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- August 28, 2008 |
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"Genetics of Type 2 Diabetes and the Metabolic Syndrome?"Prof. Leif C Groop (biography)
English - 2005-04-14 - 27 minutes
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 | (30 slides) |
Summary :
Whereas diabetes can be diagnosed by measuring blood glucose, there are few laboratory tests for diagnosing diabetic subgroups like type 1 and type 2 diabetes (T2D). In general, everything which is not type 1 diabetes has been considered as type 2 diabetes. Therefore, T2D has accounted between 85-99% of all cases with diabetes around the world. This certainly represents an oversimplification of the situation and the black box known as T2D.
There is clear evidence that T2D is inherited; therefore much hope has been given to attempts to identify genetic markers which could aid in the diagnosis of T2D. Success has been limited but not lacking; probably the worst limitation has been our desire to find a simple explanation for a polygenic multifactorial disease like T2D. Several single nucleotide polymorphisms (SNPs) or combinations of them (haplotypes) have been identified in T2D individuals in genes encoding for the PPARg, calpain 10, Kir 6.2 , PGC-1a etc. Only one of them (CAPN10) was identified by a genome wide scan. For other genes like adiponectin or the uncoupling proteins, the association has been with obesity or the metabolic syndrome rather than with T2D. However, each of these genes contributes only a small proportion to the individual and population risk of T2D and this contribution seems to differ between different parts of the world. The population attributable risk for the Pro12Ala polymorphism in the PPARg gene is about 20 % whereas for the calpain 10 haplotype 14% in Mexican Americans but only 4% in Europeans. More importantly, the risk is further influenced by environmental factors like diet (PPARg ) or exercise (GYS1).
Analysis of large scale expression profiles in target tissues of patients with T2D and prediabetes has also provided new insights into the pathogenesis. Applying a novel statistical approach (Gene Set Enrichment Analysis) we could show co-ordinated 20% down regulation of genes regulating oxidative phosphorylation in patients with T2D and IGT. Gene expression correlated with aerobic capacity, which is known to predict T2D. Also, the master regulator of these genes, PGC-1 was downregulated; overexpression of PGC-1a in a muscle cell line normalized expression of these respiratory chain genes. We could also show that a genetic variant in the gene was associated with more pronounced decrease in expression of PGC-1a with aging, a finding which may explain why some people are more responsible to the deleterious effects of aging on glucose and energy metabolism.
Unfortunately, we do not yet have enough information to use these variants to support or confirm the diagnosis of T2D. For that purpose we will need large epidemiological studies in which a large number of patients and controls (>5000 each) are being typed not only for the SNPs but also for the haplotypes. These studies should also be prospective to define the risk for non-diabetic carriers of these variants to develop diabetes or for diabetic carriers to develop diabetic complications.
The rapid development of new efficient tools for high throughput genotyping will allow these data to be collected during the next years. Particularly, a gene atlas of all genetic variation in T2D should be obtained by a genome wide SNP association study.
Learning objectives :
After viewing this presentation the participant will be able to discuss:
- Metabolic disturbances leading to type 2 diabetes
- Some important susceptibility genes for type 2 diabetes
Bibliographic references :
Charlotte Ling, Pernille Poulsen, Emma Carlsson, Martin Ridderstråle, Peter Almgren, Jørgen Wojtaszewski, Henning Beck-Nielsen, Leif Groop and Allan VaagMultiple environmental and genetic factors influence skeletal muscle PGC-1(alpha) and PGC-1ß gene expression in twins
J. Clin. Invest. 114:1518-1526 (2004).
Valeriya Lyssenko, Peter Almgren, Dragi Anevski, Roland Perfekt, Kaj Lahti, Michael Nissén, Bo Isomaa, Björn Forsen, Nils Homström, Carola Saloranta, Marja-Riitta Taskinen, Leif Groop, and Tiinamaija Tuomi for the Botnia Study Group Predictors of and Longitudinal Changes in Insulin Sensitivity and Secretion Preceding Onset of Type 2 Diabetes
Diabetes 54:166-174, 2005.
Vamsi K Mootha, Cecilia M Lindgren, Karl-Fredrik Eriksson, Aravind Subramanian, Smita Sihag, Joseph Lehar, Pere Puigserver, Emma Carlsson, Martin Ridderstråle, Esa Laurila, Nicholas Houstis, Mark J Daly, Nick Patterson, Jill P Mesirov, Todd R Golub, Pablo Tamayo, Bruce Spiegelman, Eric S Lander, Joel N Hirschhorn, David Altshuler & Leif C GroopPGC-1-(alpha) responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes
Nature Genetics 34, 267 - 273 (2003).
David Altshuler, Joel N. Hirschhorn, Mia Klannemark, Cecilia M. Lindgren, Marie-Claude Vohl, James Nemesh, Charles R. Lane, Stephen F. Schaffner, Stacey Bolk, Carl Brewer, Tiinamaija Tuomi, Daniel Gaudet, Thomas J. Hudson, Mark Daly, Leif Groop & Eric S. LanderThe common PPAR(gamma) Pro12Ala polymorphism is associated with decreased risk of type 2 diabetesNature Genetics.2000;volume 26 no. 1 pp 76 - 80.
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