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Diabetes & Metabolic Health Research Group Centre for Biomedical Science, Cardiff School of Health Sciences. Diabetes & Metabolic Health Research Group. Inflammatory/cell-signaling aspects of diabetes-associated cardiovascular disease (CVD).

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Diabetes & Metabolic Health Research Group

Centre for Biomedical Science,

Cardiff School of Health Sciences

Diabetes & Metabolic Health Research Group.

  • Inflammatory/cell-signaling aspects of diabetes-associated cardiovascular disease (CVD).

    • The effect of PPAR ligands in modulating inflammatory processes in complications of Type 2 Diabetes (T2D).

    • The effect of exercise, and of dietary lipids, on the prevention and progression of T2D, obesity and CVD.

What are ppar ligands
What are PPAR Ligands?

  • Natural Ligands

    • Dietary Ligands (eg. conjugated linoleic acid(CLA))

      • Prostaglandin metabolites. (e.g. 15-deoxy-delta 12,14-prostaglandin J2 (15d-PGJ2 )

  • oxidised LDL as a source of HODEs (hydroxy-octadecadienoic acid)

  • Synthetic Ligands.

    • Thiazolidinediones (eg. Rosiglitazone)

  • Rosiglitazone

    The role of PPARligands in T2D.

    • On binding of a ligand, PPAR acts as a transcription factor, regulating expression of specific target genes(eg. CD36, LPL, LXRa, etc) .

    • PPAR exerts beneficial effects in T2D by regulating the expression of genes involved in:-

      • glucose & lipid metabolism; cell differentiation.

      • inflammatory processes relevant to the progression of Type 2 Diabetes & its complications.

    • PPAR ligands also exert PPAR -independent effects (eg. the Unfolded Protein Response) that are relevant to T2D.

    Diabetes & Metabolic Health Research Group - Principal Investigators

    • Richard Webb

    • (Head of group 2009-2010;

    • Intracellular Signalling)

    • Intracellular signalling events triggered by exercise in normal subjects.

    • The role of the Unfolded Protein Response (UPR) and ER stress in diabetes and obesity.

    • Keith Morris

    • (Inflammatory Biology; Biostatistics)

    • Effect of endogenous dietary and other ligands of PPARs on inflammatory processes associated with diabetes and atherosclerosis.

    • The effects of low intensity exercise on cardiovascular risk markers and lipid metabolism

    • Andrew Thomas

    • (Molecular Biology)

    • Role of PPAR in diabetes and the process of atherosclerosis

    • Exercise-induced modulation of PPAR activity in normal and diabetic subjects

    • Role of endothelial and macrophage AGE-RAGE interaction in diabetes and atherosclerosis.

    • Rachel Adams

    • (Rheology)

    • Effect of air borne particles on cardiovascular risk markers

    • Factors affecting blood flow and blood cell deformability in diabetes

    • Barry McDonnell

    • (Vascular Biology; Early career researcher)

    • Arterial stiffness

    Group strategy research areas
    Group Strategy - Investigators Research Areas:

    • Main theme: Advantageous effects of PPAR activation in T2D/obesity/CVD, & elucidation of the mechanisms by which they occur.

    • Interventions leading to PPAR activation (exercise; dietary supplementatn), as investigated in terms of the following:

      • Generation of PPAR & other ligands (eg. oxLDL? HODEs? Oxysterols?)

      • Triggering of signalling pathways that lead to PPAR activation (eg. AMPK/sirtuin/PGC1α axis)

      • Anti-Atherogenic/Anti-Inflammatory processes linked to PPAR activation (eg. M1/M2 subtypes; RAGE splicing; arterial stiffness; etc)

    • Subsidiary Themes:

      • Strategies for alleviation of ER stress, as seen in macrophage lipotoxicity in obesity/T2D.

      • Cytoskeletal remodelling and leukocyte rigidity, leading to prevention of microvascular diabetic complications

    Ongoing projects
    Ongoing projects:- Investigators

    • Low-intensity exercise modulates PPAR-regulated expression of target genes responsible for reverse cholesterol transport, in previously sedentary adults.

      • Nia Davies (PhD) [PI: RW]

  • The Effect of Dietary/Natural PPAR Ligands and other Lipids On Cell Signalling Processes Relevant To The Development Of T2D And Its Complications.

    • Lowri Mainwaring (PhD), Hemanth Bolusani (MD), Khalid Al-Murraimi (PhD), Gertrude Yakeu (MPhil) [PI: KM in all cases]

  • The Induction of ER Stress Responses by Cholesterol, Rosiglitazone and various natural PPARgamma Ligands.

    • Jo Caddy (PhD), Suleiman Isa (PhD) [PI: RW in all cases]

  • The Effects of lifestyle, disease and the environment on blood flow.

    • Michael Melhuish (PhD (in collab with Prince Charles Hospital, Merthyr)), Halima Al-Bulushi (MPhil) [PI: RA in all cases]

  • Pending funding applications
    Pending Funding Applications Investigators

    • EASD Postdoctoral Scientist (TBA).

      • Submitted Nov 2009; Outcome expected March 2010

    • WORD Early Career Researcher (Barry McDonnell). The effects of exercise on serum lipid profiles, arterial stiffness and PPAR-activated gene expression in patients with Metabolic Syndrome.

      • Submitted May 2009; Outcome expected early 2010

    • WORD PhD studentship (Jose Ruffino).

      • Submitted July 2009; Outcome expected Jan 2010

    • Diabetes UK Project Grant (in preparation). - Community walking & PPAR-activated gene expression in patients with Diabetes (with Swansea Uni/Cardiff Uni).

    Current students
    Current students:- Investigators

    • 7 PhD/MPhil students - Joanne Caddy, Suleiman Isa, Nia Davies, Khalid Al-Muharrami, Lowri Mainwaring, Gertrude Yakeu, Halima Al-Bulushi.

    • 1 MD student – Hemanth Bolusani (UHW)

    • 1 External PhD student – Michael Melhuish (Prince Charles Hospital, Merthyr)

    Recent funding awards
    Recent Funding Awards Investigators

    • WORD Health PhD studentship (£60K; awarded April 2009) The mechanisms underpinning potentially anti-atherogenic PPARγ-agonist generation during low-intensity exercise: a molecular rationale for prescribing exercise to patients?

    • HEFCW Postgraduate PhD Scholarship (£110K; awarded Oct 2007) The Role of CLA in PPAR-activated gene expression, with relation to low-intensity exercise, markers of inflammation and cardiovascular disease.

    Collaborators:- Investigators

    • Welsh Diabetes Research Network

    • Welsh Cardiovascular Interdisciplinary Research Group

    • Dr M Evans (Llandough Hospital)

    • Dr A Roberts, Dr M Ludgate (School of Medicine, Cardiff University)

    • Dr D Lang, Dr P James (Wales Heart Research Institute, Cardiff University)

    • Prof S Jackson (UWE)

    • Dr R Bracken (Swansea University)

    • Dr K Backx, Dr M Hughes (UWIC School of Sport)

    • Dr John Geen (Prince Charles Hospital, Merthyr)

    Recent publications
    Recent Publications. Investigators

    • Isa, S.A., Mainwaring, L.S., Webb. R. and Thomas, A.W. (2009): “The Non-Genomic Effects of High Doses of Rosiglitazone on Cell Growth and Apoptosis in Cultured Monocytic Cells”Bayero Journal of Pure and Applied Sciences 2(2): pp.1-8.

  • Butcher et al (2008) Low Intensity Exercise Exerts Beneficial Effects on Plasma Lipids via PPAR. J. Med Sci Sports Ex. 40 (7): 1–7

  • Caddy et al (2008) Rosiglitazone Transiently Disturbs Calcium Homeostasis in Monocytic Cells. BiochemBiophys Res Comm. 366(1):149-55

  • Atkin et al (2008) Rosiglitazone-Induced SERCA2b Inhibition: Implications for MonocyteCytoskeletalRemodeling and Diabetic Microangiopathy. Bioscience Horizons1:1-8.

  • Khanolkar et al (2008) Rosiglitazone produces a greater reduction in circulating platelet activity compared with gliclazide in patients with type 2 diabetes mellitus-An effect probably mediated by direct platelet PPARgamma activation. Atherosclerosis 197(2):718-24

  • Moir, H., et al (2008) AMPK Inactivation in Mononuclear Cells: A Potential Intracellular Mechanism For Exercise-Induced Immunosuppression. Applied Physiology, Nutrition and Metabolism33:. 75-85

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