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Autor     Alicia M. McCarthy, Jeffrey S. Elmendorf
Titel    GLUT4’s itinerary in health & disease
Zeitschrift    Indian J Med Res
Ausgabe    125
Datum    March 2007
Seiten    373-388
URL    http://www.ncbi.nlm.nih.gov/pubmed/17496362 , [1]

Literaturverz.   

no
Fußnoten    no
Fragmente    5


Fragmente der Quelle:
[1.] Sj/Fragment 012 09 - Diskussion
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In the basal state, GLUT4 cycles continuously between the plasma membrane and one or more intracellular compartments, with 90-95 percent of the transporter residing within the cell interior, tightly packaged into vesicles. The overall insulin-induced GLUT4 vesicle trafficking results in a >10-fold increase of GLUT4 protein at the cell surface (38). GLUT4 is found within large tubulo-vesicular structures in the perinuclear region of the cell and within small vesicles dispersed throughout the cytoplasm, also known as GLUT4 storage vesicles (GSVs) (39) (40). Perinuclear GLUT4 is likely localized in endosomes. GSVs on the other hand co-localize with insulin-responsive aminopeptidase (IRAP) and vesicle-associated membrane protein 2 (VAMP2). Upon insulin stimulation, it appears that GSVs are translocated to the cell surface, as there is an increase of GLUT4 at the plasma membrane that is proportional to the reduction in GLUT4-containing vesicles from the cytosolic compartment (41) (42), while the level of perinuclear GLUT4-containing vesicles remains relatively the same. Furthermore, total internal reflection fluorescence microscopy has revealed that in basal adipocytes, GLUT4-containing vesicles are located near the plasma membrane and are recruited to the cell surface with insulin stimulation (43) (Figure 2).

1.3.5 Role of insulin signalling in GLUT4 regulation

Activation of the insulin receptor triggers a cascade of phosphorylation events that ultimately promote GLUT4 vesicle exocytosis. The classical insulin signaling pathway (Figure 2) involves docking of the insulin receptor substrate (IRS) to the insulin receptor (IR), activation of phosphatidylinositol 3-kinase (PI3K) which leads to formation of plasma membrane phosphatidylinositol 3,4,5-trisphosphate (PI -P3), subsequent PI -P3-mediated activation of Akt and atypical protein kinase C (aPKC). Additionally, a PI3K-independent pathway involving c-Cbl, c-Cbl associated protein (CAP), and the GTPase TC10 may also regulate GLUT4 translocation. Insulin action is initiated when this peptide hormone binds to its receptor.


38. Malide,D, Ramm,G, Cushman,SW, Slot,JW: Immunoelectron microscopic evidence that GLUT4 translocation explains the stimulation of glucose transport in isolated rat white adipose cells. J.Cell Sci. 113 Pt 23:4203-4210, 2000

39. Kandror,KV, Pilch,PF: Compartmentalization of protein traffic in insulin-sensitive cells. Am.J.Physiol 271:E1-14, 1996

40. Rea,S, James,DE: Moving GLUT4: the biogenesis and trafficking of GLUT4 storage vesicles. Diabetes 46:1667-1677, 1997

41. Sehgal,SN, Baker,H, Vezina,C: Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J.Antibiot.(Tokyo) 28:727-732, 1975

42. Shi,J, Kandror,KV: Sortilin is essential and sufficient for the formation of Glut4 storage vesicles in 3T3-L1 adipocytes. Dev.Cell 9:99-108, 2005

43. Lizunov,VA, Matsumoto,H, Zimmerberg,J, Cushman,SW, Frolov,VA: Insulin stimulates the halting, tethering, and fusion of mobile GLUT4 vesicles in rat adipose cells. J.Cell Biol. 169:481-489, 2005

[Page 374]

In the basal state, GLUT4 cycles continuously between the plasma membrane and one or more intracellular compartments, with 90-95 per cent of the transporter residing within the cell interior, tightly packaged into vesicles3,4. [...] The overall insulin-dependent shift in the cellular dynamics of GLUT4 vesicle trafficking results in a >10-fold increase of GLUT4 protein at the cell surface7. [...]

GLUT4 is found within large tubulo-vesicular structures in the perinuclear region of the cell and within small vesicles dispersed throughout the cytoplasm, also known as GLUT4 storage vesicles (GSVs). Perinuclear GLUT4 is likely localized in endosomes and trans-Golgi network (TGN) structures, as evidence has shown that it co-localizes with endosomal and TGN markers, including transferrin receptor (TfR) and syntaxin 16, respectively9. GSVs on the other hand co-localize with insulin-responsive aminopeptidase (IRAP) and vesicle-associated membrane protein 2 (VAMP2). Upon insulin stimulation, it appears that GSVs are mobilized to the cell surface, as there is an increase of GLUT4 at the plasma membrane that is proportional to the reduction in GLUT4-containing vesicles from the cytosolic compartment10,11, while the level of perinuclear GLUT4-containing vesicles remains relatively unaffected10,12. Furthermore, total internal reflection fluorescence microscopy has revealed that in basal adipocytes, GLUT4-containing vesicles are located near the plasma membrane and are recruited to the cell surface with insulin stimulation13. [...]

[Page 375]

[...]

Insulin signaling systems regulating GLUT4

Activation of the insulin receptor triggers a cascade of phosphorylation events that ultimately promote GLUT4 vesicle exocytosis (Fig.). The classical insulin signaling pathway involves docking of the insulin receptor substrate (IRS) to the insulin receptor (IR), activation of phosphatidylinositol 3-kinase (PI3K) which leads to formation of plasma membrane phosphatidylinositol 3,4,5-trisphosphate (PI 3,4,5-P3), subsequent PI 3,4,5-P3-mediated activation of Akt and atypical protein kinase C (aPKC), and phosphorylation of AS160 (Akt substrate of 160 kDa) by Akt (Fig. A). Additionally, a PI3K-independent pathway involving c-Cbl, c-Cbl associated protein (CAP), and the GTPase TC10 may also regulate GLUT4 translocation (Fig. B), although this pathway appears to be exclusive to adipocytes. Here, we detail steps within both insulin signaling pathways.

IR and its substrates: Insulin action is initiated when this peptide hormone binds to its receptor.


3. Kandror KV, Pilch PF. Compartmentalization of protein traffic in insulin-sensitive cells. Am J Physiol 1996; 271 : E1-14.

4. Rea S, James DE. Moving GLUT4: the biogenesis and trafficking of GLUT4 storage vesicles. Diabetes 1997; 46 : 1667-77.

7. Malide D, Ramm G, Cushman SW, Slot JW. Immunoelectron microscopic evidence that GLUT4 translocation explains the stimulation of glucose transport in isolated rat white adipose cells. J Cell Sci 2000; 113 : 4203-10.

9. Larance M, Ramm G, Stockli J, van Dam EM, Winata S, Wasinger V, et al. Characterization of the role of the Rab GTPase-activating protein AS160 in insulin-regulated GLUT4 trafficking. J Biol Chem 2005; 280 : 37803-13.

10. Ramm G, Slot JW, James DE, Stoorvogel W. Insulin recruits GLUT4 from specialized VAMP2-carrying vesicles as well as from the dynamic endosomal/trans-Golgi network in rat adipocytes. Mol Biol Cell 2000; 11 : 4079-91.

11. Shi J, Kandror KV. Sortilin is essential and sufficient for the formation of Glut4 storage vesicles in 3T3-L1 adipocytes. Dev Cell 2005; 9 : 99-108.

12. Martin S, Millar CA, Lyttle CT, Meerloo T, Marsh BJ, Gould GW, et al. Effects of insulin on intracellular GLUT4 vesicles in adipocytes: evidence for a secretory mode of regulation. J Cell Sci 2000; 113 : 3427-38.

13. Lizunov VA, Matsumoto H, Zimmerberg J, Cushman SW, Frolov VA. Insulin stimulates the halting, tethering, and fusion of mobile GLUT4 vesicles in rat adipose cells. J Cell Biol 2005; 169 : 481-9.

Anmerkungen

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(Graf Isolan), WiseWoman

[2.] Sj/Fragment 013 01 - Diskussion
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Insulin binding to the two high-affinity extracellular α subunits leads to activation of intrinsic tyrosine kinase activity of the transmembrane β subunits and autophosphorylation of specific tyrosine residues (44), (45). Phosphorylation enhances tyrosine kinase activity of the b subunits towards a host of proteins including members of the insulin receptor substrate family (IRS-1, -2, -3, -4, -5, and -6), Cbl, SIRP (signal regulatory protein) family members, and APS [adapter protein containing a pleckstrin homology (PH) and Src-homology 2 (SH2) domain , (46). [...]

[...]

Insulin-dependent tyrosine phosphorylation of IRS-1/2 creates docking sites for downstream effector molecules including Class IA PI3K. Activated PI3K catalyzes the phosphorylation of PI-P2 on the 3 position of the inositol ring, forming PI-P3. Increased membrane PI-P3 is crucial for insulin-stimulated GLUT4 translocation, as this phospholipid provides docking sites for downstream molecules via their pleckstrin homology (PH) domains. Inhibition of PI-P3 formation with wortmannin or LY29004 effectively blocks insulin-stimulated GLUT4 translocation and glucose transport (47), (48) . Phosphatase regulators of PI3K generated lipids include PTEN and SHIP2. The PTEN catalyzes the dephosphorylation of phosphatidylinositols at the D3 position, while the latter catalyzes dephosphorylation of PI - P3 to yield PI -P2 (49). PI -P3 formation mediates the plasma membrane translocation of two PH domain containing proteins which is important for insulin-regulated glucose uptake: Akt (protein kinase B, PKB) and phosphoinositide-dependent-kinase-1 (PDK1). PDK2 is recently identified as the protein kinase mTOR (mammalian target of rapamycin) complexed to the regulatory protein rictor (50). There are three isoforms of protein kinase AKT (1-3) (51) in which GLUT4 translocation is dependent on AKT2 (52). AKT2 acts through it downstream molecule AS160 (53). AS160 contains a GTPase activating domain for Rabs, small G proteins which is involved in the vesicle trafficking (54), (55). Along with recruiting and activating Akt, PI 3,4,5-P3 formation in concert with PDK1 also leads to the activation of atypical protein kinase C (aPKC), and both aPKC isoforms z and l [sic] have been implicated in GLUT4 translocation (56). PKC knockout models and expression of kinase-inactive PKC-z/l [sic] inhibits GLUT4 translocation and glucose uptake in a variety of cell types, and this phenotype can be reversed in PKC-l–/– [sic] cells by expressing wild-type aPKC.


44. Bjornholm,M, Zierath,JR: Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes. Biochem.Soc.Trans. 33:354-357, 2005

45. Luo,RZ, Beniac,DR, Fernandes,A, Yip,CC, Ottensmeyer,FP: Quaternary structure of the insulin-insulin receptor complex. Science 285:1077-1080, 1999

46. Rocchi,S, Tartare-Deckert,S, Murdaca,J, Holgado-Madruga,M, Wong,AJ, Van Obberghen,E: Determination of Gab1 (Grb2-associated binder-1) interaction with insulin receptor-signaling molecules. Mol.Endocrinol. 12:914-923, 1998

47. Okada,T, Kawano,Y, Sakakibara,T, Hazeki,O, Ui,M: Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. J.Biol.Chem. 269:3568- 3573, 1994

48. Clarke,JF, Young,PW, Yonezawa,K, Kasuga,M, Holman,GD: Inhibition of the translocation of GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinositol 3- kinase inhibitor, wortmannin. Biochem.J. 300 ( Pt 3):631-635, 1994

49. Scheid,MP, Woodgett,JR: Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett. 546:108-112, 2003

50. Sarbassov,DD, Guertin,DA, Ali,SM, Sabatini,DM: Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098-1101, 2005

51. Bae,SS, Cho,H, Mu,J, Birnbaum,MJ: Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J.Biol.Chem. 278:49530-49536, 2003

52. Calera,MR, Martinez,C, Liu,H, Jack,AK, Birnbaum,MJ, Pilch,PF: Insulin increases the association of Akt-2 with Glut4-containing vesicles. J.Biol.Chem. 273:7201-7204, 1998

53. Kane,S, Sano,H, Liu,SC, Asara,JM, Lane,WS, Garner,CC, Lienhard,GE: A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain. J.Biol.Chem. 277:22115-22118, 2002

54. Sano,H, Kane,S, Sano,E, Miinea,CP, Asara,JM, Lane,WS, Garner,CW, Lienhard,GE: Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J.Biol.Chem. 278:14599-14602, 2003

55. Jordens,I, Marsman,M, Kuijl,C, Neefjes,J: Rab proteins, connecting transport and vesicle fusion. Traffic. 6:1070-1077, 2005

56. Farese,RV, Sajan,MP, Standaert,ML: Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. Exp.Biol.Med.(Maywood.) 230:593-605, 2005

Insulin binding to the two high-affinity extracellular a [sic] subunits leads to activation of intrinsic tyrosine kinase activity of the transmembrane β subunits and autophosphorylation of specific tyrosine residues1,16. Phosphorylation enhances tyrosine kinase activity of the β subunits towards a host of proteins including members of the insulin receptor substrate family (IRS-1, -2, -3, -4, -5, and -6), Gab-1, Shc, p62dok, Cbl, SIRP (signal regulatory protein) family members, and APS [adapter protein containing a pleckstrin homology (PH) and Src-homology 2 (SH2) domain]17-23.

[...]

PI3K-dependent signaling: Insulin-dependent tyrosine phosphorylation of IRS-1/2 creates docking sites for downstream effector molecules including Class IA PI3K32.

[page 377]

[...] Activated PI3K catalyzes the phosphorylation of PI 4,5-P2 on the 3 position of the inositol ring, forming PI 3,4,5-P3. Increased membrane PI 3,4,5-P3 is essential for insulin-stimulated GLUT4 translocation, as this phospholipid provides docking sites for downstream molecules via their pleckstrin homology (PH) domains. Inhibiting the formation of PI 3,4,5-P3 with wortmannin or LY29004 effectively blocks insulin-stimulated GLUT4 translocation and glucose transport33,34. Phosphatase regulators of PI3K generated lipids include PTEN and SHIP2. The former catalyzes the dephosphorylation of phosphatidylinositols at the D3 position, while the latter catalyzes dephosphorylation of PI 3,4,5-P3 to yield PI 3,4-P2 35.

PI 3,4,5-P3 formation mediates the plasma membrane translocation of two PH domaincontaining proteins crucial for insulin-regulated glucose uptake: Akt (protein kinase B, PKB) and phosphoinositide-dependent-kinase-1 (PDK1)35. Following membrane recruitment, the 60 kDa serine/threonine kinase Akt is phosphorylated at two key sites, threonine 308 (Thr308) and serine 473 (Ser473), resulting in enzyme activation. Ser473 phosphorylation occurs first and is accomplished by the once elusive PDK2, which was recently identified as the protein kinase mTOR (mammalian target of rapamycin) complexed to the regulatory protein rictor36-38.[...]

There are three existing Akt isoforms (Akt1-3)41, and studies have identified Akt2 as the relevant isoform in insulin-stimulated GLUT4 translocation. [...]

[...] Also, a number of key properties of the protein have since been elucidated. First, AS160 contains a GTPaseactivating domain (GAP) for Rabs, small G proteins involved in vesicle trafficking49,53.

[page 378]

Along with recruiting and activating Akt, PI 3,4,5-3 formation in concert with PDK1 also leads to the activation of atypical protein kinase C (aPKC), and both aPKC isoforms ζ and λ have been implicated in GLUT4 translocation. As recently reviewed58, aPKC knockout models and expression of kinase-inactive PKC-ζ/λ inhibits GLUT4 translocation and glucose uptake in a variety of cell types, and this phenotype can be reversed in PKC-λ–/– cells by expressing wild-type aPKC.


1. Bjornholm M, Zierath JR. Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes. Biochem Soc Trans 2005; 33 : 354-7.

16. Luo RZ, Beniac DR, Fernandes A, Yip CC, Ottensmeyer FP. Quaternary structure of the insulin-insulin receptor complex. Science 1999; 285 : 1077-80.

17. Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, et al. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 1992; 70 : 93-104.

18. Holgado-Madruga M, Emlet DR, Moscatello DK, Godwin AK, Wong AJ. A Grb2-associated docking protein in EGF- and insulin-receptor signalling. Nature 1996; 379 : 560-4.

19. Fujioka Y, Matozaki T, Noguchi T, Iwamatsu A, Yamao T, Takahashi N, et al. A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion. Mol Cell Biol 1996; 16 : 6887-99.

20. White MF. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem 1998; 182 : 3-11.

21. Rocchi S, Tartare-Deckert S, Murdaca J, Holgado-Madruga M, Wong AJ, Van Obberghen E. Determination of Gab1 (Grb2-associated binder-1) interaction with insulin receptor-signaling molecules. Mol Endocrinol 1998; 12 : 914-23.

22. Moodie SA, Alleman-Sposeto J, Gustafson TA. Identification of the APS protein as a novel insulin receptor substrate. J Biol Chem 1999; 274 : 11186-93.

23. Cai D, Dhe-Paganon S, Melendez PA, Lee J, Shoelson SE. Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. J Biol Chem 2003; 278 : 25323-30.

32. Shepherd PR. Mechanisms regulating phosphoinositide 3-kinase signalling in insulin-sensitive tissues. Acta Physiol Scand 2005; 183 : 3-12.

33. Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M. Essential role of phosphatidylinositol 3-kinase in insulininduced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. J Biol Chem 1994; 269 : 3568-73.

34. Clarke JF, Young PW, Yonezawa K, Kasuga M, Holman GD. Inhibition of the translocation of GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinositol 3-kinase inhibitor, wortmannin. Biochem J 1994; 300 : 631-5.

35. Scheid MP, Woodgett JR. Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett 2003; 546: 108-12.

36. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictormTOR complex. Science 2005; 307 : 1098-101.

37. Sarbassov dos D, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005; 17 : 596-603.

38. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124 : 471-84.

41. Bae SS, Cho H, Mu J, Birnbaum MJ. Isoform-specific regulation of insulin-dependent glucose uptake by Akt/ protein kinase B. J Biol Chem 2003; 278 : 49530-6.

49. Sano H, Kane S, Sano E, Miinea CP, Asara JM, Lane WS, et al. Insulin-stimulated phosphorylation of a Rab GTPaseactivating protein regulates GLUT4 translocation. J Biol Chem 2003; 278 : 14599-602.

53. Jordens I, Marsman M, Kuijl C, Neefjes J. Rab proteins, connecting transport and vesicle fusion. Traffic 2005; 6 : 1070-7.

58. Farese RV, Sajan MP, Standaert ML. Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. Exp Biol Med (Maywood) 2005; 230 : 593-605.

Anmerkungen

The source is not given.

Note that in the dissertation one finds "z and l" instead of "ζ and λ", and sub-/superscripts that have disappeared. Copying and pasting from a PDF file often leads to this kind of a mistake.

Sichter
(Hindemith), WiseWoman

[3.] Sj/Fragment 014 01 - Diskussion
Zuletzt bearbeitet: 2016-11-25 21:45:05 WiseWoman
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[Furthermore, expression of] constitutively active aPKC recapitulates the effects of insulin on GLUT4 translocation and glucose transport.

1.3.7 PI3-K independent pathway

It is well established that activation of GLUT4 translocation by insulin requires a PI3K signal involving the upstream IR and IRS activators and the downstream Akt and PKC target enzymes and AS160 protein. Some studies over the past decade have also suggested that a second pathway occurs as a consequence of Cbl tyrosine phosphorylation (57), (58). Cbl and the adaptor protein CAP are recruited to the insulin receptor by APS (59). Once tyrosine phosphorylated by the receptor, Cbl can recruit the adaptor protein CrkII to lipid rafts, along with the guanyl nucleotide exchange factor C3G (60). C3G can then activate the GTP-binding protein TC10, which resides in lipid rafts . The correct spatial compartmentalization of these signaling molecules in the lipid raft microdomain appears to be essential or insulinstimulated GLUT4 translocation and glucose transport, as these insulin-mediated events are abolished by dominant-interfering mutants of CAP that prevent the localization of Cbl to lipid rafts (61). Nevertheless, investigation suggests a role of TC10 in the regulation of actin dynamics and phosphoinositides. Cellular cortical actin exists in two forms: monomeric globular actin (G-actin) and filamentous actin (F-actin). In the case of cytosketal fusion, microtubules and cortical actin plays the important role. When the actin network (62) in skeletal muscle is treated with actin depolymerizing agent cytochalasin D or the actin monomer binding red sea sponge toxins Latrunculin A or B, it leads to the inhibition of glucose uptake and GLUT4 translocation (63). Two potentially overlapping models hypothesizing the role of actin in glucose uptake. According to the first one, insulin causes cortical actin remodeling, such that incoming vesicles can travel through the peripheral actin mesh to fuse with the plasma membrane (64) . The second suggests that actin filaments function as “highways,” upon which vesicles travel to reach the plasma membrane. Regardless of the exact actin function, it is apparent that insulin signaling to rearrange cortical actin represents a required pathway for optimal movement or fusion of GLUT4-containing vesicles and plasma membranes.


57. Ribon,V, Saltiel,AR: Insulin stimulates tyrosine phosphorylation of the protooncogene product of c-Cbl in 3T3-L1 adipocytes. Biochem.J. 324 ( Pt 3):839-845, 1997

58. Liu,J, DeYoung,SM, Hwang,JB, O'Leary,EE, Saltiel,AR: The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport. J.Biol.Chem. 278:36754-36762, 2003

59. Liu,J, Kimura,A, Baumann,CA, Saltiel,AR: APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes. Mol.Cell Biol. 22:3599-3609, 2002

60. Chiang,SH, Baumann,CA, Kanzaki,M, Thurmond,DC, Watson,RT, Neudauer,CL, Macara,IG, Pessin,JE, Saltiel,AR: Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature 410:944-948, 2001

61. Baumann,CA, Ribon,V, Kanzaki,M, Thurmond,DC, Mora,S, Shigematsu,S, Bickel,PE, Pessin,JE, Saltiel,AR: CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature 407:202-207, 2000

62. Omata,W, Shibata,H, Li,L, Takata,K, Kojima,I: Actin filaments play a critical role in insulin-induced exocytotic recruitment but not in endocytosis of GLUT4 in isolated rat adipocytes. Biochem.J. 346 Pt 2:321-328, 2000

63. Brozinick,JT, Jr., Hawkins,ED, Strawbridge,AB, Elmendorf,JS: Disruption of cortical actin in skeletal muscle demonstrates an essential role of the cytoskeleton in glucose transporter 4 translocation in insulin-sensitive tissues. J.Biol.Chem. 279:40699-40706, 2004

64. Jiang,ZY, Chawla,A, Bose,A, Way,M, Czech,MP: A phosphatidylinositol 3-kinaseindependent insulin signaling pathway to N-WASP/Arp2/3/F-actin required for GLUT4 glucose transporter recycling. J.Biol.Chem. 277:509-515, 2002

Furthermore, expression of constitutively active aPKC recapitulates the effects of insulin on GLUT4 translocation and glucose transport. [...]

PI3K-independent signaling: It is well established that activation of GLUT4 translocation by insulin requires a PI3K signal involving the upstream IR and IRS activators and the downstream Akt and PKC target enzymes and AS160 protein as presented above (Fig.A). Some studies over the past decade have also suggested that a second pathway (Fig.B) occurs as a consequence of Cbl tyrosine phosphorylation59,60. Cbl and the adaptor protein CAP are recruited to the insulin receptor by APS61. Once tyrosine phosphorylated by the receptor, Cbl can recruit the adaptor protein CrkII to lipid rafts, along with the guanyl nucleotide exchange factor C3G62. C3G can then activate the GTP-binding protein TC10, which resides in lipid rafts63. The correct spatial compartmentalization of these signaling molecules in the lipid raft microdomain appears to be essential for insulin-stimulated GLUT4 translocation and glucose transport, as these insulin-mediated events are abolished by dominant-interfering mutants of CAP that prevent the localization of Cbl to lipid rafts64. [...]

Nevertheless, investigation suggests a role of TC10 in the regulation of actin dynamics69-74 and phosphoinositides75.

[page 379]

Cortical actin: Cellular cortical actin exists in two forms: monomeric globular actin (G-actin) and filamentous actin (F-actin).[...] Disrupting the actin network in cultured cells or in intact rat skeletal muscle with the actin-depolymerizing agent cytochalasin D, or the actin monomer binding Red Sea Sponge toxins Latrunculin A or B, inhibits insulin-stimulated GLUT4 translocation and glucose uptake77,80,81. [...] Overall, these studies have given rise to two potentially overlapping models hypothesizing the role of actin in glucose uptake. The first proposes that insulin causes cortical actin remodeling, such that incoming vesicles can travel through the peripheral actin mesh to fuse with the plasma membrane. The second suggests that actin filaments function as “highways,” upon which vesicles travel to reach the plasma membrane71. Regardless of the exact actin function, it is apparent that insulin signaling to rearrange cortical actin represents a required pathway for optimal movement or fusion of GLUT4-containing vesicles and plasma membranes.


59. Ribon V, Saltiel AR. Insulin stimulates tyrosine phosphorylation of the proto-oncogene product of c-Cbl in 3T3-L1 adipocytes. Biochem J 1997; 324 : 839-45.

60. Liu J, DeYoung SM, Hwang JB, O’Leary EE, Saltiel AR. The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport. J Biol Chem 2003; 278 : 36754-62.

61. Liu J, Kimura A, Baumann CA, Saltiel AR. APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes. Mol Cell Biol 2002; 22 : 3599-609.

62. Chiang SH, Baumann CA, Kanzaki M, Thurmond DC, Watson RT, Neudauer CL, et al. Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature 2001; 410 : 944-8.

63. Watson RT, Shigematsu S, Chiang SH, Mora S, Kanzaki M, Macara IG, et al. Lipid raft microdomain compartmentalization of TC10 is required for insulin signaling and GLUT4 translocation. J Cell Biol 2001; 154 : 829-40.

64. Baumann CA, Ribon V, Kanzaki M, Thurmond DC, Mora S, Shigematsu S, et al. CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature 2000; 407 : 202-7.

69. Chunqiu Hou J, Pessin JE. Lipid Raft targeting of the TC10 amino terminal domain is responsible for disruption of adipocyte cortical actin. Mol Biol Cell 2003; 14 : 3578-91.

70. Inoue M, Chang L, Hwang J, Chiang SH, Saltiel AR. The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin. Nature 2003; 422 : 629-33.

71. Jiang ZY, Chawla A, Bose A, Way M, Czech MP. A phosphatidylinositol 3-kinase-independent insulin signaling pathway to N-WASP/Arp2/3/F-actin required for GLUT4 glucose transporter recycling. J Biol Chem 2002; 277 : 509-15.

72. Kanzaki M, Pessin JE. Insulin-stimulated GLUT4 translocation in adipocytes is dependent upon cortical actin remodeling. J Biol Chem 2001; 276 : 42436-44.

73. Kanzaki M, Pessin JE. Caveolin-associated filamentous actin (Cav-actin) defines a novel F-actin structure in adipocytes. J Biol Chem 2002; 277 : 25867-9.

74. Kanzaki M, Watson RT, Hou JC, Stamnes M, Saltiel AR, Pessin JE. Small GTP-binding protein TC10 differentially regulates two distinct populations of filamentous actin in 3T3L1 adipocytes. Mol Biol Cell 2002; 13 : 2334-46.

75. Maffucci T, Brancaccio A, Piccolo E, Stein RC, Falasca M. Insulin induces phosphatidylinositol-3-phosphate formation through TC10 activation. EMBO J 2003; 22 : 4178-89.

77. Tsakiridis T, Vranic M, Klip A. Disassembly of the actin network inhibits insulin-dependent stimulation of glucose transport and prevents recruitment of glucose transporters to the plasma membrane. J Biol Chem 1994; 269 : 29934-42.

80. Omata W, Shibata H, Li L, Takata K, Kojima I. Actin filaments play a critical role in insulin-induced exocytotic recruitment but not in endocytosis of GLUT4 in isolated rat adipocytes. Biochem J 2000; 346 : 321-8.

81. Brozinick JT, Jr., Hawkins ED, Strawbridge AB, Elmendorf JS. Disruption of cortical actin in skeletal muscle demonstrates an essential role of the cytoskeleton in glucose transporter 4 translocation in insulin-sensitive tissues. J Biol Chem 2004; 279 : 40699-706.

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1.3.8 Role of SNARE proteins in GLUT4 regulation

After the insulin-mediated arrival of GLUT4-containing vesicles from intracellular storage sites to the plasma membrane, regulated fusion of these vesicles ensues. Exocytosis of GLUT4-containing vesicles is mediated by interactions between specific vesicular and plasma membrane protein complexes known as SNAREs. Vesicle SNAREs (v-SNARES, vesicle soluble N-ethylmaleimide-sensitive factor attachment protein receptors) bind target membrane SNAREs (t-SNAREs) in company with numerous accessory proteins. Syntaxin4 and SNAP23 (23 kDa synaptosomal-associated protein) are the t-SNARES and VAMP2 is the v-SNARE involved in GLUT4 vesicle fusion (67) While SNAREs are essential in GLUT4 exocytosis, they themselves do not appear to be the direct targets of insulin action. Rather, studies suggest that the accessory proteins Munc18 and Synip may be regulated by insulin to accomplish fusion events. Three Munc18 isoforms (Munc18ac) have been identified in mammalian cells: Munc18a (67) is a neuronal isoform and Munc18b and Munc18c are expressed in muscle and adipose tissues. In addition to Munc18, the accessory protein Synip may also play a role in insulin stimulated GLUT4 vesicle fusion (68), although data are conflicting. Synip was first identified by Min and colleagues, who determined that this protein dissociates from syntaxin4 in an insulin-dependent manner and is directly involved in GLUT4 translocation. Recently, it was reported that Akt2 phosphorylates Synip on serine 99 and this phosphorylation mediates the Synip-syntaxin4 dissociation necessary for GLUT4 vesicle exocytosis (69). However, recent studies argue against this possibility and show that a serine-to-alanine Synip mutant (S99A) does not impair GLUT4 translocation.

1.3.9 Role of GLUT4 dysfunctions in obesity and type 2 diabetes

Insulin resistance is significantly caused by both genetic and environmental components. Mutations in the insulin receptor are rare but result in extremely severe insulin resistance. These include Leprechaunism, Rabson-Mendenhall Syndrome, and the type A syndrome of insulin resistance (70). Type 2 diabetes is polygenic, probably involving defects at numerous points in the glucose regulatory system. For example, skeletal muscle analyzed from type 2 diabetic subjects displays diminished insulin-stimulated IRS-1 tyrosine phosphorylation and decreased PI3K activity coupled to impaired glucose transport. These defects could not be explained by alterations in protein expression. Likewise, skeletal muscle and adipocytes from obese, Type 2 diabetic patients demonstrate impaired insulin-triggered IRS-1 associated [PI3K activity (71), (44).]


44. Bjornholm,M, Zierath,JR: Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes. Biochem.Soc.Trans. 33:354-357, 2005

67. Thurmond,DC, Pessin,JE: Molecular machinery involved in the insulin-regulated fusion of GLUT4-containing vesicles with the plasma membrane (review). Mol.Membr.Biol. 18:237-245, 2001

68. Min,J, Okada,S, Kanzaki,M, Elmendorf,JS, Coker,KJ, Ceresa,BP, Syu,LJ, Noda,Y, Saltiel,AR, Pessin,JE: Synip: a novel insulin-regulated syntaxin 4-binding protein mediating GLUT4 translocation in adipocytes. Mol.Cell 3:751-760, 1999

69. Yamada,E, Okada,S, Saito,T, Ohshima,K, Sato,M, Tsuchiya,T, Uehara,Y, Shimizu,H, Mori,M: Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4- containing vesicles. J.Cell Biol. 168:921-928, 2005

70. Saltiel,AR, Kahn,CR: Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799-806, 2001

71. Krook,A, Bjornholm,M, Galuska,D, Jiang,XJ, Fahlman,R, Myers,MG, Jr., Wallberg- Henriksson,H, Zierath,JR: Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 49:284-292, 2000

SNAREing GLUT4

Following the insulin-mediated arrival of GLUT4-containing vesicles from intracellular storage sites to the plasma membrane, regulated fusion of these vesicles ensues. Exocytosis of GLUT4-containing vesicles is mediated by interactions between specific vesicular and plasma membrane protein complexes known as SNAREs (Fig. C). Vesicle SNAREs (v-SNARES, vesicle soluble N-ethylmaleimide-sensitive factor attachment protein receptors) bind target membrane SNAREs (t-SNAREs) in company with numerous accessory proteins. Syntaxin4 and SNAP23 (23 kDa synaptosomal-associated protein) are the t-SNARES and VAMP2 is the v-SNARE involved in GLUT4 vesicle fusion106. While SNAREs are essential in GLUT4 exocytosis, they themselves do not appear to be direct targets of insulin action. Rather, studies suggest that the accessory proteins Munc18 and Synip may be regulated by insulin to accomplish fusion events. Three Munc18 isoforms (Munc18ac) have been identified in mammalian cells: Munc18a is a neuronal isoform and Munc18b and Munc18c are expressed in muscle and fat. [...] In addition to Munc18c, the accessory protein Synip may also play a role in insulin-stimulated GLUT4 vesicle fusion, although data are conflicting. Synip was first identified by Min and colleagues112, who determined that this protein dissociates from syntaxin4 in an insulin-dependent manner and is directly involved in GLUT4 translocation. Recently, it was reported that Akt2 phosphorylates Synip on serine 99 and this phosphorylation mediates the Synip-syntaxin4 dissociation necessary for GLUT4 vesicle exocytosis113. However, recent studies argue against this possibility and show that a serine-to-alanine Synip mutant (S99A) does not impair GLUT4 translocation114.

[page 381]

[...]

GLUT4 dysregulation in obesity and type 2 diabetes

Abundant studies of insulin resistance demonstrate defects at numerous levels in the insulin-regulated glucose transport pathway. Insulin sensitivity is profoundly affected by both genetic and environmental components. Mutations in the insulin receptor are rare but result in extremely severe insulin resistance. These include Leprechaunism, Rabson-Mendenhall Syndrome, and the type A syndrome of insulin resistance117. Type 2 diabetes is polygenic, probably involving defects at numerous points in the glucose regulation system. For example, skeletal muscle analyzed from type 2 diabetic subjects versus lean controls displays diminished insulin-stimulated IRS-1 tyrosine phosphorylation and decreased PI3K activity coupled to impaired glucose transport118. These defects could not be explained by alterations in protein expression. Likewise, skeletal muscle and adipocytes from obese, insulin-resistant individuals demonstrate impaired insulin-triggered IRS-1 associated PI3K activity compared to matching tissue from lean individuals119,120.


106. Thurmond DC, Pessin JE. Molecular machinery involved in the insulin-regulated fusion of GLUT4-containing vesicles with the plasma membrane. Mol Membr Biol 2001; 18 : 237-45.

112. Min J, Okada S, Kanzaki M, Elmendorf JS, Coker KJ, Ceresa BP, et al. Synip: a novel insulin-regulated syntaxin 4-binding protein mediating GLUT4 translocation in adipocytes. Mol Cell 1999; 3 : 751-60.

113.Yamada E, Okada S, Saito T, Ohshima K, Sato M, Tsuchiya T, et al. Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. J Cell Biol 2005; 168 : 921-8.

114. Sano H, Kane S, Sano E, Lienhard GE. Synip phosphorylation does not regulate insulin-stimulated GLUT4 translocation. Biochem Biophys Res Commun 2005; 332 : 880-4.

117. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414 : 799-806.

118. Krook A, Bjornholm M, Galuska D, Jiang XJ, Fahlman R, Myers MG, Jr., et al. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 2000; 49 : 284-92.

119. Bjornholm M, Al-Khalili L, Dicker A, Naslund E, Rossner S, Zierath JR, et al. Insulin signal transduction and glucose transport in human adipocytes: effects of obesity and low calorie diet. Diabetologia 2002; 45 : 1128-35.

120. Brozinick JT, Jr., Roberts BR, Dohm GL. Defective signaling through Akt-2 and -3 but not Akt-1 in insulinresistant human skeletal muscle: potential role in insulin resistance. Diabetes 2003; 52 : 935-41.

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Impaired insulin signaling through downstream Akt2 and AS160 proteins has also been reported in skeletal muscle. Furthermore, the fatty acid metabolite ceramide causes insulin resistance that is coupled to impaired membrane recruitment and phosphorylation of Akt (72). Knowledge on mechanisms of such defects has remained underdeveloped. Increased IRS-1 serine phosphorylation may also help explain insulin resistance, as phosphorylated serine residues are thought to sterically hinder interactions with downstream PI3K. Dysregulated PKC activity in insulin resistance could increase serine phosphorylation (73) and PKC knockout mice are protected from insulin resistance (74).

Membrane and cytoskeletal defects are also a possible basis of insulin resistance. We now know that moderate increase in plasma membrane fluidity increase glucose transport . Furthermore, it has been shown that basal glucose transport is not fully active in fat cells and that it can be increased further by augmenting membrane fluidity. Consistent with membrane fluidity influencing insulin responsiveness, insulin-stimulated glucose transport is decreased when fluidity diminishes (75). Recent data suggest that the anti-diabetic drug metformin enhances insulin action by increasing membrane fluidity (76). Interestingly, the beneficial effects of chromium supplementation on insulin responsiveness may also be linked to membrane fluidity (77). With regards to cytoskeletal defects, recent study of various cell culture models of insulin resistance suggests that an underlying basis of reduced cellular insulin sensitivity may be perturbations in phosphoinositide-regulated cortical F-actin structure. In particular, PI -P2 control of cortical F-actin is disturbed by hyperinsulinaemic (78) and hyperendothelinaemic insulin-resistant conditions (79). Furthermore, isolated adipocytes from ethanol-induced insulin resistant Wistar rats (80) and skeletal muscle from obese insulin-resistant Zucker rats display altered actin polymerization. These findings agree with the necessity of an intact cytoskeleton for proper glucose regulation and suggest a membrane/cytoskeletal component of insulin resistance. Finally, some study has also revealed that insulin-resistant conditions are associated with defects in the SNARE pathway. As future research continues to expand our understanding of the signaling pathways of insulinregulated GLUT4 translocation and glucose transport, our ability to develop interventions to prevent, reverse, and ameliorate insulin resistance in obesity and type 2 diabetes will be favourably reached.


72. Teruel,T, Hernandez,R, Lorenzo,M: Ceramide mediates insulin resistance by tumor necrosis factor-alpha in brown adipocytes by maintaining Akt in an inactive dephosphorylated state. Diabetes 50:2563-2571, 2001

73. De Fea,K, Roth,RA: Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. Biochemistry 36:12939-12947, 1997

74. Kim,JK, Fillmore,JJ, Sunshine,MJ, Albrecht,B, Higashimori,T, Kim,DW, Liu,ZX, Soos,TJ, Cline,GW, O'Brien,WR, Littman,DR, Shulman,GI: PKC-theta knockout mice are protected from fat-induced insulin resistance. J.Clin.Invest 114:823-827, 2004

75. Czech,MP: Insulin action and the regulation of hexose transport. Diabetes 29:399-409, 1980

76. Wiernsperger,NF: Membrane physiology as a basis for the cellular effects of metformin in insulin resistance and diabetes. Diabetes Metab 25:110-127, 1999

77. Chen,G, Liu,P, Pattar,GR, Tackett,L, Bhonagiri,P, Strawbridge,AB, Elmendorf,JS: Chromium activates glucose transporter 4 trafficking and enhances insulinstimulated glucose transport in 3T3-L1 adipocytes via a cholesterol-dependent mechanism. Mol.Endocrinol. 20:857-870, 2006

78. Chen,G, Raman,P, Bhonagiri,P, Strawbridge,AB, Pattar,GR, Elmendorf,JS: Protective effect of phosphatidylinositol 4,5-bisphosphate against cortical filamentous actin loss and insulin resistance induced by sustained exposure of 3T3-L1 adipocytes to insulin. J.Biol.Chem. 279:39705-39709, 2004

79. Strawbridge,AB, Elmendorf,JS: Endothelin-1 impairs glucose transporter trafficking via a membrane-based mechanism. J.Cell Biochem. 97:849-856, 2006

80. Sebastian,BM, Nagy,LE: Decreased insulin-dependent glucose transport by chronic ethanol feeding is associated with dysregulation of the Cbl/TC10 pathway in rat adipocytes. Am.J.Physiol Endocrinol.Metab 289:E1077-E1084, 2005

Impaired insulin signaling through downstream Akt2 and AS160 proteins has also been reported in skeletal muscle51,120. Furthermore, the fatty acid metabolite ceramide causes insulin resistance that is coupled to impaired membrane recruitment and phosphorylation of Akt121. Knowledge on mechanisms of such defects has remained underdeveloped. [...] Increased IRS-1 serine phosphorylation may also help explain insulin resistance, as phosphorylated serine residues are thought to sterically hinder interactions with downstream PI3K. Dysregulated PKC activity in insulin resistance could increase serine phosphorylation124, and PKC knockout mice are protected from insulin resistance125.

Membrane and cytoskeletal defects are also a possible basis of insulin resistance. We now know that moderate increases in plasma membrane fluidity increase glucose transport126-128. Furthermore, it has been shown that basal glucose transport is not fully active in fat cells and that it can be increased further by augmenting membrane fluidity126. Consistent with membrane fluidity influencing insulin responsiveness, insulin-stimulated glucose transport is decreased when fluidity diminishes127. Recent data suggest that the anti-diabetic drug metformin enhances insulin action by increasing membrane fluidity129,130. Interestingly, the beneficial effects of chromium supplementation on insulin responsiveness may also be linked to membrane fluidity131-133. With regards to cytoskeletal defects, recent study of various cell culture models of insulin resistance suggests that an underlying basis of reduced cellular insulin sensitivity may be perturbations in phosphoinositide-regulated cortical F-actin structure. In particular, PI 4,5-P2 control of cortical F-actin is disturbed by hyperinsulinaemic134 and hyperendothelinaemic135,136 insulin-resistant conditions and reversal of these changes by experimental manipulation of PI 4,5-P2 corresponds with a restoration in insulin sensitivity. Furthermore, isolated adipocytes from ethanol-induced insulinresistant Wistar rats82 and skeletal muscle from obese insulin resistant Zucker rats137 display altered actin polymerization. These findings agree with the necessity of an intact cytoskeleton for proper glucose regulation and suggest a membrane/cytoskeletal

[page 382]

component of insulin resistance. Finally, some study has also revealed that insulin-resistant conditions are associated with defects in the SNARE machinery138. As future research continues to expand our understanding of the signaling pathways of insulinregulated GLUT4 translocation and glucose transport, our ability to develop interventions to prevent, reverse, and ameliorate insulin resistance in obesity and type 2 diabetes will be favourably impacted.


51. Karlsson HK, Zierath JR, Kane S, Krook A, Lienhard GE, Wallberg-Henriksson H. Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects. Diabetes 2005; 54 : 1692-7.

82. Sebastian BM, Nagy LE. Decreased insulin-dependent glucose transport by chronic ethanol feeding is associated with dysregulation of the Cbl/TC10 pathway in rat adipocytes. Am J Physiol Endocrinol Metab 2005; 289 : E1077-84.

120. Brozinick JT, Jr., Roberts BR, Dohm GL. Defective signaling through Akt-2 and -3 but not Akt-1 in insulinresistant human skeletal muscle: potential role in insulin resistance. Diabetes 2003; 52 : 935-41.

121.Teruel T, Hernandez R, Lorenzo M. Ceramide mediates insulin resistance by tumor necrosis factor-alpha in brown adipocytes by maintaining Akt in an inactive dephosphorylated state. Diabetes 2001; 50 : 2563-71.

124.De Fea K, Roth RA. Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. Biochemistry 1997; 36 : 12939-47.

125. Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim DW, et al. PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest 2004; 114 : 823-7.

126.Czech MP. Insulin action and the regulation of hexose transport. Diabetes 1980; 29 : 399-409.

127. Pilch PF, Thompson PA, Czech MP. Coordinate modulation of D-glucose transport activity and bilayer fluidity in plasma membranes derived from control and insulin-treated adipocytes. Proc Natl Acad Sci USA 1980; 77 : 915-8.

128. Whitesell RR, Regen DM, Beth AH, Pelletier DK, Abumrad NA. Activation energy of the slowest step in the glucose carrier cycle: break at 23 degrees C and correlation with membrane lipid fluidity. Biochemistry 1989; 28 : 5618-25.

129. Muller S, Denet S, Candiloros H, Barrois R, Wiernsperger N, Donner M, et al. Action of metformin on erythrocyte membrane fluidity in vitro and in vivo. Eur J Pharmacol 1997; 337 : 103-10.

130.Wiernsperger NF. Membrane physiology as a basis for the cellular effects of metformin in insulin resistance and diabetes. Diabetes Metab 1999; 25 : 110-27.

131.Evans GW, Bowman TD. Chromium picolinate increases membrane fluidity and rate of insulin internalization. J Inorg Biochem 1992; 46 : 243-50.

132. Chen G, Liu P, Pattar GR, Tackett L, Bhonagiri P, Strawbridge AB, et al. Chromium activates GLUT4 trafficking and enhances insulin-stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol-dependent mechanism. Mol Endocrinol 2006; 20 : 857-70.

133. Pattar GR, Tackett L, Liu P, Elmendorf JS. Chromium picolinate positively influences the glucose transporter system via affecting cholesterol homeostasis in adipocytes cultured under hyperglycemic diabetic conditions. Mutat Res 2006; 610 : 93-100.

134. Chen G, Raman P, Bhonagiri P, Strawbridge AB, Pattar GR, Elmendorf JS. Protective effect of phosphatidylinositol 4,5-bisphosphate against cortical filamentous actin loss and insulin resistance induced by sustained exposure of 3T3-L1 adipocytes to insulin. J Biol Chem 2004; 279 : 39705-9.

135. Strawbridge AB, Elmendorf JS. Phosphatidylinositol 4,5-bisphosphate reverses endothelin-1-induced insulin resistance via an actin-dependent mechanism. Diabetes 2005; 54 : 1698-705.

136. Strawbridge AB, Elmendorf JS. Endothelin-1 impairs glucose transporter trafficking via a membrane-based mechanism. J Cell Biochem 2006; 97 : 849-56.

137. McCarthy AM, Spisak KO, Brozinick JT, Jr., Elmendorf JS. Phosphatidylinositol 4,5-bisphosphate and cortical Factin abnormalities in insulin resistant skeletal muscle. Diabetes 2005; 54 : A319.

138.Chen G, Liu P, Thurmond DC, Elmendorf JS. Glucosamine-induced insulin resistance is coupled to Olinked glycosylation of Munc18c. FEBS Lett 2003; 534 : 54-60.

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