Diabetes & Metabolic Health Research Group Centre for Biomedical Science,

1. Diabetes & Metabolic Health Research Group Centre for Biomedical Science, Cardiff School of Health Sciences

2. 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.

3. 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

4. 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.

5. 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

6. Group Strategy - 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

7. Ongoing projects:- • 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]

8. Pending Funding Applications • 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).

9. Current students:- • 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)

10. Recent Funding Awards • 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.

11. Collaborators:- • 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)

12. Recent Publications. • 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