Kim, Jung2015-11-062015-11-062015-08https://hdl.handle.net/11299/175213University of Minnesota Ph.D. dissertation. August 2015. Major: Biological Science. Advisor: Thomas Neufeld. 1 computer file (PDF); iv, 82 pages.Secreted ligands of the insulin family promote cell growth and maintain sugar homeostasis. Insulin release is tightly regulated in response to dietary conditions, but how insulin producing cells (IPCs) coordinate their responses to distinct nutrient signals is unclear. Here I show that regulation of insulin secretion in Drosophila larvae has been segregated into distinct branches: circulating sugars selectively promote the release of Drosophila insulin-like peptide 3 (Dilp3), whereas amino acids selectively promote secretion of Dilp2. Dilp3 is uniquely required for sugar-mediated activation of TOR signaling and suppression of autophagy in the larval fat body. Sugar levels are not sensed directly by the IPCs, but rather by the adipokinetic hormone (AKH)-producing cells of the corpora cardiaca, and I demonstrate that AKH signaling is required in the IPCs for sugar-dependent Dilp3 release. Thus, IPCs integrate multiple cues to regulate secretion of distinct insulin subtypes under varying nutrient conditions. The sensitivity of insulin signaling determines the activity of insulin in the presence of insulin, and misregulation of insulin sensitivity leads to metabolic diseases such as type-2 diabetes. Mechanical stress is a known regulator of insulin sensitivity, but the mechanisms by which mechanical stress regulates insulin sensitivity are unclear. Here, I showed that mechanical stress is required for activation of insulin signaling in the Drosophila larval fat body both ex vivo and in vivo. Interestingly, mechanical stress affects most of components in the insulin pathway: localization of insulin receptor (InR), chico, and lnk, and the activities of PI3K, AKT, and TOR. I demonstrated that integrin signaling, previously shown to sense mechanical stress, is necessary for the insulin- and mechanical stress-dependent activation of TOR. Together, my data suggest that mechanical stress sensed by integrin signaling regulates insulin sensitivity by altering upstream components of insulin signaling, such as InR, chico and lnk.enAKHDilpDrosophilaInsulin signalingTOR signalingtrehaloseThesis or Dissertation