Grant: Project Grant

Diabetes is a life-threatening condition that severely impacts quality of life, health, and life expectancy. The global prevalence of diabetes and its major risk factor, obesity, are rapidly increasing, with ~1/4 Canadians diagnosed as obese and ~1/3 currently living with diabetes or prediabetes. This highlights the urgent need for preventative therapeutics. Obesity and prediabetes are characterized by metabolic deterioration associated with increased insulin resistance of tissues such as the fat and liver, and progressive dysregulation of insulin release from pancreatic beta cells. Insufficient insulin signaling causes tissues to alter their activity and secretion profiles, producing factors that promote further dysfunction. We have recently identified the Fabkin hormone complex as one such factor. Fabkin is elevated in obesity and prediabetes, and contributes to diabetes by promoting liver fat accumulation and beta cell dysfunction/death. Our studies show that antibody-based targeting of Fabkin reduces body weight and reverses diabetes in high fat diet fed mice. However, to advance therapeutic targeting of Fabkin, we require further mechanistic insight into how it works to regulate metabolism and contribute to disease. The goal of our research is to characterize the role and mechanisms of the least studied Fabkin complex component, Nucleoside Diphosphate Kinase (NDPK), in the regulation of metabolic health. We propose to use a combination of genetically modified mouse models, cell lines, and advanced molecular techniques to comprehensively determine the role of NDPK in the regulation of fat, liver, and beta cell health in the development of obesity and diabetes. Preliminary studies demonstrate that mice genetically lacking NDPK are significantly protected against these conditions. The proposed studies will facilitate development of targeted therapeutics against NDPK/Fabkin, representing a much-needed novel therapy for the prevention of obesity and diabetes.