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"Anti-atherogenic Effects of PPAR gamma Activators – From Bench to Bedside"Prof. Nikolaus Marx (biography)
English - 2005-09-14 - 32 minutes
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Summary :
During this presentation Prof. Marx talks about the role of peroxisome proliferator-activated receptor gamma (PPARγ) activators in vascular disease.
PPARγ activators are regulators of gene expression in adipocytes and in muscle, increasing insulin sensitivity and modulating glucose homeostasis (1). PPARγ which is activated by thiazolidinediones (TZDs/glitazones), has been found to be expressed in all kinds of vascular cells (2-4).
Atherogenesis is an inflammatory process in the vessel wall that starts with endothelial dysfunction, followed by fatty streak formation and finally the formation of an advanced, potentially complicated lesion. In terms of endothelial dysfunction, diabetic patients exhibit accelerated monocyte recruitment into the vessel wall, due to high levels of advanced glycation end-products (AGEs) which bind to their receptors (RAGEs) on the surface of endothelial cells. This interaction leads to endothelial cell activation, subsequent release of chemokines and monocyte recruitment. Endothelial RAGE expression has been found to be reduced (5) and vascular smooth muscle cell migration inhibited (6), by PPARγ activators of the TZD class.
The vulnerability of a plaque is determined by thinning of the fibrous cap, which in turn is to a large extent determined by the release of matrix-degrading enzymes (MMPs) from the foam cells underneath. The expression of one of these enzymes, MMP-9, was found to be inhibited by troglitazone in human macrophages (2), and this might be a mechanism whereby glitazones protect against plaque rupture.
Turning to clinical data in patients with type 2 diabetes, glitazone treatment has been associated with reduced serum levels of inflammatory biomarkers (7-9), and improved endothelium-dependent vasodilation (10). Further, glitazone treatment was found to reduce in-stent restenosis in type 2 diabetic patients with coronary artery disease (CAD) (11). To what extent could this improvement in restenosis be due to improvement in glycemic control? Of interest are results from the Pioglitazone and ultrasound evaluation (PIUS) trial in which nondiabetic patients with CAD who were treated with pioglitazone had a significant reduction in neointima volume after coronary stenting, independently of any significant metabolic effects.
Copyright © 2005 E-MedHosting.com Inc.
Learning objectives :
After viewing this presentation the participant will be able to discuss:
PPARγ activators – background
PPARγ activators – anti-atherogenic effects
-- in vitro
-- in vivo
Bibliographic references :
1. Nikolaus Marx, Hélène Duez, Jean-Charles Fruchart, Bart Staels Peroxisome Proliferator-Activated Receptors and Atherogenesis: Regulators of Gene Expression in Vascular Cells Circulation Research. 2004;94:1168.
2. Nikolaus Marx, Galina Sukhova, Curran Murphy, Peter Libby and Jorge Plutzky Macrophages in Human Atheroma Contain PPAR{gamma}: Differentiation-Dependent Peroxisomal Proliferator-ActivatedReceptor {gamma} (PPAR{gamma}) Expression and Reduction of MMP-9 Activity through PPAR{gamma} Activation in Mononuclear Phagocytes inVitro American Journal of Pathology. 1998;153:17-23.
3. Nikolaus Marx; Todd Bourcier; Galina K. Sukhova; Peter Libby; Jorge PlutzkyPPAR{gamma} Activation in Human Endothelial Cells Increases Plasminogen Activator Inhibitor Type-1 Expression: PPAR{gamma} as a Potential Mediator in Vascular Disease Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:546-551.
4. Nikolaus Marx, Bettina Kehrle, Klaus Kohlhammer, Miriam Grüb, Wolfgang Koenig, Vinzenz Hombach, Peter Libby, Jorge Plutzky PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes: Implications for Atherosclerosis and Transplantation-Associated Arteriosclerosis Circulation Research. 2002;90:703.
5. Nikolaus Marx, Daniel Walcher, Nina Ivanova, Kirstin Rautzenberg, Annelie Jung, Reinhard Friedl, Vinzenz Hombach, Raffaele de Caterina, Giuseppina Basta, Marie-Paule Wautier, and Jean-Luc Wautiers Thiazolidinediones Reduce Endothelial Expression of Receptors for Advanced Glycation End Products Diabetes 53:2662-2668, 2004.
6. Nikolaus Marx, Uwe Schönbeck, Mitchell A. Lazar, Peter Libby, , Jorge PlutzkyPeroxisome Proliferator-Activated Receptor Gamma Activators Inhibit Gene Expression and Migration in Human Vascular Smooth Muscle Cells Circulation Research. 1998;83:1097-1103.
7. Pfutzner A, Marx N, Lubben G, Langenfeld M, Walcher D, Konrad T, Forst T.Improvement of Cardiovascular Risk Markers by Pioglitazone Is Independent From Glycemic Control: Results From the Pioneer Study Journal of the American College of Cardiology.Volume 45, Issue 12 , 21 June 2005, Pages 1925-1931.
8. Nikolaus Marx; Johannes Froehlich; Laila Siam; Jochen Ittner; Gerhard Wierse; Arnold Schmidt; Hubert Scharnagl; Vinzenz Hombach; Wolfgang KoenigAntidiabetic PPAR{gamma}-Activator Rosiglitazone Reduces MMP-9 Serum Levels in Type 2 Diabetic Patients With Coronary Artery Disease Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:283.
9. Nikolaus Marx, MD; Armin Imhof, MD; Johannes Froehlich, MS; Laila Siam, MS; Jochen Ittner, MD; Gerhard Wierse, MD; Arnold Schmidt, MD; Winfried Maerz, MD; Vinzenz Hombach, MD; Wolfgang Koenig, MDEffect of Rosiglitazone Treatment on Soluble CD40L in Patients With Type 2 Diabetes and Coronary Artery Disease Circulation. 2003;107:1954.
10. Dandona P. Diabetologia 2001; 44 (Suppl 1): A36, Abs 136.
11. Donghoon Choi, MD, PHD, Soo-Kyung Kim, MD, Sung-Hee Choi, MD, Young-Guk Ko, MD, Chul-Woo Ahn, MD, PHD, Yangsoo Jang, MD, PHD, Sung-Kil Lim, MD, PHD, Hyun-Chul Lee, MD, PHD1, and Bong-Soo Cha, MD, PHD. Preventative Effects of Rosiglitazone on Restenosis After Coronary Stent Implantation in Patients With Type 2 Diabetes Diabetes Care 27:2654-2660, 2004.
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