Signaling Mechanisms That Regulate Glucose Transport (1999)

phosphotyrosine-binding Pleckstrin homology Src homology 2 phosphatidylinositol insulin-like growth factor platelet-derived growth factor 5′-AMP-activated protein kinase. Insulin, the major hormonal regulator of glucose transport in humans, has served as a prototypic molecule for understanding cell signaling pathways since its discovery in 1922. It was among the first proteins for which primary amino acid sequence and three-dimensional structure were determined. The insulin receptor was likewise among the first peptide receptors to be identified by ligand binding, and its subunit structure was deduced in the earliest days of modern receptor biology (1Massague J. Pilch P.F. Czech M.P. Proc. Natl. Acad. Sci. U. S. A. 1980; 77: 7137-7141Crossref PubMed Scopus (161) Google Scholar). The structure of its tyrosine kinase domain was the first of the tyrosine kinases to be solved by x-ray crystallography (2Hubbard S.R. EMBO J. 1997; 16: 5572-5581Crossref PubMed Scopus (769) Google Scholar). Further, much is now known about downstream insulin receptor signaling components (3Avruch J. Mol. Cell. Biochem. 1998; 182: 31-48Crossref PubMed Scopus (319) Google Scholar). Despite these advances, our understanding of how insulin and the related proteins, insulin-like growth factors I and II, stimulate glucose transport (via the translocation of glucose transporter proteins from intracellular to plasma membranes) is fragmentary. One reason for this is that the major target for insulin signaling to glucose transport is a complex membrane trafficking pathway that is likely to contain many unknown components. As summarized in the preceding introductory comments (4Olefsky J.M. J. Biol. Chem. 1999; 274: 1863Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar) and detailed in the companion minireviews to be published subsequently (5Pessin J.E. Thurmond D.C. Elmendorf J.S. Coker K.J. Okada S. J. Biol. Chem. 1999; 274: 2593-2596Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar, 6Charron M.J. Katz E.B. Olson A.L. J. Biol. Chem. 1999; 274: 3253-3256Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar), glucose uptake via the GLUT4 isoform of mammalian hexose transporters accounts for most of the stimulatory effect of insulin on this process in muscle and fat cells. GLUT4 rapidly recycles through the plasma membrane/endosomal membrane system in the presence of insulin. However, in the basal state this transporter protein is directed to and retained within specific intracellular membranes through the action of distinct elements within the GLUT4 structure (7Corvera S. Czech M.P. Cell. Dev. Biol. 1996; 7: 249-257Crossref Scopus (5) Google Scholar). Insulin causes movement of GLUT4 out of this sequestered localization, leading to an increase in its steady state concentration on the cell surface membrane where it can catalyze glucose uptake. However, to accomplish this, insulin signaling is likely to regulate GLUT4 trafficking at multiple steps, consistent with data showing insulin also enhances cell surface display of proteins such as transferrin receptor and GLUT1 that recycle to a large extent independently of GLUT4. To further complicate our understanding of this system, different signaling elements may be required to modulate each of these different putative regulated steps in the GLUT4 trafficking pathway. Substrate phosphorylation by the insulin receptor tyrosine kinase appears to involve the binding of phosphorylated receptor tyrosine 960 to phosphotyrosine-binding (PTB)1 domains of substrate proteins (8White M.F. Mol. Cell. Biochem. 1998; 182: 3-11Crossref PubMed Scopus (622) Google Scholar). Adjacent Pleckstrin homology (PH) domains on some substrate proteins also appear critical for receptor binding and phosphorylation. Tyrosine kinase signaling is often initiated by the recruitment of signaling proteins through their Src homology 2 (SH2) or PTB domains to phosphotyrosine sites. In the case of insulin receptor, tyrosine phosphorylation of four related substrate (IRS) proteins (8White M.F. Mol. Cell. Biochem. 1998; 182: 3-11Crossref PubMed Scopus (622) Google Scholar) and Gab-1 (9Rocci S. Tartare-Deckert S. Murdaca J. Wong A.J. Van Obberghen E. Mol. Endocrinol. 1998; 12: 914-923Crossref PubMed Scopus (65) Google Scholar) causes many candidate signaling proteins to be recruited, including: 1) the p110-type phosphatidylinositol 3-kinase (PI 3-kinase) through the SH2 domains of p85 regulatory subunits; 2) Grb2 and the protein tyrosine phosphatase SH-PTP2, which appear to be necessary for p21ras activation (10Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2211) Google Scholar); 3) the tyrosine kinase Fyn, which in turn may also activate the PI 3-kinase and p21raspathways; and 4) Rho-associated protein serine/threonine kinase ROKα (11Farah S. Agazie Y. Ohan N. Ngsee J.K. Liu X.J. J. Biol. Chem. 1998; 273: 4740-4746Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar), which may modulate processes such as actin assembly and mitogenesis under control of the small GTPase Rho. Insulin receptor signaling can also engage p21ras through tyrosine phosphorylation of Shc and its subsequent binding to complexes of Grb2 and Sos (12Klarlund J.K. Cherniack A.D. Czech M.P. J. Biol. Chem. 1995; 270: 23421-23428Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Recently, it has been discovered that proteins can bind directly to the autophosphorylated insulin receptor through their SH2 domains, opening new avenues for investigation (13Lui F. Roth R.A. Mol. Cell. Biochem. 1998; 182: 73-78Crossref PubMed Scopus (31) Google Scholar). As illustrated in Fig. 1, p21rasand the p85/p110-type PI 3-kinases represent two major initial switch elements for insulin receptor signaling. There is also evidence that the p21ras-related GTP-binding proteins Rap (14Okada S. Matsuda M. Anafi M. Pawson T. Pessin J.E. EMBO J. 1998; 17: 2554-2565Crossref PubMed Scopus (82) Google Scholar), Rho (15Karnam P. Standaert M.L. Galloway L. Farese R.V. J. Biol. Chem. 1997; 272: 6136-6140Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar), and Rac (16Kotani K. Hara K. Yonezawa K. Kasuga M. Biochem. Biophys. Res. Commun. 1995; 208: 985-990Crossref PubMed Scopus (81) Google Scholar) are engaged by insulin receptor signal transduction. A central paradigm of insulin signaling is the involvement of multiple protein serine/threonine kinases downstream of both the p21ras and PI 3-kinase elements (Fig. 1). More recently, a group of non-receptor tyrosine kinases denoted Btk/Itk/Tec has been found in hemopoietic cells to respond to the generation of 3′-polyphosphoinositide, apparently by recruitment through their PH domains to membranes where they can be tyrosine-phosphorylated and activated (17Scharenberg A.M. Kinet J.P. Cell. 1998; 94: 5-8Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar). It is not yet known whether insulin or insulin-like growth factor-1 receptor signaling can act through 3′-phosphoinositides on these or other tyrosine kinases, and they are therefore not included in Fig. 1. Another recently discovered class of likely downstream effectors of 3′-phosphoinositides includes proteins that regulate membrane-related functions (Fig. 1) such as actin assembly (Rac GTPase), early endosome fusion (EEA1), and guanine nucleotide exchange (GRP1, cytohesin-1, and ARNO) or possibly GTPase activation (α-centaurin) of ARF proteins. It is certain that the list of potential downstream effectors of insulin receptor signaling will rapidly expand, as additional protein targets of 3′-phosphoinositides are discovered. Much effort has been directed toward identifying which of the above insulin receptor signaling elements are actually linked to GLUT4 translocation. Although some evidence suggested p21rasactivation might influence glucose transport in fat (18Kozma L. Baltensperger K. Klarlund J.K. Porras A. Santos E. Czech M.P. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4460-4464Crossref PubMed Scopus (87) Google Scholar) and muscle (19Manchester J. Kong X. Lowry O.H. Lawrence Jr., J.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 4644-4648Crossref PubMed Scopus (39) Google Scholar), the weight of most of the data available indicates no direct requirement of p21ras function for insulin action on GLUT4 trafficking (20Hausdorff S.F. Frangioni J.V. Birnbaum M.J. J. Biol. Chem. 1994; 269: 21391-21394Abstract Full Text PDF PubMed Google Scholar). Rather, strong indications that p85/p110-type PI 3-kinase activity is necessary for this insulin response have accumulated. Such evidence includes complete inhibition of insulin action on glucose transport by specific inhibitors of PI 3-kinase such as wortmannin (21Okada T. Kawano Y. Sakakibara T. Hazeki O. Ui M. J. Biol. Chem. 1994; 269: 3568-3573Abstract Full Text PDF PubMed Google Scholar) and LY29004 (22Cheatham B. Vlahos C.J. Cheatham L. Wang L. Blenis J. Kahn C.R. Mol. Cell. Biol. 1994; 14: 4902-4911Crossref PubMed Scopus (996) Google Scholar) and by microinjection or expression of dominant inhibitory constructs of the p85 regulatory subunit of PI 3-kinase (23Sharma P.M. Egawa K. Huang Y. Martin J.L. Huvar I. Boss G.R. Olefsky J.M. J. Biol. Chem. 1998; 273: 18528-18537Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). Further, in some experiments expression of an activated form of the p110 PI 3-kinase in cultured adipocytes mimics the stimulatory effect of insulin on glucose transport (24Martin S.S. Haruta T. Morris A.J. Kippel A. Williams L.T. Olefsky J.M. J. Biol. Chem. 1996; 271: 17605-17608Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar), suggesting PI 3-kinase activity is also sufficient for glucose transporter translocation. Although the above results strongly support the hypothesis that p85/p110-type PI 3-kinase activation through its recruitment to phosphotyrosine sites on insulin receptor substrate proteins mediates GLUT4 translocation, it is instructive to review the limitations related to the current supporting data. First, the inhibitors wortmannin and LY29004 are not fully specific for PI 3-kinase activity and in any case are known to block PI 3-kinase isoforms lacking known regulatory subunits that contain SH2 or other domains that can be recruited to phosphotyrosine sites. Such other PI 3-kinase isoforms (25Vanhaesebroeck B. Leevers S.J. Waterfield M.D. Trends Biochem. Sci. 1997; 22: 267-272Abstract Full Text PDF PubMed Scopus (825) Google Scholar) rather than, or in addition to, the type p110 PI 3-kinase may be necessary for exocytosis of GLUT4. The use of the truncated p85 subunit containing SH2 domains as a dominant inhibitory reagent to inhibit native p85/p110 PI 3-kinase function also has the potential limitation of inadequate specificity. When expressed at high concentrations, SH2 domains can be promiscuous in binding phosphotyrosines within various amino acid sequences and thus may not be restricted to binding sites specific for endogenous p85/p110-type PI 3-kinase. Thus, although a key role for this PI 3-kinase in GLUT4 regulation by insulin seems almost certain, there are potential gaps in our understanding of even this point. Recent results call into question the hypothesis that PI 3-kinase activation by insulin is sufficient for GLUT4 translocation. For example, it is well established that recruitment of PI 3-kinase to phosphotyrosines on the platelet-derived growth factor (PDGF) receptor in response to PDGF, which occurs in 3T3-L1 adipocytes to the same extent as recruitment of PI 3-kinase to protein phosphotyrosines in response to insulin, has virtually no effect on GLUT4 translocation (26Nave B.T. Haigh R.J. Hayward A.C. Siddle K. Sheperd P.R. Biochem. J. 1996; 318: 55-60Crossref PubMed Scopus (129) Google Scholar). Recruitment of PI 3-kinase to IRS proteins in response to interleukin-4 (27Isakoff S.J. Taha C. Rose E. Marcusohn J. Klip A. Skolnik E.Y. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10247-10251Crossref PubMed Scopus (140) Google Scholar) or cell surface integrin cross-linking (28Guilherme A. Czech M.P. J. Biol. Chem. 1998; 273: 33119-33122Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar) also fails to enhance glucose transport in the absence or presence of submaximal concentrations of insulin. Conversely, severe inhibition of insulin-mediated IRS protein tyrosine phosphorylation and recruitment of PI 3-kinase in response to incubation of 3T3-L1 adipocytes with PDGF failed to diminish glucose transport stimulation by insulin at all concentrations along the dose-response relationship (29Staubs P.A. Nelson J.G. Reichart D.R. Olefsky J.M. J . Biol . Chem. 1998; 273: 25139-25147Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). The lack of correlation between PI 3-kinase activation and GLUT4 translocation in the studies cited above may reflect an additional insulin-specific signaling pathway or pathways required to operate in conjunction with PI 3-kinase activation to effect this biological response. According to this model, agents such as interleukin-4 and anti-integrin antibody fail to enhance glucose transport because they are unable to mimic the effect of insulin on this other signaling pathway. Recent surprising results support this hypothesis. In these experiments, a cell-permeable analog of the PI 3-kinase product PI(3,4,5)P3, thought to be a downstream effector for insulin action through PI 3-kinase, was unable to cause GLUT4 translocation when added alone to cells (30Jiang T. Sweeney G. Rudolf M.T. Kip A. Traynor-Kaplan A. Tsien R.Y. J. Biol. Chem. 1998; 273: 11017-11024Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). However, in the presence of insulin and wortmannin, a condition where no stimulation of glucose transport is observed, the PI(3,4,5)P3 analog was able to enhance cellular uptake of glucose (30Jiang T. Sweeney G. Rudolf M.T. Kip A. Traynor-Kaplan A. Tsien R.Y. J. Biol. Chem. 1998; 273: 11017-11024Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). These results suggest that insulin may uniquely act to initiate PI 3-kinase-independent signaling events in the presence of wortmannin that collaborate with the PI 3-kinase signaling pathway to effect GLUT4 translocation. Substantial recent information suggests that PI 3-kinase-independent mechanisms also regulate GLUT4 translocation in skeletal muscle during contraction. For example, the stimulations of glucose transport in skeletal muscle caused by insulin and contraction are additive, but only the effect of the former is blocked by wortmannin (31Cortright R.N. Dohm G.L. Can. J. Appl. Physiol. 1997; 22: 519-530Crossref PubMed Scopus (43) Google Scholar). In concert with this result, insulin but not contraction stimulates PI 3-kinase activity and the downstream protein kinase Akt/protein kinase B (32Brozinick J.T. Birnbaum M.J. J. Biol. Chem. 1998; 273: 14679-14682Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Conversely, the 5′-AMP-activated protein kinase (AMPK), thought to be responsive to cell stress, is stimulated by rat hind limb contraction but not insulin (33Hayashi T. Hirshman M.F. Kurth E.J. Winder W.W. Goodyear L.J. Diabetes. 1998; 47: 1369-1373Crossref PubMed Scopus (702) Google Scholar). Another activator of AMPK, 5-aminoimidazole-4-carboximide ribonucleoside, mimicked the action of contraction to enhance glucose uptake in a wortmannin-insensitive mode (33Hayashi T. Hirshman M.F. Kurth E.J. Winder W.W. Goodyear L.J. Diabetes. 1998; 47: 1369-1373Crossref PubMed Scopus (702) Google Scholar). Taken together, these recent findings suggest the hypothesis that AMPK may mediate, at least in part, exercise-stimulated glucose uptake in skeletal muscle. Another cell signaling pathway that appears to markedly stimulate glucose uptake in muscle involves nitric oxide, which stimulates guanylate cyclase to produce cyclic GMP. The NO donor sodium nitroprusside and dibutyryl-cGMP both accelerated epitrochlearis (34Etgen G.J. Fryburg D.A. Gibbs E.M. Diabetes. 1997; 46: 1915-1919Crossref PubMed Google Scholar), soleus (35Young M.E. Radda G.K. Leighton B. Biochem. J. 1997; PubMed Scopus Google Scholar, S. S. B. A. Diabetes. 1997; 46: PubMed Scopus Google Scholar), and S. S. B. A. Diabetes. 1997; 46: PubMed Scopus Google Scholar) muscle glucose NO by cellular concentrations were found to in epitrochlearis as but contraction not (34Etgen G.J. Fryburg D.A. Gibbs E.M. Diabetes. 1997; 46: 1915-1919Crossref PubMed Google Scholar). 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J. 1996; PubMed Scopus Google in a new the regulatory mechanisms for glucose transport on the PI 3-kinase pathways has been the most IRS proteins are required for PI 3-kinase signaling to act on the GLUT4 system is at or expression of the dominant inhibitory PTB or domains of in cultured adipocytes is able to block the and of insulin but not the stimulation of glucose transport P.M. Egawa K. Martin J.L. Olefsky J.M. Mol. Cell. Biol. 1997; 17: PubMed Scopus (65) Google Scholar). These dominant inhibitory constructs are to block binding of all IRS protein isoforms to the insulin receptor through binding to the insulin receptor sequence the for IRS and Shc protein PTB complete inhibition of tyrosine phosphorylation by insulin was caused by expression of its PTB domain in these studies P.M. Egawa K. Martin J.L. Olefsky J.M. Mol. Cell. Biol. 1997; 17: PubMed Scopus (65) Google Scholar). In to be from these expression of IRS proteins in primary rat adipocytes apparently enhances GLUT4 translocation M.J. A.J. M.J. G. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar). of insulin receptor tyrosine the of IRS protein binding required for its insulin action of glucose transport M.F. J.M. A. Kahn C.R. Cell. Full Text PDF PubMed Scopus Google Scholar). studies in in which the or has been support for a role of these proteins in glucose transport lacking some insulin although no E. M.E. J.C. B. Kahn C.R. Nature. 1994; PubMed Scopus Google Scholar, T. K. T. Y. K. Y. S. S. Y. Y. Kasuga M. Y. S. Nature. 1994; PubMed Scopus Google Scholar), and for of both and insulin receptor are both and J.C. J. S. Kahn C.R. Cell. 1997; Full Text Full Text PDF Scopus Google in alone causes both insulin signaling to glucose uptake and J.S. J.M. S. Y. S. S. M.F. Nature. 1998; PubMed Scopus Google Scholar). Insulin action on glucose uptake in adipocytes from lacking protein has been suggested to involve the isoform Y. S. K. K. T. E. S. Y. Y. T. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus (87) Google Scholar), which is tyrosine-phosphorylated in response to insulin. Such may in for some of these apparently The information from IRS support for a role of these proteins in glucose transport regulation by insulin, with the that in response to IRS during may to the Taken together, the data to related to the role of IRS proteins in GLUT4 translocation are to the hypothesis that PI protein complexes are necessary but not sufficient for GLUT4 translocation by insulin. question about the role of PI 3-kinase proteins in GLUT4 trafficking is whether they function to the to specific cellular sites required for regulation of GLUT4 R.A. M. Czech M.P. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar), J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar), and to a extent G. Cheatham B. Kahn C.R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar) are in cells as both and proteins, both in basal and binding of PI 3-kinase, through its binding to proteins, is to be necessary for the to into with its The cellular of PI complexes is not but and through binding complexes B. M. Czech M.P. R.A. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar) and elements S.F. Martin S. A.J. J. Biol. 1998; PubMed Scopus Google Scholar), have been a small of the PI 3-kinase activity with but the downstream protein kinase appears to be recruited as well C. Liu Birnbaum M.J. Pilch P.F. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). expression of PI 3-kinase activity on these in adipocytes a SH2 domain failed to stimulate GLUT4 translocation C. S.R. Kahn J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). is not with the hypothesis that a signaling pathway is necessary for GLUT4 translocation, The p85/p110 PI 3-kinases can catalyze phosphorylation of or at the of the to produce the or Recent results PI(3,4,5)P3 is necessary for insulin action on glucose on the inhibitory effect of microinjection of a phosphatase specific for this into 3T3-L1 adipocytes P. M. Martin S.S. T. Olefsky J.M. Mol. Cell. Biol. 1999; Scholar). It is not yet whether the other two PI 3-kinase are also but the recent of a protein that through its and functions in the of in early endosome fusion D.C. J.V. A. S. Nature. 1998; PubMed Scopus Google Scholar) further investigation (Fig. 1). a class of proteins J.K. A. J.V. A. Czech M.P. 1997; PubMed Scopus Google Scholar) denoted and containing PH domains that bind high and a domain that guanine nucleotide exchange of and proteins has been to be recruited to plasma membranes in response to insulin K. J.M. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The data available suggest these proteins may be in function in membrane and actin in response to insulin S. S. J.E. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar), but studies on these and proteins in to GLUT4 translocation are The potential between PI 3-kinase signaling in insulin action and ARF function is by the discovery of protein which some sequence to ARF protein K. S. T. Y. S. K. Y. T. Y. K. S. Y. J. Biochem. 1997; PubMed Scopus (82) Google Scholar). Taken together, these of proteins that bind directly to PI 3-kinase and regulate known membrane such as ARF proteins a between signaling and membrane has on protein serine/threonine kinases downstream of and PI(3,4,5)P3 that may regulate GLUT4. For example, recent G. Standaert M.L. L. B. A. Galloway L. P. J. Farese R.V. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar) have that protein kinase (Fig. 1) is activated by is stimulated in cells by insulin in a and may to glucose transport Another candidate has been Akt/protein kinase which is activated in conjunction with its binding to these by the protein kinase and protein kinase J. Biochem. J. 1998; PubMed Scopus Google Scholar). of constructs of Akt/protein kinase B in 3T3-L1 adipocytes A.D. Birnbaum M.J. Roth R.A. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar), primary adipocytes Y. L. M.J. Mol. Endocrinol. 1997; PubMed Google Scholar), and E. D.R. Diabetes. 1998; 47: PubMed Scopus Google Scholar) stimulates GLUT4 translocation, and it is that a dominant inhibitory this process Y. L. M.J. Mol. Endocrinol. 1997; PubMed Google Scholar). However, in well experiments a Akt/protein kinase B with at phosphorylation sites and as a dominant inhibitory in both cells and 3T3-L1 protein but not glucose transport was T. Y. S. M. M. T. U. Kasuga M. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar). These studies have recently been M. Mol. Cell. Biol. 1998; Scholar) to suggest that protein kinase is directly in GLUT4 translocation. Taken together, there is not yet a of data from multiple that any of the known protein kinases downstream of PI 3-kinase directly mediates insulin action on glucose the many new components of the insulin receptor signaling have been discovered and their has been the of downstream targets of the PI 3-kinase protein kinase isoforms and regulatory protein kinases of the Akt/protein kinase B system, tyrosine kinases the early endosome regulator and ARF exchange factors and PI 3-kinase appears to be required for glucose transport regulation by insulin, is likely to or of these proteins additional to be to specific membrane trafficking components in GLUT4 translocation. have also that additional cellular signaling elements such as proteins, and can regulate glucose transport and that unknown signaling events may be required in conjunction with PI 3-kinase for insulin to In the is on understanding the components of membrane through which GLUT4 in as will be in the minireviews on this (5Pessin J.E. Thurmond D.C. Elmendorf J.S. Coker K.J. Okada S. J. Biol. Chem. 1999; 274: 2593-2596Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar, 6Charron M.J. Katz E.B. Olson A.L. J. Biol. Chem. 1999; 274: 3253-3256Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). these two signaling and membrane will be the of on the mechanisms that GLUT4