SFEBES2023 Poster Presentations Metabolism, Obesity and Diabetes (70 abstracts)
Investigating the role of CaSR in mediating effect on glucose tolerance via α-cell and β-cell signalling
Pei-En Chung 1 , Jiabai Zhang 1 , Mariana Norton 1 , Leah Meyer 1 , Cecilia Dunsterville 1 , Jieruo Liu 1 , Fiona Gribble 2 , Frank Reimann 2 , Wehan Chang 3 & Kevin Murphy 1
1Imperial College London, London, United Kingdom. 2University of Cambridge, Cambridge, United Kingdom. 3University of California,
San Francisco, California, USA
High protein diets are hypothesised to improve glucose tolerance by modulating the secretion of gastroenteropancreatic hormones via amino-acid sensing. Glucagon, traditionally associated with hyperglycaemia, has beneficial effects on glucose homeostasis, potentially due to its role as an insulin secretagogue via intra-islet signalling and as a regulator of pulsatile insulin secretion. The calcium sensing receptor (CaSR), known for its role in calcium homeostasis, also functions as an amino-acid sensor and modulates secretion of gastroenteropancreatic hormones. We hypothesize that CaSR also functions as an amino-acid sensor in the pancreatic islets to mediate protein’s beneficial effects on glucose tolerance. To test this hypothesis, we examined the effects of different amino-acids on mobilization of intracellular calcium ([Ca2+]i) in α-cells and β-cells in islets isolated from preproglucagon promoter-driven (PPG-Cre;GCaMP6f) and insulin promoter-driven (Ins1Cre;GCaMP6f) [Ca2+]i-reporter mice, respectively. The role of CaSR signalling in mediating the effect of oral administration of 10% whey on glucose tolerance was assessed in vivo in the PPG-Cre;flox-CaSR mice, characterized by deletion of exon 7 of the Casr gene in PPG-expressing α-cells and gastrointestinal L-cells. Our results showed various potencies of amino-acids in mobilizing [Ca2+]i in the α-cells in the order of glutamic acid > ornithine > alanine. L-phenylalanine, which is the most potent amino-acid modulator of CaSR, also increased [Ca2+]i, but to a lesser extent. Similar effects of amino acids on [Ca2+]i were observed in β-cells, except that activation with 6mM-glucose was required for some amino acids. Whey-induced improvement on glucose tolerance was blunted in PPG-Cre;flox-CaSR mice, supporting a role of CaSR in α-cells and/or L-cells in mediating the actions of protein on glucose tolerance. These data suggest that CaSR signalling in PPG-expressing cells partially mediates protein-induced beneficial effects on glucose tolerance. We are investigating the in vivo action of CaSR in β-cells using Ins1Cre;flox-CaSR mice.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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