GIP receptor signaling mechanisms - Abstract The incretin hormones, GIP and GLP-1, have fundamental roles in the control of whole-body metabolic tone (e.g., insulin secretion and insulin sensitivity). Therapeutics targeting GIP and GLP-1 receptors have several positive health impacts, including but not limited to improved insulin sensitivity and improved cardiovascular health. These therapies are also being explored as treatments for cancer and neurodegenerative diseases, (e.g., Parkinson's disease). Despite the expanded use of incretin hormone-targeted therapy, there remain significant gaps in understanding how, at the molecular level, incretin hormones work. Because of the large numbers of people currently taking these drugs, a number that will certainly increase in the future, it is imperative to understand their mechanism(s) of action. Addressing these gaps will provide a deeper understanding of the biology of the incretin hormones, advances that should lead to the improved therapeutic application of these drugs. We engineered a mouse to express a common variant of the GIP receptor (GIPR) that is linked in humans to reduced weight and alterations in glucose metabolism. We have shown that upon activation, this variant (GIPR-Q354), accumulates in the TGN to a greater degree than the most prevalent allele, GIPR-E354. This increased localization to the TGN is associated with increased binding of b-arrestin2 (bAR2) to GIPR-Q. The GIPR-Q mice, as compared to GIPR-E mice, are more sensitive to GIP, as reflected by increased insulin secretion. Intriguingly, they are also more glucose tolerant after intraperitoneal glucose challenge, in which endogenous GIP should be minimal. The former phenotype reflects the acute activity of GIP, and the latter reveals a GIPR-Q driven developmental (transcriptional) program making GIPR-Q b-cells/ islets more responsive to glucose than those of GIPR-E mice. GIPR-Q mice provide a unique opportunity to molecularly dissect and describe GIPR signaling, both its acute and developmental effects, data that will address many unanswered questions in the field. We hypothesize that bAR2-biased signaling downstream of GIPR-Q is responsible for the metabolic differences between GIPR-E and -Q mice. To test this hypothesis, we will use quantitative microscopy methods to contrast GIPR-Q and GIPR-E signaling in pancreatic b-cells and adipocytes, two physiologically relevant cell types. Differences in signaling mechanisms will be linked to differences in GIP enhancement of glucose stimulated insulin secretion (b-cells) and to enhanced insulin sensitivity (adipocytes). To advance our understanding of GIPR impact on development, we will use bulk and single cell RNAseq to profile islets from the two genotypes of mice. Finally, insulin secretion and insulin sensitivity of GIPR-E and GIPR-Q mice of both sexes will be characterized in vivo using the frequently sampled IV glucose tolerance test and a dual tracer glucose uptake assay. Our timely and comprehensive study of GIPR signaling and function, from cell biology experiments, studies of tissue-level cellular functional organization, and systemic physiology, will provide a coherent comprehensive leap forward for the field.
