Dr. Musselman focused on the effects of a high sugar diet on hyperglycemia and insulin sensitivity in the fruit fly Drosophila melanogaster. Work done with the support of this training grant defined a novel model of type 2 diabetes in the fly. New methods were developed both independently by the trainee as well as in collaboration with core facilities on site. These methods enabled complete characterization of affected flies that compares favorably with methods used to diagnose humans with insulin resistance. Genetic tools were used to rapidly screen pathways that may play a role in the pathophysiology of diet-induced type 2 diabetes, and novel players were identified that were previously unknown to contribute to insulin sensitivity in any organism. Training included significant exposure to human pathophysiology to provide a broad disease-focused context for the fly type 2 diabetes model. Dr. Musselman has four publications (two first author) from this training. She has won several awards, joined the Wash U faculty in 2011, and competed successfully for Diabetes Research Center (DRC) Pilot and Feasibility funding as well as funds from private foundations. In late 2014, Dr. Palanker accepted an attractive startup package and joined the faculty as an Assistant Professor on the tenure track at Binghamton University in New York.
BIRCWH Scholar from 07/01/2011 until 08/30/2014
Hormonal control of diet-induced type 2 diabetes in Drosophila
Nuclear hormone receptors (NHRs) play important roles in women’s health and disease. These transcription factors regulate a woman’s risk of developing type 2 diabetes (T2D) and its complications, including cardiovascular defects and infertility, as well as breast, ovarian, and endometrial cancers. We have developed a Drosophila model of T2D where a high sugar diet induces hyperglycemia and insulin resistance in larvae. This model compares favorably with data in rodents and humans where a high glycemic diet is also associated with T2D, particularly in women. I propose to exploit this Drosophila model to understand more about the role of nuclear hormone receptors (NHRs) in T2D. NHRs are of interest to me for several reasons. As described below, NHRs function in insulin resistance and other diseases in women. Their known ligands are hormones and other lipids, and their targets include enzymes with roles in almost every metabolic pathway. NHR expression and activity appear to be central to the larva’s response to high sugar feeding. NHR mRNA levels vary with hyperglycemia and insulin resistance in the fat body. Transcriptional network analysis places NHRs in nodes that appear to control several metabolic pathways in the presence of insulin resistance. I hypothesize that NHRs play a central role in the pathophysiology of diet-induced modeled type 2 diabetes. After characterizing all NHRs via expression and activation analyses, I will ID those receptors most likely to function in insulin sensitivity. Next, I will test NHR loss-of-function in a tissue-specific manner to search for effects on insulin sensitivity. Insight into the interactions between the NHR and insulin signaling pathways is expected to provide insight into female-specific mechanisms of type 2 diabetes.