Regulation of Gut Hormone Release by Calcium-Sensing Receptor Activity
Overview
The calcium-sensing receptor (CaSR) in the gastrointestinal tract detects extracellular calcium and aromatic amino acids, notably L-tryptophan and L-phenylalanine, to stimulate gut hormone secretion. This activation leads to reduced energy intake and improved postprandial glycemic control, highlighting CaSR as a potential target for obesity and type 2 diabetes management.
Background
Gut hormones regulate digestion, nutrient absorption, appetite, and glucose metabolism. Enteroendocrine cells throughout the gastrointestinal mucosa release hormones such as gastrin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY) in response to nutrient sensing. The calcium-sensing receptor (CaSR), initially identified for its role in calcium homeostasis, is expressed in these cells and responds to extracellular calcium and aromatic amino acids. Preclinical and clinical studies have demonstrated that CaSR activation promotes gut hormone secretion, influencing energy intake and glycemic responses.
Data Highlights
Studies show intraluminal administration of L-tryptophan or L-phenylalanine increases plasma gut hormone levels and reduces energy intake and postprandial glucose. Co-administration of calcium enhances these effects, increasing hormones such as CCK, GLP-1, and PYY. In healthy and obese individuals, calcium chloride administration elevated GLP-1 and PYY plasma levels. Animal models confirm CaSR knockout or inhibition reduces amino acid-stimulated hormone secretion.
Key Findings
CaSR senses extracellular calcium and aromatic amino acids, particularly L-tryptophan and L-phenylalanine, to stimulate gut hormone release.
Activation of CaSR increases secretion of gastrin, CCK, GIP, GLP-1, and PYY from enteroendocrine cells.
Extracellular calcium enhances amino acid-induced gut hormone secretion and suppresses food intake and postprandial glucose levels.
In humans, intraluminal calcium and aromatic amino acids increase plasma gut hormone levels and reduce energy intake.
CaSR modulators are clinically used for calcium disorders and have potential for metabolic disease treatment.
Clinical Implications
Targeting CaSR with dietary calcium and aromatic amino acids may represent a novel strategy to enhance gut hormone secretion, thereby reducing appetite and improving glycemic control in obesity and type 2 diabetes. Understanding CaSR's role could guide development of nutrient-based therapies or pharmacologic modulators to optimize metabolic outcomes.
Conclusion
The calcium-sensing receptor is a critical multimodal nutrient sensor in the gut that regulates hormone secretion influencing energy intake and glucose metabolism. Leveraging CaSR activation offers promising avenues for managing metabolic diseases.
References
Conigrave et al. 2023 -- Regulation of Gut Hormone Release by Calcium-Sensing Receptor Activity
