Abstract

Type 2 diabetes (T2D) is a common disease in humans leading to serious adverse consequences. While a number of drugs are available to ameliorate the consequences of T2D, to date none is available that modifies the course of T2D. In T2D there are three key organ targets for drug discovery: pancreatic islets with the goal to enhance glucose mediated insulin secretion, the liver to enhance insulin mediated suppression of hepatic glucose release and skeletal muscle to enhance insulin mediated glucose uptake. Mice are used for testing drug candidates, but it is unlikely that any one mouse model is ideal for all three organ targets in humans with T2D.

We plan to establish the mouse model most closely aligned with humans with T2D for each target organ. We will use an unbiased statistical approach to establish the most closely matched transcriptome for each target organ from several widely available mouse models with that in humans with T2D. We will then analyze the interaction between genes in best matched diseased tissue to identify key hub genes (an approach proven effective in uncovering targets for drug discovery), and validate their role in tissue function.

The proposed research will provide novel tissue-specific insights into the merits of available murine models for T2D and empower investigators to select the most relevant model to screen drug candidates.