FGFR5 expression in pancreatic beta-cells promotes maturity and glucose-stimulated metabolism "
Vidhant Pal (1); Romario Regeenes (1); Dawn M. Kilkenny (1); Jonathan V. Rocheleau (1)
Institute of Biomaterials and Biomedical Engineering, University of Toronto
The role of Fibroblast growth factor receptors 5 (FGFR5) in pancreatic beta cell physiology has yet to be fully understood. A recently published study revealed increased FGFR5 expression in mature, glucose responsive cells compared to non-responsive cells. We hypothesize that FGFR5 expression promotes beta-cell function and maturity and therefore is a therapeutic target for the treatment of metabolic disorders such as type 2 diabetes. Our studies focus on identifying the contribution of FGFR5 in regulating normal glucose metabolism. We first explored how FGFR5 overexpression affects the glucose-stimulated metabolism of insulin-secreting cell lines (e.g. INS1E, MIN6) using a newly developed genetically encoded sensor for NADPH/NADP+ redox state (Apollo-NADP+ sensor). We show that FGFR5 expression increases the dynamic range of the glucose-stimulated NADPH response (i.e., reduced NADPH response to low glucose and elevated NADPH response to high glucose, as compared to control cells). qPCR analysis revealed FGFR5 expression changes the expression of transcripts relevant to beta cell metabolism (e.g., Glucokinase, PKM2, Fatty acid synthase) and beta-cell maturation (e.g., p16, Urocortin 3). Our results suggest that FGFR5 expression positively correlates with beta-cell glycolytic flux and maturation. We are currently translating these studies to ex vivo islets using microfluidic-based adenovirus transduction (termed “HEAT-on-a-chip”), which will allow for optimized FGFR5 expression in the context of the islet’s native architecture. Collectively, we propose that regulating FGFR5 activity to drive beta-cells to a mature phenotype, will enhance glucose stimulated insulin secretion and cell survival, and is a relevant strategy in the treatment and prevention of metabolic disorders.