SFEBES2026 Oral Communications Metabolism, Obesity and Diabetes (6 abstracts)
Beneficial effect of protein-induced glucose tolerance is independent of protein-induced insulin release
Mariana Norton 1 , Pei-En Chung 1 , Anna Roberts 1 , Aldara Martin Alonso 1 , Yateen Patel 1 , Phyllis Phuah 1 , Chai Lee 1 , Jieruo Liu 1 , Leah Meyer 1 , Jiping Zhang 1 , Cecilia Dunsterville 1 , Frank Reimann 2 , Fiona Gribble 2 , Ben Jones 1 , Wenhan Chang 3 & Kevin Murphy 1
1Imperial College London, London, United Kingdom; 2Cambridge University, Cambridge, United Kingdom; 3University of California San Francisco, San Francisco, USA
Acute protein ingestion is suggested to improve glucose tolerance through secretion of glucoregulatory hormones such as glucagon-like peptide-1 (GLP-1), insulin and glucagon upon sensing of amino acids. Calcium sensing receptor (CaSR), known for regulating calcium homeostasis, also functions as an amino acid sensor and is expressed in key glucoregulatory tissues including vagal afferent neurons, enteroendocrine cells, and pancreatic islets. We investigated the role of CaSR signalling in the vagus, enteroendocrine L-cells and pancreatic α- and β-cells in mediating protein’s effect on glucose tolerance and hormone secretion. To understand the role of CaSR, pharmacological antagonists, surgical vagal CaSR knockdown, and tissue-specific CaSR knockout mice (PPG-Cre x CaSR-flox for enteroendocrine L-cells and α-cells and Ins1Cre x CaSR-flox for β-cells) were used. Pdx1CreERT x GLP-1R fl/fl mice were used to investigate the role of GLP-1 receptor signalling in β-cells. Our results suggested a vagal CaSR pathway mediating protein-induced insulin secretion, while a separate NMDA-dependent central pathway modulates glucose tolerance independently of insulin. Pharmacologically inhibiting central glutamate NMDA receptors prevented the effects of protein on glucose tolerance without affecting insulin secretion, whereas inhibition of major vagal efferent pathways to the pancreas via peripheral injection of a M3-muscarinic receptor antagonist inhibited both insulin and glucose tolerance effects. Vagal CaSR knockdown prevented only the effect on insulin. Protein’s effect on glucose-stimulated insulin secretion (GSIS) was blunted in mice with CaSR knocked out in both L-cells and α-cells but unaffected when CaSR was deleted in α- or β-cells alone, suggesting that protein does not act directly on CaSR in these pancreatic cells to mediate its effects. Furthermore, protein-enhanced GSIS was lost in mice with β-cell-specific GLP-1R knockout, highlighting the role of gut-derived GLP-1. In summary, protein improves glucose tolerance via a central, insulin-independent pathway, while its insulinotropic effect involves vagal CaSR signalling and pancreatic GLP-1R signalling.
Volume 117
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Endocrine Abstracts
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