SFEBES2021 Early Careers and Plenary Orals Clinical Endocrinology Trust Best Abstract Basic (1 abstracts)
The vagal Calcium Sensing Receptor mediates the effect of protein ingestion on insulin release and regulates macronutrient metabolism
Mariana Norton 1 , Anna Roberts 1 , Aldara Martin Alonso 1 , Ye Cao 1 , Fiona Gribble 2 , Frank Reimann 2 , Wenhan Chang 3 , Victoria Salem 1 & Kevin G Murphy 1
1Imperial College, London, UK; 2Cambridge University, Cambridge, UK; 3University of California, San Francisco, USA
Protein stimulates insulin release and improves post-prandial glycaemic excursions. The underlying mechanism has previously been attributed to gastric emptying, incretin release and direct pancreatic stimulation. However, our studies suggest the calcium sensing receptor (CaSR) in the vagus nerve plays an important role. The CaSR has a well characterised role in calcium homeostasis, but also acts as a protein metabolite sensor. In response to the amino acid products of protein digestion it mediates the secretion of gut hormones including the incretin Glucagon-like peptide-1 (GLP-1). Peripheral administration of a CaSR antagonist blocked protein’s ability to improve glucose tolerance and stimulate insulin secretion. This was independent of GLP-1 as neither CaSR knockdown in GLP-1 secreting cells of the gut or inhibition of the GLP-1 receptor with exendin 9-39 affected protein’s ability to improve glucose tolerance. The vagus nerve provides bi-directional communication between the brain and key metabolic organs. Oral administration of amino acids in rodents increased neuronal activation in central nervous system regions directly innervated by the vagus. Pharmacological inhibition of vagal afferent and efferent pathways in mice blocked improvements in glucose tolerance, following a protein pre-load, in a nutrient specific manner. Moreover, inhibition of vagal efferent signalling blocked protein stimulated insulin secretion. Interestingly, the CaSR is one of the few nutrient sensors expressed in vagal afferents. CaSR knockdown in vagal afferents, using both germline and adult transgenic models, blunted protein stimulated insulin secretion. Though this did not affect glucose tolerance, it did lead to changes in circulating levels of amino acids. This suggests vagal CaSR may be important in mediating the effects of insulin on protein metabolism, and that there may be distinct entero-vagal circuits regulating different metabolic pathways. Overall this suggests the vagus nerve plays an important role in protein’s ability to modulate insulin release and metabolic pathways.
Volume 77
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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