G-Protein Coupled Receptors Modulating Incretin Hormone Secretion

Abstract

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), secreted from K-cells and L-cells respectively, augment insulin secretion. In addition, GIP facilitates triglyceride storage and GLP-1 has anorexic effects. Incretins are released from the gastrointestinal tract in response to food ingestion. Great interest exists on how to enhance secretion of these peptides for the treatment of diabetes and obesity, as injectable GLP-1 mimetics are now routinely used in the treatment of type 2 diabetes, and as the success of some bariatric procedures correlates with altered enteroendocrine profiles. G-protein coupled receptors (GPCR)s are considered attractive targets to modulate incretin secretion. The aim of this dissertation was to investigate the contributions of GPCRs to incretin secretion. Receptors of interest were identified based on expression analysis of fluorescent labeled enteroendocrine cells. Gene knock-out and pharmacological tools were combined with static secretion studies from mixed intestinal epithelial cultures, live cell monitoring of second messengers and the measurement of plasma hormone profiles after nutrient dosing in order to assess the importance of these receptors in incretin secretion. This study has demonstrated that phosphodiesterase (PDE) 3 and 4 modulate cAMP signals from L-cells, and that the colonic peptide guanylin can inhibit PDE 2 to increase GLP-1 secretion. By contrast, in K-cells, PDE3 alone is responsible for attenuating cAMP. It has established that FFA1 and FFA1 mediate free fatty acid detection in duodenal enteroendocrine cells, and that lipid derivatives activate GPR119 in the colonic L-cell to increase GLP-1 secretion. The inhibition of GIP secretion by cannabinoid-receptor 1 agonists revealed crosstalk between K-cells and the endocannabinoid system. These results have helped to clarify the role of a number of GPCRs in primary murine K- and L-cells. In addition, they have highlighted some of the similarities and differences between K- and L-cells. Results of the thesis are expected to guide the on-going development of drugs targeting the investigated GPCRs for treatment of diabetes and obesity.