Glucocorticoids (GCs) are often prescribed for the treatment of inflammatory diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and psoriasis
[1–3]. Despite their excellent efficacy, usage is limited because of side-effects such as insulin resistance, glucose intolerance, diabetes, central adiposity, dyslipidemia, skeletal muscle wasting and osteoporosis
GCs bind to the glucocorticoid receptor (GR), which then dimerizes and translocates to the nucleus where it influences gene transcription. Positive regulation of genes (transactivation) is mainly mediated by direct binding of the GR-GC complex to glucocorticoid response elements located in the regulatory region of a target gene. The GR-GC complex may also bind to negative glucocorticoid response elements, which leads to a negative regulation of genes (transrepression). It is believed that transrepression, in which proinflammatory genes are downregulated, is mainly responsible for the efficacy of GCs as anti-inflammatory drugs
[5, 7], while transactivation might be responsible for the GC-induced adverse effects
An important side effect is the development of insulin resistance (IR), because it is the onset of many metabolic diseases and conditions such as obesity, diabetes mellitus and hypertension. IR is a physiological condition in which a given concentration of insulin produces a less-than-expected biological effect. These biological effects are different depending on the tissue in which they occur. For instance, under IR conditions, fat and muscle cells fail to adequately respond to circulating insulin, which results in reduced glucose uptake, and subsequently higher glucose levels in blood
[10, 11]. In liver cells the IR- effects can be seen in reduced glycogen synthesis and storage, and a failure to suppress glucose production and release into the blood.
One way by which GCs induce IR is by inhibition of the recruitment of GLUT4 glucose transporter, which results in reduced insulin-stimulated glucose transport in skeletal muscle
. However, not all mechanisms involved in GC-induced side effects are not completely understood. To gain more insight into mechanisms behind GC induced IR, it is important to understand which genes play a role in the development of insulin resistance and which genes are affected by GCs.
It has been widely recognized that a system approach in which networks of genes in their functional context are studied, contributes to a better understanding of the mechanisms and pathways related to the disease and the drug effects
[13–17]. To study a gene network related to a disease such as IR, a list of disease related genes as well as a notion of the interactions between these genes is needed.
Literature databases such as Medline contain many studies about IR and the molecular effects of synthetic glucocorticoids and thus are a good resource that can be used to create and study disease related gene networks.
The retrieval of relevant gene-disease associations out of the millions of abstracts in Medline is very labor intensive and thus a text mining system is needed to this in an automated fashion.
In previous work we reported about CoPub
[18–20], a publicly available text mining system, which has successfully been used for the analysis of microarray data and in toxicogenomics studies
[21–26]. CoPub calculates keyword co-occurrences in titles and abstracts from the entire Medline database, using thesauri for genes, diseases, drugs and pathways. We used this technology to develop CoPubGene, a rapid gene – disease network building tool. To evaluate the importance of genes in these networks we implemented a method to score the importance of genes in biological processes of interest by incorporating their functional neighborhood.
We used CoPubGene to create a network of genes related to insulin resistance and to evaluate the importance of the genes in this network for glucocorticoid induced metabolic side effects and anti-inflammatory processes.
By using this method, we identified several genes that already are considered markers of GC induced IR, such as phosphoenolpyruvate carboxykinase (PCK) and glucose
phosphatase, catalytic subunit (G6PC)
[27, 28]. Even more importantly, we were able to identify genes involved in steroid synthesis that have not yet been recognized as mediators of GC induced IR.