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- December 1, 2008 |
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"Microvascular Complications of Type 2 Diabetes: New Insight into Pathogenesis and Risk Reduction"Dr. Luigi Gnudi (biography)
English - 2005-06-18 - 44 minutes
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Summary :
In this presentation Dr. Gnudi discusses experimental evidence providing new insight into the pathogenesis of microvascular complications of diabetes, with a focus on kidney disease, and new therapeutic opportunities addressing root causes.
In the UKPDS, a trend was observed for increasing risk of CV death with increasing diabetic nephropathy (1), and excess mortality has been associated with hypertension and proteinuria in type 2 diabetes (2). In a recent study it was also reported that raised albumin creatinine ratio was associated with higher aortic pulse wave pressure in type 2 diabetic patients, and this relationship was likely mediated by increased blood pressure (3).
Haemodynamic and metabolic perturbations are important contributors in the development of diabetic glomerulosclerosis, and studies conducted by Dr. Gnudi's group suggest a link between these 2 kinds of factors. GLUT-1 and TGFbeta -1 protein expression were found to be upregulated in the glomeruli of hypertensive Dahl salt-sensitive rats, which exhibit intraglomerular hypertension (4). Further, when human mesangial cells were subjected to mechanical stretching as a type of haemodynamic perturbation, there was an upregulation of GLUT-1 protein and basal glucose transport that was prevented by treatment with an anti-TGFbeta-1- neutralizing antibody, suggesting a cause-effect relationship (4).
Diabetic nephropathy is characterized by early infiltration of macrophages within the glomeruli, paralleled by an increase in cytokines such as MCP-1. In a recently published paper it was reported that human mesangial cell stretching also induced monocyte chemotaxis due to upregulation of MCP-1, which was prevented by inhibition of NF-kB, an important transcription factor for MCP-1 (5).
Turning to treatment of diabetic patients, Dr. Gnudi discusses classic and modern approaches. In the RENAAL Study, proteinuria was found to be a determinant of renal events in patients with type 2 diabetes, and the antiproteinuric response to treatment with an ARB lowered that risk (6). Proteinuria is also reduced with ACE inhibitors (7). Dr. Gnudi further reviews important results from the Steno-2, UKPDS and BENEDICT studies showing the effects of different therapies on microvascular outcomes.
With regards to new therapeutic opportunities, relatively new data show favourable anti-inflammatory effects in the kidney and prevention of albuminuria with rosiglitazone treatment in an experimental diabetes model. In the previously mentioned study by Gruden et al. on human mesangial cell stretching, rosiglitazone significantly reduced stretch-induced NF-kB DNA binding, MCP-1 production and monocyte chemotaxis (5). Dr. Gnudi also presents data on combination therapy with rosiglitazone and metformin in terms of the effect on ACR and blood pressure. These and other findings suggest that interventions targeting the root causes of microvascular complications may further strengthen therapeutic and preventive strategies.
Copyright © 2005 E-MedHosting.com Inc.
Learning objectives :
After viewing this presentation the participant will be able to discuss:
- Experimental evidence suggesting a mechanism of interaction between haemodynamic and metabolic factors in the pathogenesis of glomerular injury
- Classic and modern therapeutic approaches to reduce the risk of microvascular complications in diabetes
- New therapeutic opportunities addressing the root causes of microvascular complications
Bibliographic references :
1. Amanda I. Adler, Richard J. Stevens, Sue E. Manley, Rudy W. Bilous, Carole A. Cull, and Rury R. Holman, on behalf of the UKPDS GROUP Development and progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study (UKPDS 64)Kidney International. Volume 63 Issue 1 Page 225 - January 2003.
2. SL Wang, J Head, L Stevens and JH Fuller. Excess mortality and its relation to hypertension and proteinuria in diabetic patients. The world health organization multinational study of vascular disease in diabetes Diabetes Care. 1996;19(4):305-312.
3. Andrew Smith, Janaka Karalliedde, Lorenita De Angelis, David Goldsmith and Giancarlo Viberti Aortic Pulse Wave Velocity and Albuminuria in Patients with Type 2 Diabetes J Am Soc Nephrol 16: 1069-1075, 2005.
4. Luigi Gnudi; GianCarlo Viberti; Leopoldo Raij; Veronica Rodriguez; Davina Burt; Pedro Cortes; Barry Hartley; Stephen Thomas; Sabrina Maestrini; Gabriella Gruden GLUT-1 Overexpression: Link Between Hemodynamic and Metabolic Factors in Glomerular Injury? Hypertension. 2003;42:19.
5. Gabriella Gruden, Giorgia Setti, Anthea Hayward, David Sugden, Sara Duggan, Davina Burt, Robin E. Buckingham, Luigi Gnudi and Giancarlo VibertiMechanical Stretch Induces Monocyte Chemoattractant Activity via an NF-B-Dependent Monocyte Chemoattractant Protein-1-Mediated Pathway in Human Mesangial Cells: Inhibition by Rosiglitazone J Am Soc Nephrol 16: 688-696, 2005.
6. Dick de Zeeuw, Giuseppe Remuzzi, Hans-Henrik Parving, William F. Keane, Zhongxin Zhang, Shahnaz Shahinfar, Steve Snapinn, Mark E. Cooper, William E. Mitch, and Barry M. Brenner
Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL Kidney International.Volume 65 Issue 6 Page 2309 - June 2004.
7. Palla R, Panichi V, Finato V, Parrini M, Andreini B, Bianchi AM, Giovannini L, Migliori M, Bertelli AA Effect of increasing doses of lisinopril on proteinuria of normotensive patients with IgA nephropathy and normal renal function. Int J Clin Pharmacol Res. 1994;14(1):35-43.
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