Insulin stimulates glucose uptake in muscle and adipose cells primarily by recruiting GLUT4 from an intracellular storage pool to the plasma membrane. Dysfunction of this process known as insulin resistance causes hyperglycemia, a hallmark of diabetes and obesity. Thus the understanding of the mechanisms underlying this process at the molecular level may give, an insight into the prevention and treatment of these health problems. GLUT4 in rat adipocytes, for example, constantly recycles between the cell surface and an intracellular pool by endocytosis and exocytosis, each of which is regulated by an insulin-sensitive and GLUT4-selective sorting mechanism. Our working hypothesis has been that this sorting mechanism includes a specific interaction of a cytosolic protein with the GLUT4 cytoplasmic domain. Indeed, a synthetic peptide of the C-terminal cytoplasmic domain of GLUT4 induces an insulin-like GLUT4 recruitment when introduced in rat adipocytes. Relevance of these observations to a novel euglycemic drug design is discussed.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Backer, J. M., Myers, M. G. Jr., Shoelson, S. E., Chin, D. J., Sun, X. J., Miralpeix, M., Hu, P., Margolis, B., Skolnik, E. Y. and Schlessinger, J., Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation.EMBO J., 11, 3469–3479 (1992).
Begum, N., Stimulation of protein phosphatase-1 activity by insulin in rat adipocytes. Evaluation of the role of mitogen-activated protein kinase pathway.J. Biol. Chem., 270, 709–714 (1995).
Birnbaum, M. J., The insulin-sensitive glucose transporterInt. Rev. Cytol., 137A, 239–297 (1992).
Calera, M. R., Martinez, C., Liu, H. Z., El Jack, A. K., Birnbaum, M. J. and Pilch, P. F., Insulin increases the association of Akt-2 with GLUT4-containing vesicles.J. Biol. Chem., 273, 7201–7204 (1998).
Chin, J. J., Jung, E. K. Y. and Jung, C. Y., Structural basis of human erythrocyte glucose transporter function in reconstituted vesicles. Circular dichroism studies.Proc. Natl. Acad. Sci. USA, 84, 4113–4116 (1987).
Clancy, B. M. and Czech, M. P., Hexose transport stimulation and membrane redistribution of glucose transporter isoforms in response to cholera toxin, dibutyryl cyclic AMP, and insulin in 3T3-L1 adipocytes.J. Biol. Chem., 265, 12434–12443 (1990).
Corvera, S., Chawla, A., Chakrabarti, R., Joly, M., Buxton, J. and Czech, M. P., A double leucine within the GLUT4 glucose transporter COOH terminal domain functions as an endocytosis signal.J. Cell Biol., 126, 979–989 (1994).
Cushman, S. W. and Wardzala, L. J., Potential mechanism of insulin action on glucose transport in the isolated rat adipose cells: Apparent translocation of intracellular transport systems to the plasma membrane.J. Biol. Chem., 255, 4758–4762 (1980).
DeFronzo, R. A., Jacto, E., Jequire, E., Meader, E., Wahren, J. and Felber, J. P., The effect of insulin on the disposal of intravenous glucose.Diabetes, 30, 1000–1007 (1981).
DeFronzo, R. A., The triumvirate: beta cell, muscle, liver; a collusion responsible for NIDDM.Diabetes, 37, 667–684 (1988).
Del Vecchio, R. L. and Pilch, P. F., Phosphatidylinositol 4-kinase is a component of glucose transporter (GLUT4)-containing vesicles.J. Biol. Chem. 266, 13278–13283 (1991).
Garvey, W. T., Glucose transport and NIDDM.Diabetes Care, 15, 396–417 (1992).
James, D. E., Piper, R. C. and Slot, J. W., Insulin stimulation of GLUT4 translocation: a model for regulated recycling.Trends in Cell Biol., 4, 120–126 (1994).
Jhun, B. H., Rampal, A. L., Liu, H. Z., Lachaal, M. and Jung, C. Y., Effects of insulin on steady state kinetics of GLUT4 subcellular distribution in rat adipocytes: Evidence of constitutive GLUT4 recycling.J. Biol. Chem., 267, 17710–17715 (1992).
Jung, C. Y., Proteins that interact with facilitative glucose transporters: Implication for function.Exptl. Physiol., 83, 267–273 (1998).
Kahn, B. B., Glucose transport: Pivotal step in insulin action. Lilly Lecture 1995 Diabetes, 45, 1644–1654 (1996).
Kanai, F., Ito, K., Todaka, M., Hayashi, H., Kamohara, S., Ishii, K., Okada, T., Hazeki, O., Ui, M. and Ebina, Y., Insulin-stimulated GLUT4 translocation is relevant to the phosphorylation of IRS-1 and the activity of P13-kinase.Biochem. Biophys. Res. Commun., 195, 762–768 (1993).
Kasuga, M., Zick, Y., Blith, D. L., Karlsson, F. A., Haring, H. U. and Kahn, C. R., Insulin stimulation of phosphorylation of the beta subunit of the insulin receptor. Formation of both phosphoserine and phosphotyrosine.J. Biol. Chem., 257, 9891–9894 (1982).
Katagiri, H., Asano, T., Ishihara, H., Inugkai, K., Shibasaki, Y., Kikuchi, M., Yazaki, Y. and Oka, Y.J. Biol. Chem., 271, 16987–16990 (1996).
Keller, S. R., Kitagawa, K., Aebersold, R., Lienhard, G. E. and Garner, C. W., Isolation and characterization of the 160,000-Da phosphotyrosyl protein, a putative participant in insulin signaling.J. Biol. Chem., 266, 12817–12820 (1991).
Kohn, A. D., Summers, S. A., Birnbaum, M. J. and Roth, R. A., Expression of a constitutively active Akt ser/thr kinase in 3T3-L1 adipocytes, stimulates glucose uptake and glucose transporter 4 translocation.J. Biol. Chem., 271, 31372–31378 (1996).
Lachaal, M. and Jung, C. Y., Interaction of facilitated glucose transporter with glucokinase and its modulation by glucose-6-phosphate.J. Cell Physiol., 156, 326–332 (1993).
Lachaal, M., Berenski, C. J., Kim, J. and Jung, C. Y., An ATP-modulated specific association of glyceraldehyde-3-phosphate dehydrogenase with human erythrocyte glucose transporter.J. Biol. Chem., 265, 15449–15454 (1990).
Lawrence, J.C. Jr., Hiken, J. F. and James, D. E., Stimulation of glucose transport and glucose transporter phosphorylation by okadaic acid in rat adipocytes.J. Biol. Chem. 265, 19768–19776 (1990).
Lee, W. and Jung, C. Y., A synthetic peptide corresponding to the GLUT4 C-terminal cytoplamic domain causes insulin-like glucose transport stimulation and GLUT4 recruitment in rat adipocytes.J. Biol. Chem., 272, 21427–21431 (1997).
Liu, H. Z., Xiong, S. H., Samuel, S. J., Shi, Y. W., Lachaal, M. and Jung, C. Y., ATP sensitive binding of a 70kDa cytosolic protein to glucose transporter in rat adipocytes.J. Biol. Chem., 270, 7869–7875 (1995).
Moore, M. S., Mahaffey, D. T., Brodsky, F. M. and Anderson, R. G. W., Assembly of clathrin-coated pits onto purified plasma membranes.Science, 338, 558–563 (1987).
Mueckler, M., Facilitative glucose transporters.Eur. J. Biochem., 219, 713–725 (1994).
Office of the Director, NIH, NIDDKD. 1997, Diabetes mellitus: Challenges and Opportunities, Final Report and Recommendations. Natcher Conference Center, NIH, September 4–5.
Oka, Y. Asano, T., Shibasaki, Y., Lin, J. L., Tsukuda, K., Katagiri, H., Akanuma, Y. and Takaku, F., C-Terminal truncated glucose transporter is locked into an inwardfacing form without transport activity.Nature, 345, 550–553 (1990).
Pessin, J. E. and Bell, G. I., Mammalian facilitative glucose transporter family: Structure and molecular regulation.Annu. Rev. Physiol., 54, 911–930 (1992).
Ragolia, L. and Begum, N., The effect of modulating the glycogen-associated regulatory subunit of protein phosphatase-1 on insulin action in rat skeletal muscle cells.Endocrin., 138, 2398–2404 (1997).
Rampal, A.L., Jhun, B. H., Kim, S. S., Liu, H. Z., Manka, M., Lachaal, M., Spangler, R. A. and Jung, C. Y., Okadaic acid stimulates glucose transport in rat adipocytes by increasing the externalization rate constant of GLUT4 recycling.J. Biol. Chem., 270, 3938–3943 (1995).
Rothenberg, P. L., Lane, W. S., Karasik, A., Baker, J., White, M. and Kahn, C. R., Purification and partial sequence analysis of pp185, the major cellular substrate of the insulin receptor tyrosine kinase.J. Biol. Chem., 266, 8302–8311 (1991).
Schmid, S. L., Clathrin-coated vesicle formation and protein sorting: an integrated process.Annu. Rev. Biochem. 66, 511–548 (1997).
Shi, Y. W. H., Liu, H. Z., Vanderburg, G., Samuel, S. J., Ismail-Beigi, F. and Jung, C. Y., Modulation of GLUT1 intrinsic activity in Clone 9 cells by inhibition of oxidative phosphorylation.J. Biol. Chem., 270, 21772–21778 (1995).
Standaert, M. L., Galloway, L., Karnam, P., Bandyopadhyay, G. Moscat, J. and Farese, R. V., Protein kinase C-zeta as a downstream effector of phosphatidylinositol 3-kinase during insulin stimulation I rat adipocytes.J. Biol. Chem., 272, 30075–30082 (1997).
Stephens, J. M. and Pilch, P. F., The metabolic regulation and vesicular transport of GLUT4, the major insulin-responsive glucose transporter.Endocrinology Reviews, 16, 529–546 (1995).
Suzuki, K. and Kono, T., Evidence that insulin cause translocation of glucose transport activity to the plasma membrane from an intracellular storage site.Proc. Natl. Acad. Sci. USA, 77, 2542–2545 (1980).
Tung, H. Y. L., Pelech, S., Fisher, M. J., Pogson, C. I. and Ohen, P., The protein phosphatases involved in cellular regulation. Influence of polyamines on the activities of protein phosphatase-1 and protein phosphatase-2A.Eur. J. Biochem., 149, 305–313 (1985).
Verhey, K. J. and Birnbaum, M. J., A leu-leu sequence is essential for COOH-terminal targeting signal of GLUT4 glucose transporter in fibroblasts.J. Biol. Chem., 269, 2353–2356 (1994).
Verhey, K. J., Hausdorff, S. F. and Birnbaum, M. J., Identification of the carboxy termines as important for the isoform-specific subcellular targeting of glucose transporter proteins.J. Cell Biol., 123, 137–147 (1993).
Warram, J. H., Martin, B. C., Krolewski, A. S., Soeldner, J. S. and Kahn, C. R., Slow glucose removal rate and hyperinsulinemia precede the development of type II in the offspring of diabetic parents.Ann. Intern. Med. 113, 909–915 (1990).
Warren, G., Intracellular transport: Vesicular consumptionNature 345, 382–383 (1990).
Yang, X., Hubbard, E. J. A. and Carlson, M., A protein kinase substrate identified by the two-hybrid system.Science, 257, 680–682 (1992).
Zheng, H., Rampal, A. L., Parthasarathy, R. and Jung, C. Y., Proposed structure of putative glucose channel in GLUT1 facilitative glucose transporter.Biophysical J., 70, 14–21 (1996).
About this article
Cite this article
Jung, C.Y., Lee, W. Glucose transporters and insulin action: Some insights into diabetes management. Arch Pharm Res 22, 329 (1999). https://doi.org/10.1007/BF02979053
- Insulin action
- Glucose transporter