The Influence of Genetics and Epigenetics on the Development of Diabetes

Coordinators:

Annette Schürmann | Johannes Beckers | Martin Hrabě de Angelis

Genetic predisposition, diet and physical activity are factors that influence the occurrence of type 2 diabetes. Lifestyle not only has a direct effect on the metabolism, but can also lead to long-term changes in the expression of metabolically relevant genes via epigenetic mechanisms.

In this research focus, researchers are looking for genes that are important for metabolism. If the expression of these genes is disturbed due to mutations, this can lead to an increased risk of diabetes. DZD researchers have already succeeded in identifying more than 50 new genes that have an impact on metabolism. However, it is not only the genetic code itself that influences the risk of diabetes. Lifestyle can also influence the extent to which certain genes are transcribed (epigenetics). Anyone who eats an unhealthy diet or smokes for a long time, or by contrast has a healthy lifestyle, influences their genetic makeup. Such changes can occur, for example, in intestinal, fat or liver cells, but also in sperm and egg cells.

This academy is dedicated to the study of genetic and epigenetic mechanisms in metabolism in animal models and human samples, and to correlate observations and results. Furthermore, based on epidemiologically or clinically observed correlations, animal models are being developed to elucidate possible (epi-)genetic mechanisms. One aspect is the investigation of treatment methods for epigenetically caused disorders. Presumably there are certain time windows in which a reversal of epigenetic information can take place.

The researchers are working on the following tasks:

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  • Identification of (epi-)genetic changes and their effects on diabetes in animal models
  • Demonstration of the relevance of the novel genetic and epigenetic elements in patients and cohorts
  • Validation of epidemiological correlations and results of clinical studies in animal models
  • Evaluation of interventions that are sufficient to influence epigenetic mechanisms

Current findings
With Pop4, the DZD scientists have identified a gene in cultured beta cells that could be responsible for reduced insulin production. The expression of the gene correlated with the amount of insulin. Mouse studies shall provide more information.

Parental lifestyle influences offspring phenotype
Researchers have shown that parental lifestyle influences the phenotype of offspring through epigenetic mechanisms. Parental mutations in epigenetic factors such as the histone demethylases Kdm1a and Kdm6a, the DNA methyltransferase Dnmt1, the chromatin remodeling protein Smarca5, or the core component of the PRC2 histone methyltransferase complex play a role here. This can affect the metabolic health and cancer susceptibility of the offspring.

An important aspect of the Academy's work is research into treatment methods for epigenetically caused disorders. For example, the DZD investigated epigenetic, metabolic and gene expression changes after bariatric surgery: initially, despite weight loss, unfavorable metabolic changes occur after surgery, and insulin sensitivity remains impaired. However, 52 weeks after surgery, epigenetic changes in genes involved in muscle energy metabolism were found, which should contribute to long-term improvement in insulin sensitivity.

Publications

Epigenetic Changes in Islets of Langerhans Preceding the Onset of Diabetes. Diabetes (2020), DOI: doi.org/10.2337/db20-0204

Single-cell tracing dissects regulation of maintenance and inheritance of transcriptional reinduction memory.  Mol Cell (2020), DOI: 10.1016/j.molcel.2020.04.016

iTAG-RNA Isolates Cell-Specific Transcriptional Responses to Environmental Stimuli and Identifies an RNA-Based Endocrine Axis.  Cell Rep (2020), DOI: https://doi.org/10.1016/j.celrep.2020.02.020

Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity. J Clin Invest. (2020), DOI: 10.1172/JCI136363

Histone deacetylase 5 regulates interleukin 6 secretion and insulin action in skeletal muscle. Mol Metab (2020), DOI: 10.1016/j.molmet.2020.101062

Dynamic changes of muscle insulin sensitivity after metabolic surgery. Nature Communications (2019), DOI: 10.1038/s41467-019-12081-0

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nature Genetics (2019), DOI: 10.1038/s41588-018-0334-2

Prof. Dr. Annette Schürmann, Head DZD Academy Genetics and Epigenetics

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Talk at the 10th anniversary celebration of the DZD on June 24, 2019 in Berlin (in English).

Members of the Academy

Hadi Al-Hasani, DDZ
Johannes Beckers, HMGU
Alexandra Chadt, DDZ
Fabian Eichelmann, DIfE
Harald Grallert, HMGU
Martin Hrabě de Angelis, HMGU
Henriette Kirchner, Lübeck
Meriem Ouni, DIfE
Fabiana Perocchi, HMGU
Robert Schneider, HMGU
Tim Schulz, DIfE
Matthias Schulze, DIfE
Annette Schürmann, DIfE
Michele Solimena, PLID
Raffaele Teperino, HMGU
Henriette Uhlenhaut, HMGU
Heike Vogel, DIfE