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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 diabetesassociated 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?
• 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) .
1. PPAR exerts beneficial effects in T2D by regulating the
expression of genes involved in:a) glucose & lipid metabolism; cell differentiation.
b) inflammatory processes relevant to the progression of
Type 2 Diabetes & its complications.
2. 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
Keith Morris
(Head of group 2009-2010;
Intracellular Signalling)
(Inflammatory Biology;
Biostatistics)
•Intracellular
signalling events
triggered by exercise
in normal subjects.
•The role of the
Unfolded Protein
Response (UPR) and
ER stress in diabetes
and obesity.
• 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
Rachel Adams
(Molecular Biology)
•Effect of air borne
particles on
cardiovascular risk
markers
•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 AGERAGE interaction in
diabetes and
atherosclerosis.
(Rheology)
•Factors affecting
blood flow and
blood cell
deformability in
diabetes
Barry
McDonnell
(Vascular Biology; Early
career researcher)
• Arterial stiffness
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
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]
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).
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)
Recent Funding Awards
•
WORD Health PhD studentship (£60K; awarded
April 2009) The mechanisms underpinning potentially
anti-atherogenic PPARγ-agonist generation during lowintensity 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 lowintensity exercise, markers of inflammation and
cardiovascular disease.
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)
Recent Publications.
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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. Biochem Biophys Res Comm.
366(1):149-55
Atkin et al (2008) Rosiglitazone-Induced SERCA2b Inhibition:
Implications for Monocyte Cytoskeletal Remodeling and Diabetic
Microangiopathy. Bioscience Horizons 1:1-8.
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 Metabolism
33:. 75-85