Type 2 diabetes is a polygenic disease characterized by hyperglycaemia due to impaired pancreatic beta-cell function and insulin resistance in peripheral target tissues such as skeletal muscle, adipose tissue and the liver. The disease develops as a conspiracy between the genetic background and the environment. Recent genome-wide association studies have identified more than 40 genetic variants associated with type 2 diabetes. Moreover, ageing, physical inactivity and obesity represent non-genetic risk factors for type 2 diabetes. However, the interaction between genes and environment may also involve epigenetic factors, such as DNA methylation and histone modifications, to promote type 2 diabetes. Indeed, recent studies from our group and others propose that epigenetic factors may play an important role in the growing incidence of type 2 diabetes. We have previously shown that age, diet, birth weight, physical activity and genetic variation influence DNA methylation of candidate genes for type 2 diabetes in human skeletal muscle. We were further the first to demonstrate that DNA methylation plays a role in gene regulation in pancreatic islets from patients with type 2 diabetes. Nevertheless, our knowledge about the epigenetic mechanisms linking environmental factors and type 2 diabetes remains limited.
The overall objective of our research is to identify the key epigenetic mechanisms influencing the pathogenesis of T2D.
We are currently analysing DNA methylation in skeletal muscle, adipose tissue and pancreatic islets of a number of human cohorts. Here, we examine if non-genetic and genetic factors as well as type 2 diabetes affect epigenetic variation in human tissues (Figure 1). We are further relating DNA methylation to gene expression, in vivo metabolism and type 2 diabetes. Histone modifications are being analysed in clonal beta-cells and human pancreatic islets.
1. Thomas Koeck, Anders H Olsson, Marloes Dekker Nitert, Vladimir V. Sharoyko, Claes Ladenvall, Olga Kotova, Erwin Reiling, Tina Rönn, Hemang Parikh, Jalal Taneera, Johan G Eriksson, Metodi D Metodiev, Nils-Göran Larsson, Alexander Balhuizen, Holger Luthman, Alena Stancáková, Johanna Kuusisto, Markku Laakso, Pernille Poulsen, Allan Vaag, Leif Groop, Valeriya Lyssenko, Hindrik Mulder and Charlotte Ling
A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.
Cell Metabolism 2011 In Press
2. Beatrice T Yang, Tasnim A. Dayeh, Clare L. Kirkpatrick, Jalal Taneera, Rajesh Kumar, Leif Groop, Claes B Wollheim, Marloes Dekker Nitert and Charlotte Ling
Insulin promoter DNA methylation correlates negatively with insulin gene expression and positively with HbA1c levels in human pancreatic islets.
Diabetologia 2011 In Press
3. Charlotte Ling and Leif Groop
Epigenetic: a molecular link between environmental factors and type 2 diabetes
Diabtees 2009, 58(12):2718-25
4. Tina Rönn, Pernilla Puolsen, Ola Hnasson, Johan Holmkvist, Peter Almgren, Peter Nilsson, Bo Isomaa, Leif Groop, Allan Vaag and Charlotte Ling
Age influences DNA methylation and gene expression of COX7AI in human skeletal muscle
Diabetologia 2008 Jul;51(7):1159-68
5. Charlotte Ling, Silvia del Guerra, Roberto Lupi, Tina Rönn, Charlotte Granhall, Holger Luthman, Pieorro Marchetti, Leif Groop, Stefano Del Prato
Epigenetic Regulation of PPARGCIA in Human Type 2 Diabetic Diabetic Islets and Effect on Insulin Secretion.
Diabetologia 2008 51(4):615-22
6. Charlotte Ling, Pernille Poulsen, Stina Simonsson, Tina Rönn, Johan Holmkvist, Peter Almgren, Emma Nilsson, Per Hagert, Amanda G. Mabey, Peter Nilsson, Allan Vaag and Leif Groop
Genetic and epigenetic ractors are associated with expression of respiratory chain component DNUFB6 in human skeletal muscle.
The Journal of Clinical Investigation, 2007 117(11):3427-35
7. Charlotte Ling, Pernilla Poulsen, Emma Carlsson, Martin Ridderstråle, Peter Almgren, Henning Beck-Nielsen, Leif Groop, Allan Vaag.
Multiple environmental and genetic factors influence skeletal muscle PGC-Ialfa and PGC-Ibeta gene expression in twins.
The Journal of Clinical Investigation, 2004; 114:1518-26.
Last updated: September 28, 2015
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