Investigating the Role of FGFR5 in Modulating Beta-cell Metabolism
Vidhant Pal 1; Dawn Kilkenny 1; Jonathan Rocheleau 1,2
1. Institute of Biomaterials and Biomedical Engineering;
2. Toronto General Research Institute, University Health Network
There is a growing amount of literature that suggests that there exist a large degree of heterogeneity in beta-cell populations. Our studies focus on identifying the contribution of FGFR5 to the regulation of intracellular FGF signaling pathways in pancreatic beta-cells and how this receptor could potentially play a role in modulating beta cell phenotype. A recently published study comparing mature and senescent beta-cells revealed FGFR5 expression declines with cellular age. In addition to this, we have shown cytokine-induced inflammation induces FGFR5 expression in mouse and human pancreatic islets. Because both islet immaturity and aging correlate with dysfunction (i.e., reduced glucose-stimulated insulin secretion), and because we have shown that FGFR5 overexpression potentiates beta-cell survival, we hypothesize that FGFR5 promotes beta-cell maturity and function and may be a therapeutic target for treatment of metabolic disorders such as type 2 diabetes. In our current assessment of the effects of FGFR5 expression on beta-cell physiology, we have measured glucose-stimulated metabolism in the insulin-secreting cell lines INS1E and MIN6 using the genetically encoded Apollo-NADP+ sensor. Our data show 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). These studies are currently being translated to ex vivo islets using adenoviral transduction in a microfluidic device (“HEAT-on-a-chip”) which allows for optimized FGFR5 overexpression in the context of the whole micro-organ. This strategy will further allow qPCR of whole islets to correlate the expression of biomarkers for beta-cell maturation (e.g., IGFR1, FGFR1) and aging (e.g., p16) to transcripts relevant to glucose-stimulated metabolism (e.g., Glut2, Glucokinase, PKM2) and insulin secretion (e.g., insulin). Collectively, we propose that altering FGFR5 activity is a strategy to drive beta-cells to a mature phenotype, enhancing beta-cell GSIS and survival to resist the onset of metabolic disorders.