependent glucose transporters SGLT!

Small intestine and kidney

Active uptake of dietary glucose from the lu­ men of the small intestine, and reabsorption

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of filtered glucose in the proximal tubule of the kidney B. Facilitative glucose transporters GLUT!

Placenta, brain, kidney and colon

Basal uptake of glucose by cells, transport of

GLUT2

Liver, pancreatic f3-cell, small in­

Uptake and release of glucose by hepatocytes

glucose across blood-tissue barriers testine, and kidney

f3-cell glucose sensor Release of absorbed glucose across the baso­ lateral surface of absorptive epithelial cells of small intestine and kidney

GLUT3

Many tissues in humans including

Basal uptake of glucose by all cells in humans

brain, placenta and kidney; in

including those of the brain; uptake of glu­

other species may only be ex­

cose by cells of the brain in other species

pressed at high levels in the brain GLUT4

Skeletal and cardiac muscle, and

Insulin-stimulated glucose uptake

brown and white adipose tissue GLUT5

Small intestine (jejunum)

Absorption of sugars from the lumen of the small intestine (?)

cDNA clones from HepG2 hepatoblastoma and rat brain libraries, respective­ ly (5, 47). The predicted sequence of the 492 amino acidGLUT l protein was highly conserved, with 98% sequence identity between the human and rat. This high degree of sequence conservation implies that all regions ofGLUTl are functionally important. Computer. analyses of the predicted amino acid sequence of human GLUT l , including hydropathy and secondary-structure determinations, re­ vealed that it was an extremely hydrophobic protein and suggested that approximately 50% of the protein lies within the lipid bilayer. Based upon this analysis, Mueckler et al (47) proposed a model for the topology ofGLUTl in the plasma membrane in which the protein spans the plasma membrane 12 times, with its NHr and COOH-termini internally oriented (Figure 1). A large extracellular segment of 33 amino acids connects transmembrane do­ mains Ml and M2, and a very hydrophilic intracellular segment of 65 amino acids joins M6 and M7. Short regions of 7-14 amino acids connect the remaining membrane-spanning regions. GLUTl is a heterogeneously gly­ cosylated protein, and its pattern of glycosylation can vary among tissues and cell lines. There are two potential N-linked glycosylation sites in human GLUTl at Asn45 and Asn411. The former site is in the large extracellular loop connecting Ml and M2 and has been shown to be glycosylated (46), whereas

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GLUCOSE TRANSPORTER FAMILY

Figure 1

9 13

Model for the orientation of GLUT! and other facilitative glucose transporters in the

plasma membrane (adapted from References 25, 47). The 12 membrane-spanning segments are shown as boxes and are numbered M1 to M12. The potential N-linked glycosylation site in the extracellular segment connecting MI and M2 is noted. Identical amino acids in the five human facilitative glucose transporter isoforms GLUT! to GLUTS are indicated using their single-letter abbreviations, and chemically similar residues are noted by the hatched circles. Note that the lengths of the NHr and COOH-terminal domains as well as that of the extracellular loop between MI and M2 may differ between transporter isoforms. The single letter abbreviations for the amino acids are A, alanine; C, cysteine; D , aspartic acid; E, glutamic acid; F, phenylalanine; G, glycine; H, histide; I, isoleucine K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q. glutamine; R. arginine; S, serine; T, threonine; Y, valine; W, tryptophan; and Y, tyrosine. The positions at which introns interrupt the GLUT! cDNA sequence are also indicated.

the latter site is predicted to be in transmembrane segment M Il and is therefore unlikely to be modified. Glycosylation of GLUTl at a site near its NH2-terminus is also consistent with proteolytic digestion studies of the human erythrocyte glucose transporter, which localized the site of glycosyla­ tion to an NH2-terminal peptide (reviewed in 9). The isolation of cDNAs encoding human and rat GLUT I represented an important milestone in diabetes research and allowed molecular biological approaches to be used to study the regulation of glucose transport in mamma­ lian cells. In addition, the use of the human and rat cDNAs as probes to screen cDNA libraries preprared from other tissues, under conditions that promoted cross-hybridization, led to the identification of a family of glucose transporter proteins. Although biochemical studies had suggested that functionally dis­ tinct glucose transporter species might exist in erythrocytes and hepatocytes (9), the full extent of the diversity of these proteins was not anticipated_ Recent studies have identified five different facilitative glucose transporters expressed in mammalian cells (Table 1), with the likelihood that other

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members remain to be described. The members of this gene family are characterized by a similar size (-500 amino acids) and orientation in the plasma membrane, including 12 membrane-spanning segments, in­ tracellularly oriented NHr and COOH-termini, a large extracellular loop connecting transmembrane segments M l and M2, which contain a single consensus site for N-linked glycosylation, and a large hydrophilic segment joining transmembrane domains M6 and M7 (Figure 1). Despite their overall structural and functional similarity, the amino acid sequences of the mamma­ lian facilitative glucose transporters vary considerably. There is 39-65% sequence identity and 50-76% sequence similarity between isoforms; 26% of the residues are invariant in all five proteins, and another 13% represent conservative amino acid replacements. In general, the most divergent regions are the NHr and COOH-terminal domains and the extracellular segment connecting M 1 and M2 (Figure 1). The five facilitative glucose transporter isoforms identified to date are separate gene products, with no evidence for alternative splicing creating additional diversity. Each isoform has a distinct pattern of expression, both in terms of tissue sites of synthesis and levels of expression, that distinguishes it from the other members of the family. Individual tissues and cells may express more than one facilitative glucose transporter isoform, and some may also express the Na+/glucose cotransporter (Table 1). Each of the glucose transporter isoforms has been expressed in a heterologous system including bacteria, Xenopus oocytes, or cultured mammalian cells (reviewed in 7). These studies have allowed the biochemical properties of each isoform to be examined independently of the others and indicate that the mammalian facili­ tative glucose transporters can be distinguished based upon their kinetic properties and affinities for various sugars (Table 2). Table 2

Km

values

for

2-deoxy-D-glucose

and

3-0-

methylglucose of mammalian facilitative glucose transporters Km{mM) Isoform

2-deoxy-D-glucose

3-0-methylglucose

Rat GLUT!

6.9 ± 1.5

20.1 ± 2.9

Human GLUTI

N·.D.

17.2 42.3 ± 4.1

Human GLUT2

i3.2 ± 2.4

Human GLUT3

1.8 ± 0.6

10.6 ± 1.3

Human GLUT4

4.6 ± 0.3

N.D.

Synthetic RNA encoding each isofonn was prepared by in vitro transcrip­ tion of cloned cDNAs and injected into Xenopus oocytes. The Kms for

(zero-lrans entry) and 3-0-methylglucose (equilibrium ±S.E.M. were determined as described in Kayano et al (39) and Gould et al (26, 27). The Km values of human GLUTS have not been detennined. The data are from C. F. Buran! & G. I. Bell (in preparation) and Gould ct al (26, 27). N.D. � not detennined. 2-deoxy-D-glucose exchange)

GLUCOSE TRANSPORTER FAMILY

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It is now clear that the transport of glucose across the cell surface in higher organisms is carried out by a family of structurally related proteins with overlapping but distinct tissue distributions, and different kinetic and bio­ chemical properties. This diversity presumably allows for the precise disposal of glucose under varying physiological conditions and ensures efficient cellu­ lar uptake of glucose across tissues and organs where gradients of glucose concentration may exist.

TISSUE DISTRIBUTION AND PROPERTIES OF FACILITATIVE GLUCOSE TRANSPORTERS GLUT11Erythrocyte Isoform GLUT l is expressed at highest levels in fetal tissues, brain, and placenta. In many of the adult tissues in which it is expressed, GLUT 1 is concentrated in cells of ,blood-tissue barriers, which indicates a role for GLUT l in the movemehh>f glucose across these barriers and delivery to underlying tissues (7). In addition, GLUTl is the predominant facilitative glucose transporter expressed by cultured cells and is present in many tumors. Since low levels of GLUT l protein or mRNA can be detected in virtually all tissues, this glucose transporter isoform may be responsible, at least in part, for constitutive glucose uptake. The amino acid sequence of GLUTl is highly conserved, and there is 97-98% identity between the human (47), rat (5), rabbit ( 1 ), mouse (35), and pig (66) sequences, thus implying that all domains of this protein are func­ tionally important. Such a high degree of amino acid sequence conservation is not a general feature of all facilitative glucose transporter isoforms, and it is not clear why the sequence of GLUTl has remained essentially invariant. Studies examining the properties of human and rat GLUTl expressed in Xenopus oocytes have observed a Km for monosaccharides that is intermediate between those of GLUT3 with that of GLUT4 and GLUT2 (26, 27, 41, C.F. Burant & G. I. Bell, in preparation; Table 2). GLUT21Liver Isoform The tissue distribution of GLUT2, expressed in the liver, small intestine, kidney, and insulin-secreting p-cells of the endocrine pancreas (63), is more restricted than that of GLUT l . Western blot studies have demonstrated that the size of the protein expressed in these tissues differs (61, 63). This variation in apparent size is most likely due to differences in glycosylation, since the sequences of cDNA clones isolated from liver, kidney, small intestine, and pancreatic islets of Langerhans are apparently identical. The functional consequences of the tissue-specific differences in GLUT2 glycosylation are unknown. The tissue distribution of GLUT2 suggests that it mediates the uptake and release of glucose by hepatocytes and that it partici-

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PESSIN & BELL

pates in the transepithelial transport of absorbed and reabsorbed glucose by the small intestine and kidney, respectively. Its presence in the /3-cell suggests that it may function in the regulation of glucose-stimulated insulin secretion. The sequences of human (19), rat (63), and mouse (2, 59) GLUT2 have been determined and share 55% amino acid identity withGLUTl . The amino acid sequence ofGLUT2 is not as highly conserved among species as that of GLUTl , with only 8 1 % identity between human and rat or mouse GLUT2. The most divergent region ofGLUT2 is the extracellular domain that connects M l and M2 and encompasses the site of N-linked glycosylation. GLUT2 has been expressed in vitro and has a significantly higher Km for sugars than the other isoforms (27; C. F. Burant & G. I. Bell, in preparation; Table 2), as expected from biochemical studies of glucose uptake and cytochalasin B binding in hepatocytes (9). GLUT31Brain

lsoform

cDNA clones encoding GLUT3 were isolated from a human fetal skeletal muscle cDNA library (40). Human GLUT3 has 64 and 5 2% identity with humanGLUTl and GLUT2, respectively, with an 83% amino acid sequence identity between the sequences of human and mouse GLUT3 (S. Nagamatsu &G. I. Bell, in preparation). Thus, as withGLUT2, the sequence ofGLUT3 is not as highly conserved among species as that of GLUT 1. The greatest degree of sequence divergence inGLUT3 occurs in the extracellular loop and intracellular COOH-terminal domains. These are the same regions that are the most divergent among the different isoforms. GLUT3 mRNA is present at variable levels in all adult human tissues and tumors that have been examined and is found at highest levels in brain, kidney, and placenta (40). The ubiquitous distribution of GLUT3 in human tissues suggests that it, together with GLUTl , may be responsible for basal, non-insulin-stimulated, glucose transport. Interestingly, in monkeys, rabbits, rats, and mice, the pattern of expression ofGLUT3 is much different than that observed in humans (68). In these animals, GLUT3 mRNA is found at high levels in brain, and the levels ofGLUT3 are very low or undetectable in other tissues. In adult mice, in situ hybridization studies have found high levels of GLUT3 mRNA in the hippocampus (S. Nagamatsu &G. I. Bell, in prepara­ tion). The expression of GLUT3 in brain indicates that two facilitative glucose transporters are involved in the uptake and disposal of glucose in this tissue. GLUTl is primarily responsible for the transport of glucose across the blood-brain barrier, whereas GLUT3 probably controls glucose uptake into neuronal cells. The kinetic properties of GLUTl and GLUT3 (Table 2) are compatible with these proteins being responsible for the uptake of glucose in the brain. Since glucose concentrations are higher at the blood-brain barrier than in the brain itself, the apparent higher affinity for sugars of GLUT3

GLUCOSE TRANSPORTER FAMILY

917

compared to GLUT l ensures efficient uptake of glucose by neuronal cells even at low extracelluar glucose concentrations. In fact, GLUT3 has the lowest Km for hexoses of the facilitative glucose transporter isoforms char­ acterized to date (27; Table 2).

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GLUT4/Muscle-Fat Isoform Insulin causes a rapid and reversible increase in glucose transport activity in muscle and adipose tissue (reviewed in 54). The isolation and characterization of a monoclonal antibody that specifically recognized the insulin-regulatable glucose transporter indicated that it was a unique isoform, different from the glucose transporters present in erythrocytes,brain, kidney, jejunum,and liver (32). Simultaneously,four groups isolated human (18), rat (4, 11,33), and mouse (35) cDNA clones encoding this insulin-regulatable glucose transpor­ ter isoform, termed GLUT4. Human GLUT4 has 65, 54,and 58% identity with human GLUT 1 GLUT2, GLUT3, respectively. The sequence of GLUT4 is highly conserved, and there is 95 and 96% identity between the sequences of human and rat or mouse GLUT4,respectively. GLUT4 mRNA is found at highest levels in brown and white adipose tissue, in addition to cardiac and skeletal muscle (4, 10, 18, 33, 35). ,

GLUTS/Small Intestine Isoform The most recent member of the facilitative glucose transporter gene family to be identified is GLUTS (39). Human GLUTS shares 42, 40, 39, and 42% identity with human GLUTl , GLUT2, GLUT3, and GLUT4, respectively. GLUTS cDNA clones have not yet been isolated and characterized from other species. GLUTS mRNA is expressed predominantly in the jejunal region of the small intestine, although low levels can be detected in kidney, skeletal muscle,and adipose tissue (39). The subcellular distribution and function of GLUTS in these tissues are unknown.

Other Isojorms The rapid expansion of the facilitative glucose transporter family leads one to ask if all the members of this family have been identified. Analysis of the tissue distribution of the five established glucose transporters suggests that this list will continue to expand. For example, the exocrine pancreas is a metabolically active tissue; however, the levels of the known glucose transporter mRNAs in the pancreas are extremely low, which suggests that glucose uptake in this tissue is mediated by an as yet unidentified facilitative glucose transporter. In addition, the microsomal glucose transporter that is associated with glucose-6-phosphatase activity in gluconeogenic tissues and is responsible for glucose transport across the lumen of the endoplasmic reticu­ lum may also be a member of this transport family.

9 18

PESSIN & BELL

REGULATION OF GLUCOSE TRANSPORTER EXPRESSION IN VITRO' Studies of glucose transporter expression in cultured cells have focused primarily on GLUT 1, in part because it was the first isoform cloned, but also because GLUTl is the predominant and, in many cultured cells, the only isoform expressed. The levels of glucose transport activity, GLUTl protein anq mRNA in cultured cells can be altered by a number of different conditions including growth factors, insulin, transformation, glucose, agents that acti­ vate protein kinases A and C, hypoglycemic agents such as sulfonylureas, vanadate, glucocorticoids, cellular differentiation, and even stress (37, 46, 67). The effects of these factors on glucose transporter expression are, in many instances, specific for a given cell line or cell type. Although all cultured cells appear to express GLUT l , some cell lines express other isoforms as well. The human hepatoblastoma cell line, HepG2, and rat and mouse insulinoma cell lines, RINm5F and MIN6, also express GLUT2 ( 19, 45, 63). Thus these cells may be useful models for examining the regulation of GLUT2 expression in hepatocytes and pancreatic f3-cells, respectively. The mouse preadipocyte cell line, 3T3-L1, expresses GLUTI when grown as fibroblasts and, upon differentiation into adipocytes (lipob­ lasts), they begin to express GLUT4 (20, 33, 35). Thus, the differentiating 3T3-Ll adipocytes may also be used to gain a better understanding of the hormonal regulation of adipose glucose transporter expression.

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,

INSULIN REGULATION OF GLUCOSE TRANSPORTER ACTIVITY In 1980, Cushman, Kono, and their colleagues described a novel molecular mech anism by which insulin increased glucose transport in adipocytes (13,60 and reviewed in 54). These two groups independently demonstrated that the major effect of insulin on isolated rat adipocytes was to induce the transloca­ tion of an intracellular pool of glucose transporters to the plasma membrane; i.e. insulin increased the number of functional transport proteins at the surface of the cell (Figure 2). The increase in plasma membrane-associated glucose transporters was accompanied by a concomitant decrease in their abundance in the intracellular low density microsomal fraction. Although the transport of glucose itself does not require ATP, the translocation of glucose transporters in response to insulin and the reversal of this process are A TP-dependent. Insulin-stimulated glucose transport in skeletal and cardiac muscle also occurs by insulin-induced translocation of pre-formed glucose transporters from an intracellular pool to the plasma membrane (30, 43, 54). Thus the mechanism by which insulin stimulates facilitated glucose transport may be similar in both adipose and muscle tissue.

GLUCOSE TRANSPORTER FAMILY

Insulin-stimulated

Basal

+



E

......lo... �

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L-

0 Z

Diabetes

I

+-'

c:c:

=

1�n�

c:- "0

Figure 2

919



I

��

GLUT4 mANA

�-I-��

Insulin

-

+ +

GLUT4 enriched vesicles

� �

1 I

Regulation of glucose transport and GLUT4 expression in adipocytes by insulin

(adapted from Reference 7). Insulin promotes the translocation of vesicles containing GLUT4 from the trans-Golgi reticulum to the plasma membrane. The insulin-induced exocytosis of GLUT4 increases the number of functional glucose transporters at the cell surface and results in increased glucose uptake. Insulin-deficient states are associated with decreased levels of adipo­ cyte GLUT4 mRNA and protein. This chronic depletion of GLUT4 provides a molecular basis for the decrease in insulin-stimulated glucose uptake. In addition, to abnormal expression of GLUT4, translocation may also be impaired in insulin-deficient states.

The isolation and characterization of a monoclonal antibody, IF8, that recognizes the insulin regulated glucose transporter of adipocytes (32) sug­ gests that tissue-specific, insulin-regulated glucose transport is conferred by the expression of a unique facilitative glucose transporter isoform, ference subsequently confirmed with the cloning of GLUT4. Studies using isoform-specific antibodies have demonstrated that in rat adipocytes 90% of the glucose transporters are GLUT4 and -3-5% are GLUTl (48, 69). Under basal conditions, GLUT4 is predominantly localized to an intracellular vesicle population with little being present in the plasma membrane. In contrast, GLUT l is distributed approximately equally between plasma membrane and intracellular low density microsomal fractions. Moreover, GLUTl appears to be associated with a different population of vesicles than is GLUT4. In response to insulin, the amount of GLUT4 present at the cell surface increases IS-20-fold, whereas GLUTl increases -5-fold (3 1 , 69). Since insulin stimu­ lates glucose transport activity in primary rat adipocytes 2Q:-30-fold, and the -

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PESSIN & BELL

levels of GLUT4 in adipocytes are -20-30-fold greater than those of GLUT l , recruitment of GLUT4 can explain most of the insulin-stimulated increase in glucose transport activity. The small difference between the fold-increase in glucose transport activity (-20-30-fold) compared to the extent of GLUT4 translocation (- 15-20-fold) may be accounted for by differences in the turnover numbers of GLUTI and GLUT4 (see discussion in Holman et aI, 3 1). As discussed above, several cultured cell lines have been studied as model systems for investigating the effects of insulin and glucose on glucose trans­ port. The best-characterized of these are 3T3-Ll adipocytes in which insulin stimulates glucose transport -10-20-fold (8). However, in contrast to iso­ lated primary rat adipocytes, GLUT l is more abundant than GLUT4 in these cells. Quantitative immunoblotting studies indicate that there are -950,000 and 280,000 molecules of GLUTl and GLUT4, respectively, per cell (8). Insulin treatment of the 3T3-Ll cultured adipocytes caused a 6- and 17-fold increase in the amounts of plasma membrane-associated GLUTI and GLUT4 proteins, respectively. These results are qualitatively similar to those de­ termined for insulin-stimulated translocation in primary rat adjpocytes de­ scribed above and suggest that translocation may account for at least the majority if not the full effect of insulin on glucose transport in both systems. In addition to recruitment, glucose uptake may also be regulated by altering the intrinsic activity of the glucose transport protein (54). The mechanism(s) responsible for modulating the intrinsic activity of the facilitative glucose transporters are unclear. However, both GLUTl and GLUT4 can be phos­ phorylated; GLUT l by protein kinase C (24), and GLUT4 by protein kinase A (44). The site(s) of protein kinase C-mediated phosphorylation of GLUTl has not been determined. The site of phosphorylation of rat GLUT4 by protein kinase A is restricted to the region of the putative intracellular COOH­ terminal domain at Ser488 (44) and is conserved in the sequences of rat, human, and mouse GLUT4. Future studies examining the properties of a GLUT4 protein in which this amino acid has been substituted by site-directed mutagenesis will be an important approach for assessing the role of phos­ phorylation in regulating GLUT4 function.

REGULAnON OF GLUCOSE TRANSPORTER EXPRESSION IN VIVO It is now clear that the expression of the different mammalian glucose transporters is both tissue- and cell-type-specific. That this is the case should not be surprising in view of the differing requirements of tissues for glucose and of the different contributions of tissues to the maintenance of glucose homeostasis. To understand how glucose uptake is regulated in normal and altered metabolic states, the effects of fasting, diabetes mellitus, obesity, and

GLUCOSE TRANSPORTER FAMILY

921

chronic infusion of glucose or insulin on glucose transporter activity and expression have been examined (37). These studies have shown that the nature of the response of a specific glucose transporter isoform to hormonal or metabolic changes depends upon the tissue in which it is expressed.

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Adipose Tissue Adipocytes require glucose for the synthesis of triglycerides, the major storage form of metabolic energy in humans and other mammals. Since adipose tissue functions as an energy reservoir, catabolic states would be expected to be associated with decreased glucose uptake. In fact, there is a chronic decrease in glucose transport activity and glucose transporter protein levels in adipocytes isolated from rats that have been fasted or made diabetic by destruction of their insulin-producing f3-cells with the drug streptozotocin (STZ) (37, 54). These changes are fully reversible, and refeeding of fasted or insulin-treatment of diabetic animals resulted in a concomitant restoration of glucose transport activity and glucose transporter protein levels. The use of isoform-specific antibodies and cDNA probes has established that fasting and diabetes mellitus are associated with an �90% decrease in the levels of GLUT4 mRNA and protein (3, l1 , 22, 36, 56-58). Refeeding or insulin­ treatment resulted in a transient �twofold overexpression of GLUT4 mRNA and protein above the levels present in non-treated control animals. Sub­ sequently, GLUT4 mRNA levels gradually declined to normal control values over a period of about seven days (57). Since GLUT4 is the predominant isoform found in adipocytes, specific depletion of the intracellular pool of GLUT4 in fasted and diabetic animals as a result of decreased expression can directly account for the dramatic reduction in insulin-stimulated glucose uptake (Figure 2). In rat adipocytes, GLUTl represents only a minor fraction of the glucose transporter mRNA and protein, and its levels are not signifi­ cantly altered in these states of insulin deficiency. Recently, several studies (23, 55) have examined glucose transport activity and levels of GLUT4 mRNA and protein in adipocytes from lean and obese nondiabetic human subjects and in obese patients with non-insulin-dependent diabetes mellitus (NIDDM). These data suggest that the decreased insulin­ stimulated glucose transport activity observed in adipocytes from obese nondiabetic and NIDDM subjects is associated with decreased levels of GLUT4 mRNA and protein and that the magnitude of the decrease is much greater in NIDDM subjects that in their obese, nondiabetic controls. Garvey et al (23) concluded that in obesity the insulin resistance in adipocytes is caused by a chronic depletion of GLUT4, and in NIDDM there is a further reduction in GLUT4 levels that is not attributable to obesity per se. Thus suppression of GLUT4 expression may be an important mechanism for producing and maintaining the diabetic state in human subjects.

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Diabetes mellitus and fasting are both insulinopenic states, yet they are associated with opposite changes in glycemia. However, they both result in a specific decrease in GLUT4 expression in adipose tissue, which suggests that the expression of this gene may be more responsive to the levels of circulating insulin than glucose. This is supported by studies using phlorizin, a com­ pound that inhibits renal reabsorption of filtered glucose and thus reduces blood glucose levels without affecting circulating insulin levels. Normaliza­ tion of blood glucose levels in diabetic rats with phlorizin does not increase the levels of GLUT4 mRNA or protein in adipose tissue (38, 57). However, treatment with phlorizin does restore insulin-stimulated glucose transport activity (38). These results are consistent with a role for insulin, either directly or indirectly, in regulating transcription of the GLUT4 gene and, in addition, suggest that glucose levels may affect the functional activity of GLUT4. The recent demonstration that chronic hyperinsulinemia increases the abundance of GLUT4 mRNA in white adipose tissue of rats is consistent with a role for insulin in regulating its expression (14). The relative contribu­ tions of transcriptional and post-transcriptional events (i.e. mRNA stabiliza­ tion) in regulating GLUT4 mRNA levels is currently an active area of investigation.

Muscle Several laboratories have begun to examine the regulation of glucose transporter expression in skeletal muscle because of its central role in the maintenance of glucose homeostasis. However, studies using muscle tissue are complicated by the presence of multiple muscle fiber types with differing insulin sensitivities and GLUT4 levels. For example, white, fast-twitch glycolytic fibers are significantly less insulin-responsive than red, slow-twitch oxidative muscle fibers and have lower levels of GLUT4 ( 29, 4 2). In muscle, there is a good correlation between glucose transport activity stimulated by either contractile activity and/or insulin with that of GLUT4 protein content (29, 42). Differences in GLUT4 protein content in skeletal muscles of differ­ ent fiber types, together with possible differences in the regulation of transporter gene expression, may account in part for the discordant results that are described below. Fasting results in a two to threefold increase in GLUT4 protein in mixed soleus and gastrocnemius muscle preparations ( 1 1) and soleus muscle (6) relative to fed animals. This increase in muscle GLUT4 protein content was associated with a threefold increase (11) or with no change (6) in GLUT4 mRNA levels. Charron & Kahn ( 1 1) also examined the effects of fasting on GLUT 1 expression in the same mixed soleus and gastrocnemius muscle preparations and noted a concomitant twofold increase in GLUTl protein. Thus both GLUTl and GLUT4 appear to be coordinately up-regulated in

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skeletal muscle of fasted animals, whereas in adipose: tissue of fasted rats, GLUT4 expression is decreased, and there is no change in GLUTl. Glucose transporter expression has also been examined in muscle tissue of human subjects (15, 28, 5 1). In two studies (28, 51), there were no significant differences in the levels of GLUT4 and GLUTl mRNA and protein in biopsies of vastus lateralis muscle from lean and obese NlDDM subjects compared to lean or obese nondiabetic controls. In contrast, a third study (15) observed a 23% decrease in GLUT 4 protein levels in rectus abdominus muscle from obese, nondiabetic individuals and a 18% decrease in obese NIDDM patients. This discrepancy underscores the difficulties of studying the regulation of glucose transporter expression in human subjects. Moreover, since recent studies in diabetic rats have indicated that the vastus lateralis and rectus abdominus muscles do not display altered GLUT4 levels whereas soleus and gastrocnemius muscles do (21), it is possible that patient studies using these muscles may not reflect the situation in other muscle groups. In addition to the effects of insulin on glucose transport activity, exercise also increases uptake of glucose into muscle and induces the translocation of GLUT4 (16). Exercise training has also been shown to increase GLUT4 protein levels in rat skeletal muscle (17); however, the effects of training appear to be specific to certain muscle groups with a 60% increase in GLUT4 levels in plantaris muscle with no change in soleus muscle (53). Studies of the regulation of glucose transporter levels in skeletal muscle have revealed only modest changes in GLUT4 protein and mRNA expression in altered metabolic states, even though these conditions are characterized by profound changes in insulin-stimulated glucose uptake (6, 22, 58). This is in marked contrast to the situation in adipose tissue where fasting and diabetes causes a specific depletion of GLUT4 protein and mRNA levels, which may account for the decreased insulin-stimulated glucose uptake in this tissue. At the present time, the molecular basis for decreased insulin-stimulated glucose transport in skeletal muscle of humans or rodents with genetic or acquired forms of insulin resistance is unclear. However, the data accumulated to date suggest that the decreased glucose uptake may be due to a defect in the insulin signaling pathway rather than abnormal glucose transporter levels.

Liver The liver plays a central role in the regulation of glucose homeostasis because it stores glucose in the form of glycogen in times of excess and breaks down these stores and releases glucose into the circulation in times of need. It is a metabolically unique tissue in that the intracellular concentration of glucose in the hepatocyte may exceed that in the circulation. GLUT2 is the predominant glucose transporter isoforrn expressed in liver (19, 61, 63) and is responsible for both the uptake and release of glucose. GLUT 2 has a high Km and high

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Vmax for glucose (27). These kinetic parameters mean that the rate of flux through this transporter will be directly proportional to the circulating glucose concentration and that transport itself will not limit metabolism at physiolog­ ical glucose concentrations. GLUT2 expression in liver has been examined under conditions of fasting, diabetes, and chronic hypoglycemia and hyperinsulinemia. Thorens et al (62) reported that fasting rats for 48 hr decreased GLUT2 mRNA levels by 45% without any change in protein levels, whereas refeeding caused a 75 and 500% increase in GLUT2 protein and mRNA levels, respectively. Fasting was also associated with three and fourfold increases in GLUTl rnRNA and protein levels, respectively. GLUT2 mRNA and protein levels were un­ changed in STZ-diabetic rats, whereas GLUTI mRNA levels increased two to threefold and protein levels were unchanged. In contrast to these latter results, Oka et al (49) observed a twofold increase in both GLUT2 rnRNA and protein in STZ-diabetic rats, which returned to normal levels after 5 days of insulin treatment. The reason for the difference between these two studies is un­ known. Nonetheless, these data suggest that increases in either GLUT2 or GLUTl levels in the liver could contribute to the increased hepatic glucose output that occurs in diabetes mellitus. Chen et al ( 12) examined hepatic GLUT2 rnRNA levels in rats following chronic insulin-induced hypoglycemia and detected no consistent changes in liver tissue, although the levels in pancreatic (3-cells were dramatically decreased. Taken together, the studies described above indicate that hepatic GLUT2 expression is not under insulin­ dependent regulatory control and that the levels of GLUT2 rnRNA and protein do not change dramatically with altered metabolic conditions.

{3-cells of the Islets of Langerhans The GLUT2 isoform is also expressed at high levels in the insulin-secreting (3-cells of the islets of Langerhans (63). The presence of a high Km (low affinity) glucose transporter in (3-cells allows for the precise regulation of insulin secretion in response to glucose since the rate of glucose uptake will change in direct proportion to the extracellular glucose concentration over the normal physiological range of glucose, 5-10 mM. Recent studies have demonstrated reduced levels of GLUT2 mRNA and protein in (3-cells from rats with acquired and genetic forms of NIDDM (34, 50, 64, 65). Unger and colleagues also reported that insulin-induced hypoglycemia for 12 days re­ sulted in loss of GLUT2 mRNA and transport activity in islets, whereas 5 days of glucose-induced hyperglycemia increased GLUT2 mRNA levels by 46% ( 12). The temporal relationship between reduction of GLUT2 protein and mRNA levels and the loss of glucose-stimulated insulin secretion sug­ gests that GLUT2 is an integral component of the (3-cell glucose sensor and

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that decreased expression of this transporter accounts, at least in part, for J3-cell failure in diabetes mellitus. As discussed in Johnson et al (34), the reduction in GLUT2 is not secondary to hyperglycemia, but rather represents the most proximal abnormality identified in J3-cells to date. Thus identifica­ tion of the factors regulating GLUT2 expression could lead to a better understanding of the causes of diabetes mellitus.

SUMMARY AND OVERVIEW The regulation of glucose transport in vivo is complex and involves two classes of membrane proteins. One class, the Na+/dependent glucose transporter (the SGLT family), is involved in the active uptake of dietary glucose from the lumen of the small intestine and reabsorption of filtered glucose in the proximal tubule of the kidney. cDNA clones encoding one member of this family have been isolated and characterized, and it seems likely that other members of this family will be cloned in the near future. The regulation of Na+ /glucose cotransporter expression in the small intestine and kidney has not been systematically investigated. However, with the availabil­ ity of the SGLTl cDNA clone and antibodies to this protein, these studies should be forthcoming. The second class of glucose transporters found in mammalian cells, the facilitative glucose transporters, are ubiquitous proteins that appear to be present on all cells. They have distinct but overlapping tissue distributions and are responsible for mediating the passive transport of glucose across the cell membrane down its concentration gradient. The facilitative glucose carriers are a family of structurally-related membrane proteins, and currently cDNA clones encoding five functional members of this family (the GLUT family) have been isolated and characterized with continuing search for additional members. The facilitative glucose transporters have acquired distinct physiological and biochemical properties that allow them to serve specific functions in the tissues in which they are expressed. The GLUTl and GLUT3 isoforms have a high affinity for glucose that provides for efficient transport of glucose even under conditions of low circulating glucose levels and, as a consequence, the rate of glucose uptake by GLUTl and GLUT3 will be determined by their concentration in the plasma membrane rather than by the ambient glucose concentration. The GLUT2 isoform has a low affinity for glucose, but has a high capacity for transport such that the rate of flux through this transporter will be directly proportional to glucose concentration. This property allows GLUT2 to participate in glucose sensing by the pancreatic J3-cell, and in the transepithelial movement of glucose in the small intestine and kidney,

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and the regulation of circulating glucose levels by the liver. The GLUT4 isoform has a distinct subcellular localization and resides not on the cell surface but in association with an intracellular vesicle population. This sub­ cellular localization provides the basis for a novel but very specific mech­ anism by which insulin can rapidly and reversibly stimulate glucose uptake by increasing the concentration ofGLUT4 at the cell surface. Studies are under­ way in a number of laboratories to precisely define the kinetic properties (Km' Vmax, and turnover number) and substrate specificities of each isoform, as well as their abundance in tissues and cells. These studies will provide a better understanding of how this family of proteins participates in the maintenance of in vivo glucose homeostasis. Although much progress has been made over the past ten years in our understanding of insulin-stimulated glucose transport in muscle and adipose tissues, the molecular signals and protein(s) involved in the translocation of glucose transporters to the plasma membrane remain a "black box." Further studies are needed to define the characteristics of the insulin-recruitable intracellular vesicles and the signals that target them to the plasma membrane as well as those that target newly synthesizedGLUT4 protein to these specific vesicles. The effects of post-translational modifications such as phosphoryla­ tion and glycosylation on glucose transporter function also have to be de­ termined. The regulation of glucose transport activity through changes in intrinsic activity need to be unequivocally demonstrated and the underlying molecular events defined. In addition, the mechanisms by which glucose alone can alter glucose transporter levels and the role of glucose per se in altering glucose uptake needs to be established. Finally, an understanding of the mechanism(s) by which obesity and diabetes mellitus decreases glucose transport is critical for our future ability to effectively treat the two most common disorders of carbohydrate metabolism. ACKNOWLEDGMENTS

The studies from our laboratories were supported by National Institutes of Health (Research Grants: DK 20595,25295,42086,and HL 14388); Howard Hughes Medical Institute; Juvenile Diabetes Foundation, International; and American Diabetes Association. The authors wish to thank their many col­ leagues for their contributions to the concepts and results described in this review. These individuals include M. J. Birnbaum, C. F. Burant, J. B. Buse, H. Fukumoto, P. Gerrits, G. W. Gould, T. Kayano, W. S. Moye-Rowley, S. Nagamatsu, A. L. Olson, P. F. Pilch, J. M. Richardson, S. Seino, W. 1. Sivitz, 1. Takeda, Y. Yamada, and K. Yasuda. We also wish to thank Falak Kagda and Hilary Moore for their invaluable assistance in the preparation of this manuscript.

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Mammalian facilitative glucose transporter family: structure and molecular regulation.

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