We propose to study a unique canine disease model to develop new therapeutic strategies and a new comparative biology approach to understanding proglucagon biology, which has broad implications in the treatment of a variety of metabolic diseases in animal and human populations alike. The proglucagon-derived hormones, glucagon, and glucagon-like peptide-1 (GLP-1) are key metabolic regulators. Glucagon acts to increase hepatic glucose output and defend against hypoglycemia, whereas GLP-1 acts to improve islet function and insulin sensitivity. Despite our advancing knowledge of these key metabolic hormones, significant gaps in our understanding of these hormones exist, limiting our ability to target these for the treatment of metabolic disease. Fortunately, glucagon and GLP-1 are evolutionarily conserved among almost all mammals, making this field ideal for the use of comparative biology approaches. Hepatocutaneous syndrome (HCS) is a devastating disease of dogs that was initially discovered at Cornell in 1986. Canine HCS bears striking similarities with necrolytic migratory erythema (NME) in humans. Both of these diseases involve amino acid (AA) dysregulation, painful skin lesions, and diabetes mellitus (DM). While the pathophysiology of NME in humans has largely been attributed to dysregulation of proglucagon-derived hormones levels leading to AA dysregulation, the underlying pathophysiologic drivers of HCS in dogs remain poorly defined. Comparisons of four groups, dogs with HCS, HCS-DM, DM, and healthy control dogs, will define proglucagon-derived hormone responses in HCS and HCS-DM using validated ELISAs. We hypothesize that dogs with HCS have abnormal glucagon and GLP-1 fasting concentrations and postprandial (meal-induced) responses. Furthermore, that greater perturbations in proglucagon responses are associated with HCS-DM and more profound plasma AA abnormalities. Two independent specific aims test our hypothesis. (1) To determine if dogs with HCS have abnormal plasma glucagon and GLP-1 concentrations and (2) To determine if plasma proglucagon-derived hormone concentrations differ in dogs with HCS compared to HCS-DM or DM and evaluate relationships with plasma amino acid concentrations. The Loftus and Cummings labs are uniquely positioned to collaboratively execute this study through complementary expertise and the utilization of high-quality assays for these hormones that are validated for the dog. These results will further our understanding of HCS pathophysiology and are applicable to other forms of insulin resistance in the dog. Should the data support our hypothesis, GLP-1 mimetics pose a rational therapeutic option for dogs with diabetic HCS (and other forms of DM) that may also improve AA homeostasis through inhibition of glucagon. Furthermore, this work sets the stage to use HCS as a novel model of understanding proglucagon biology that has broad implications for other conditions ranging from DM to gastrointestinal disease. Finally, this proposal also maintains the legacy of Cornell in the investigation of this syndrome.