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The role of extracellular vesicles in glucose metabolism and insulin sensitivity in humans
Secondary Supervisor(s): Dr Martin Whitham (Birmingham)
University of Registration: Coventry University
BBSRC Research Themes: Integrated Understanding of Health (Diet and Health)
Project Outline
Extracellular vesicles (EVs) are secreted from most cells and seem to operate as intercellular messengers to facilitate cellular function in recipient cells (1). Our current research shows that EVs and their cargo change with the transition from normal glucose control to dysfunctional glucose metabolism in human volunteers (unpublished data). Mapping a group of individuals’ over a 9 month healthy life-style intervention, we not only saw changes in EVs found in circulation with the worsening of health, but also witness changes in EV and their protein cargo in those displaying improved health outcomes. Although these data are exciting, we still don’t know what the physiological relevance of these changes are. Thus, the planned proposal will now assess for changes in circulating EVs and their cargo in response to a series of experiments manipulating intravenous glucose and / or insulin concentrations in humans.
An exciting collaboration between the proposed supervisors aims to explore these findings under controlled experimental conditions to unpick the basic mechanisms involved. Dr Whitham’s research group examines the fundamental concept that in response to both physiological and pathological stimuli, the transfer of molecules from one tissue to another via EVs is a biologically meaningful event and importantly, that broad assessment of the molecular cargo will be insightful. Dr Mackenzie group has many years of experience in altering whole-body metabolism, under controlled clinical conditions, to assess the physiological relevance of a given intervention or treatment (2). This PhD project will use clinical procedures, including hyperinsulinemic-euglyemic clamps with and without lipid infusion to improve our understanding of the role of EVs in glucose metabolism and insulin resistance. This project will use the data steaming from the clinical human work to direct a series of in vitro laboratory experiments. More specifically, we plan to isolate key EVs and their cargo from human donors to treat different cell-lines. In doing so, we can assess if these EVs can improve insulin resistance in adipose and muscle as well as modify ß-cell function.
The proposed studentship will sit within this broad programme of research operating within a modern, ‘wet’ laboratory combining innovative, mass spectrometry-based proteomic analyses with a variety of EV isolation and nanoparticle imaging analysis methods. In addition, the candidate will become practiced in a number of in vivo clinical procedures applied to humans. More traditional laboratory approaches, such as Western Blot, RT-PCR and Cell culture, will also be employed. Experience of the more technical methods is preferred but not essential.
References
- McIlvenna, L. & Whitham, M. Exercise, healthy ageing, and the potential role of small extracellular vesicles. 2023; 601, 22.
- Barclay, R., Beals, J., Drnevich, J., Imai, B., Yau, P., Ulanov, A., Villegas-Montes, M., Tillin, N., Watt, P., Burd, N. & Mackenzie R. (2020). Ingestion of lean meat elevates muscle inositol hexakisphosphate kinase 1 protein content independent of a distinct post-prandial circulating proteome in young adults with obesity. Metabolism 102 153996.
