Elucidation of Final Stages in Coupling of Insulin Signalling to CLUT4 Translocation

Project: Research council

Project Details

Description

Maintenance of blood glucose levels is critically dependent on insulin stimulated glucose transport in adipose tissue, heart and skeletal muscle. Insulin combines with its receptor on target tissues and this initiates a cascade of linked reactions that ultimately result in the fusion of vesicles containing the glucose transporter protein GLUT4 with the plasma membrane. This latter process increases the availability of transporter molecules and thereby increases glucose transport into the cell. Although many of the links in the cascade are well studied, many technical difficulties have prevented detailed study of the final steps in the sequence, namely the fusion process. The proposed project will utilise novel approaches to study the fusion reaction and the extent to which small G-proteins of the Rab family link with the fusion machinery. We have identified many similarities between the membrane fusion reactions that occur in the pancreatic beta cell (which lead to secretion of insulin) and in insulin target tissues (which are involved in GLUT4 vesicle fusion). These similarities will guide the research objectives and experimental plans. These plans will be directed at advancing knowledge of how specific and known components of the fusion mechanism are linked together by effector proteins that are downstream of Rab proteins. This work is important as the fundamental mechanism that links signalling to regulated membrane fusion underlies many processes in biology and is relevant to human health. Elucidation of common mechanisms for pancreatic insulin-vesicle traffic and insulin target cell GLUT4-vesicle traffic will allow a unification of our understanding of those key reactions that are critical for control of blood glucose. These may become dysfunctional by a common route in metabolic disease including obesity and type 2 diabetes.
StatusFinished
Effective start/end date1/07/1230/06/15

Funding

  • MRC

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  • Research Output

    Highly potent and isoform-selective dual-site-binding tankyrase/Wnt signaling inhibitors that increase cellular glucose uptake and have anti-proliferative activity

    Nathubhai, A., Haikarainen, T., Koivunen, J., Murthy, S., Koumanov, F., Lloyd, M., Holman, G., Pihlajaniemi, T., Tosh, D., Lehtio, L. & Threadgill, M., 26 Jan 2017, In : Journal of Medicinal Chemistry. 60, 2, p. 814-820 7 p.

    Research output: Contribution to journalArticle

    Open Access
    File
  • 19 Citations (Scopus)
    105 Downloads (Pure)

    Identification of Insulin-Activated Rab Proteins in Adipose Cells Using Bio-ATB-GTP Photolabeling Technique

    Koumanov, F. & Holman, G. D., 8 Dec 2017, Glucose Transport: Methods and Protocols. Lindkvist-Petersson, K. & Hansen, J. S. (eds.). New York City, USA: Humana Press, p. 137-150 14 p. (Methods in Molecular Biology; vol. 1713).

    Research output: Chapter in Book/Report/Conference proceedingChapter

  • Rab28 is a TBC1D1/TBC1D4 substrate involved in GLUT4 trafficking

    Zhou, Z., Menzel, F., Benninghoff, T., Chadt, A., Du, C., Holman, G. D. & Al-Hasani, H., 1 Jan 2017, In : FEBS Letters. 591, 1, p. 88-96 9 p.

    Research output: Contribution to journalLetter

  • 9 Citations (Scopus)