Network screening of Goto-Kakizaki rat liver microarray data during diabetic progression

Type 2 diabetes mellitus (T2DM) is a complex systemic disease, with significant disorders of metabolism. The liver, a central energy metabolic organ, plays a critical role in the development of diabetes. Although gene expression levels are able to be measured via microarray since 1996, it is difficult to evaluate the contributions of one altered gene expression to a specific disease. One of the reasons is that a whole network picture responsible for a specific phase of diabetes is missing, while a single gene has to be put into a network picture to evaluate its importance. In the aim of identifying significant transcriptional regulatory networks in the liver contributing to diabetes, we have performed comprehensive active regulatory network survey by network screening in 4 weeks (w), 8-12 w, and 18-20 w Goto-Kakizaki (GK) rat liver microarray data.

We identify active regulatory networks in GK rat by network screening in the following procedure. First, the regulatory networks are compiled by using the known binary relationships between the transcriptional factors and their regulated genes and the biological classification scheme, and second, the consistency of each regulatory network with the microarray data measured in GK rat is estimated to detect the active networks under the corresponding conditions. The comprehensive survey of the consistency between the networks and the measured data by the network screening approach in the case of non-insulin dependent diabetes in the GK rat reveals: 1. More pathways are active during inter-middle stage diabetes; 2. Inflammation, hypoxia, increased apoptosis, decreased proliferation, and altered metabolism are characteristics and display as early as 4 weeks in GK strain; 3. Diabetes progression accompanies insults and compensations; 4. Nuclear receptors work in concert to maintain normal glycemic robustness system.

Notably this is the first comprehensive network screening study of non-insulin dependent diabetes in the GK rat based on high throughput data of the liver. Several important pathways have been revealed playing critical roles in the diabetes progression. Our findings also implicate that network screening is able to help us understand complex disease such as diabetes, and demonstrate the power of network systems biology approach to elucidate the essential mechanisms which would escape conventional single gene-based analysis.