The role of bile acids in physiology and pathophysiology of pancreatic beta-cells

• Applicant: Professorin Dr. Gisela Drews
• Subject Area: Anatomy and Physiology ; Pharmacology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260646784

Bile acids (BAs) are -besides their important role in lipid metabolism- involved in the regulation of glucose homeostasis. In this project it will be clarified by which mechanisms BAs influence the function of the endocrine pancreas. Recent work of my group demonstrated that the nuclear farnesoid X receptor (FXR) is expressed in beta-cells and that stimulation of this receptor augments insulin secretion. Since the effects of BAs on different parameters of stimulus-secretion coupling (SSC) occurred within minutes, it is one aim of this project to evaluate which of the BA effects are mediated by genome activation and which occur via other signaling pathways. In this context it will be investigated under which conditions the FXR is located in the cytosol or in the nucleus and functional consequences of the receptor translocation will be studied. Our previous work showed that FXR modulates the activity of KATP channels. Therefore it is another goal to detect the molecular mechanism(s) that constitute the link between FXR and KATP channels. In vivo we will address the question how changes in the BA pool achieved by feeding of different diets (addition of BAs or BA-binding resins) alter glucose homeostasis in prediabetic mice vs. control animals. It is expected that in vitro experiments will discover molecular mechanisms involved in the mode of action of BAs. Moreover, it is anticipated that the in vivo experiments contribute to the knowledge how the BA pool can be used as a target for therapeutic intervention.

• DFG Programme: Research Grants