Project Summary / Abstract This proposal aims to develop the applicant into an independent physician-scientist in the field of diabetes and metabolism. The principal investigator Dr. Jing Hughes has undergone PhD training in the basic biological sciences and completed clinical training in internal medicine and the endocrinology subspecialty. The proposed 5-year career development plan will build on Dr. Hughes's experiences in endocrinology and provide her with further expertise in the design and conduct of basic diabetes research. Dr. Hughes's long-term goal is to establish an independent laboratory dedicated to studying islet biology, with a goal to discover new endocrine and paracrine pathways modulating islet hormone secretion. The central guidance and training environment for this project will be provided by the mentor, Dr. David W. Piston, who is the Chair of Cell Biology at Washington University, also a recognized leader in islet physiology and imaging expert. Dr. Piston has an excellent track record for training physician-scientists, especially at the incipient stages of their careers. In addition to Dr. Piston's mentoring, Dr. Hughes will be able to take advantage of the rich resources available at Washington University, including scientific as well as career guidance from her faculty advisory committee and collaborators. The research set forth herein seeks to address how brown fat restores glucose balance by modulating glucagon secretion in diabetic animals. In the past few years, the Piston laboratory has revolutionized thinking about islet physiology by demonstrating new and unexpected roles in diabetes modulation by alpha cell hormones. We now examine the mechanism by which factors secreted by brown adipose tissue act on alpha cells to regulate glucagon production, a phenomenon that has never before been investigated. Dr. Hughes will use a proteomics strategy to identify the brown adipose factor and test the hypothesis that its effect on glucagon suppression is mediated through GPCRs on islet cells. The proposed studies have the potential to provide proof-of-principle for novel translational treatments and reduce suffering from diabetes. This K08 mentored research award will provide the necessary resources for Dr. Hughes to complete these studies and to develop the necessary intellectual foundation and skill set as an independent diabetes investigator.