GIPR Trafficking

The incretin hormones, GIP and GLP-1, are gut hormones secreted in response to nutrients in the chyme. They have key roles in setting postprandial metabolic tone. Pancreatic β cells are a principal target of the incretins. About 50% of glucose-stimulated insulin secretion is the result of incretin activity. Incretins have effects beyond β cells. For example, GIP enhances insulin-sensitivity of adipocytes, reinforcing a postprandial anabolic metabolism in those cells. Because of the “pro-insulin” activity of the incretins (i.e., enhanced insulin secretion and action), they are excellent drug targets for the treatment of insulin resistance. Some of that therapeutic promise has already been met, as drugs targeting incretins are currently in use.

Incretins signal by G protein-coupled receptors (GPCRs). It is well established that the post-activation trafficking of GPCRs contributes significantly to their biological effects. We have created tools to study the behavior of the GIP receptor (GIPR) in adipocytes, a physiologically relevant cell type. Using those tools, we have:

• Defined the effect of GIP effect on cultured adipocytes

• Established that GIPR trafficking does not conform to canonical GPCR behavior

• Established that the intracellular trafficking of a GIPR coding variant (E354Q) is altered compared to the predominant human GIPR sequence. The E354Q variant is associated with human metabolic alterations. Therefore, those results provide a link between aberrant trafficking and GIPR function.

To gain insight into the effect of GIPR E354Q altered trafficking on whole body metabolism, we generated GIPR E350Q mice, equivalent of the E354Q variant in humans. We are studying the metabolism of these mice, in vivo and ex vivo on adipose tissue and pancreatic islets.