Development of a platform to screen for insulin signaling pathway components
We have developed a model of diet-induced type 2 diabetes in Drosophila. High sugar-fed animals develop hyperglycemia, insulin resistance, increased free fatty acid levels, cardiac arrhythmia, and obesity. Recent data demonstrates the importance of insulin signaling and resistance in the fat body, a liver-like organ that stores fat and develops insulin resistance in response to rearing on high sugar diets. Insulin resistance itself is a complication of poorly controlled type 2 diabetes, and leads to unique pathophysiology or complications in each organ. We propose to use RNA-seq to characterize fat bodies with insulin receptor loss- and gain-of-function. These results will enable us to identify the transcriptionally regulated targets that act as sensors of the degree of insulin signaling. Transgenic “insulin reporter” flies will be generated to enable screening for novel factors that affect the strength of signaling along the pathway in any tissue of interest. We will use these reporters to test which tissues become insulin resistant in our high sugar feeding model of type 2 diabetes. In addition, gene ontology and homology searches will be done to gain insight into the mechanisms by which insulin signaling might influence seemingly unrelated pathways, like growth, the immune response, and longevity. The reporters we develop will enable mechanistic studies of the pathophysiology of diabetic complications in multiple tissues.

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