Activation of the gut calcium-sensing receptor by peptide agonists reduces rapid elevation of plasma glucose in response to oral glucose load in rats

Muramatsu, Maya; Hira, Tohru; Mitsunaga, Arimi; Sato, Eri; Nakajima, Shingo; Kitahara, Yoshiro; Eto, Yuzuru; Hara, Hiroshi

doi:10.1152/ajpgi.00155.2014

Cited by 26 publications

(18 citation statements)

References 38 publications

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“…Since the main function of GLP-1 and GIP is to enhance glucose-induced insulin secretion from β cells, it is possible that CaSR may play a role in nutrient (glucose/SCFA) utilization and energy homeostasis, through regulating the postprandial secretion of GLP-1, GIP, and insulin. Indeed, oral or duodenal administration of CaSR peptide agonists to experimental animals reduced rapid elevation of plasma glucose in response to oral glucose challenge (Muramatsu et al, 2014 ). Further, evidence supporting the role of CaSR as a nutrient sensor and food metabolism regulator comes from the discovery that CaSR is found in tissues that regulate appetite and satiety.…”

Section: Casr and Nutrient-sensingmentioning

confidence: 99%

“…In support of this notion, people who take high calcium are often constipated (Prince et al, 2006 ), as are patients with hypercalcemia (Ragno et al, 2012 ). Likewise, animals receiving treatment of polyamines (e.g., spermine) or peptides (e.g., γ-glutamyl cysteine), both of which are classes of agonists for CaSR, display profound inhibition on gastric emptying and/or intestinal motor activity (Belair et al, 1981 ; Tansy et al, 1982 ; Muramatsu et al, 2014 ). Polyamine inhibition of GI transit is also noted in several rodent models of diarrhea-dominate forms of irritable bowel syndrome (Bergeron et al, 1996 , 2001a , b ).…”

Section: Casr and Ens Activity And Motilitymentioning

confidence: 99%

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The Extracellular Calcium-Sensing Receptor in the Intestine: Evidence for Regulation of Colonic Absorption, Secretion, Motility, and Immunity

et al. 2016

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Different from other epithelia, the intestinal epithelium has the complex task of providing a barrier impeding the entry of toxins, food antigens, and microbes, while at the same time allowing for the transfer of nutrients, electrolytes, water, and microbial metabolites. These molecules/organisms are transported either transcellularly, crossing the apical and basolateral membranes of enterocytes, or paracellularly, passing through the space between enterocytes. Accordingly, the intestinal epithelium can affect energy metabolism, fluid balance, as well as immune response and tolerance. To help accomplish these complex tasks, the intestinal epithelium has evolved many sensing receptor mechanisms. Yet, their roles and functions are only now beginning to be elucidated. This article explores one such sensing receptor mechanism, carried out by the extracellular calcium-sensing receptor (CaSR). In addition to its established function as a nutrient sensor, coordinating food digestion, nutrient absorption, and regulating energy metabolism, we present evidence for the emerging role of CaSR in the control of intestinal fluid homeostasis and immune balance. An additional role in the modulation of the enteric nerve activity and motility is also discussed. Clearly, CaSR has profound effects on many aspects of intestinal function. Nevertheless, more work is needed to fully understand all functions of CaSR in the intestine, including detailed mechanisms of action and specific pathways involved. Considering the essential roles CaSR plays in gastrointestinal physiology and immunology, research may lead to a translational opportunity for the development of novel therapies that are based on CaSR's unique property of using simple nutrients such as calcium, polyamines, and certain amino acids/oligopeptides as activators. It is possible that, through targeting of intestinal CaSR with a combination of specific nutrients, oral solutions that are both inexpensive and practical may be developed to help in conditioning the gut microenvironment and in maintaining digestive health.

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Section: Casr and Nutrient-sensingmentioning

confidence: 99%

Section: Casr and Ens Activity And Motilitymentioning

confidence: 99%

The Extracellular Calcium-Sensing Receptor in the Intestine: Evidence for Regulation of Colonic Absorption, Secretion, Motility, and Immunity

et al. 2016

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“…A candidate receptor is Calcium-sensing receptor (CaSR), which can be activated by L-amino acids in conjunction with extracellular calcium [ 29 ]. Cinacalcet, an allosteric CaSR agonist, was reported to lower glucose in rats [ 30 ]. In addition, L-Phe regulation of gut hormones was inhibited by a CaSR antagonist in vitro [ 31 – 33 ].…”

Section: Discussionmentioning

confidence: 99%

GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism

et al. 2016

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GPR142, a putative amino acid receptor, is expressed in pancreatic islets and the gastrointestinal tract, but the ligand affinity and physiological role of this receptor remain obscure. In this study, we show that in addition to L-Tryptophan, GPR142 signaling is also activated by L-Phenylalanine but not by other naturally occurring amino acids. Furthermore, we show that Tryptophan and a synthetic GPR142 agonist increase insulin and incretin hormones and improve glucose disposal in mice in a GPR142-dependent manner. In contrast, Phenylalanine improves in vivo glucose disposal independently of GPR142. Noteworthy, refeeding-induced elevations in insulin and glucose-dependent insulinotropic polypeptide are blunted in Gpr142 null mice. In conclusion, these findings demonstrate GPR142 is a Tryptophan receptor critically required for insulin and incretin hormone regulation and suggest GPR142 agonists may be effective therapies that leverage amino acid sensing pathways for the treatment of type 2 diabetes.

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“…Activation of the CaSR in the small intestine has also been found to improve post-prandial glucose tolerance in wild-type rats218. This effect of the GI-expressed CaSR on glucose tolerance may be mediated by a reduction in gastric emptying rate218, as well as through effects on GLP-1, which plays a key role in enhancing glucose-dependent insulin release219.…”

Section: Non-calcitropic Roles Of the Casrmentioning

confidence: 99%

The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases

et al. 2018

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The Ca2+-sensing receptor (CaSR) is a dimeric family C G-protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and kidneys, and signals via G-proteins and beta-arrestin. The CaSR plays a pivotal role in bone and mineral metabolism by regulating parathyroid hormone secretion, urinary Ca2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss- and gain-of-function CaSR mutations, which cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by alterations in parathyroid CaSR expression, which contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca2+ homeostasis, where it has non-calcitropic roles that include lung and neuronal development, vascular tone, gastro-intestinal nutrient sensing, secretion of insulin and entero-endocrine hormones, and wound healing. Furthermore, abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma, but increase the malignant potential of prostate and breast cancers. This review will discuss these physiological and pathophysiological roles of the CaSR.

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Activation of the gut calcium-sensing receptor by peptide agonists reduces rapid elevation of plasma glucose in response to oral glucose load in rats

Abstract: Muramatsu M, Hira T, Mitsunaga A, Sato E, Nakajima S, Kitahara Y, Eto Y, Hara H. Activation of the gut calcium-sensing receptor by peptide agonists reduces rapid elevation of plasma glucose in response to oral glucose load in rats.

Cited by 26 publications

References 38 publications

The Extracellular Calcium-Sensing Receptor in the Intestine: Evidence for Regulation of Colonic Absorption, Secretion, Motility, and Immunity

The Extracellular Calcium-Sensing Receptor in the Intestine: Evidence for Regulation of Colonic Absorption, Secretion, Motility, and Immunity

GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism

The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases

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