Mutant mice with calcium-sensing receptor activation have hyperglycemia, that is rectified by calcilytic therapy.


Babinsky, VN, Hannan, FM ORCID: 0000-0002-2975-5170, Ramracheya, RD, Zhang, Q, Nesbit, MA, Hugill, A, Bentley, L, Hough, TA, Joynson, E, Stewart, M et al (show 9 more authors) (2017) Mutant mice with calcium-sensing receptor activation have hyperglycemia, that is rectified by calcilytic therapy. Endocrinology, 158 (8). pp. 2486-2502.

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Abstract

The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that plays a pivotal role in extracellular calcium homeostasis. The CaSR is also highly expressed in pancreatic islet α- and β-cells that secrete glucagon and insulin, respectively. To determine whether the CaSR may influence systemic glucose homeostasis, we characterized a mouse model with a germline gain-of-function CaSR mutation, Leu723Gln, referred to as Nuclear flecks (Nuf). Heterozygous- (CasrNuf/+) and homozygous-affected (CasrNuf/Nuf) mice were shown to have hypocalcemia in association with impaired glucose tolerance and insulin secretion. Oral administration of a CaSR antagonist compound, known as a calcilytic, rectified the glucose intolerance and hypoinsulinemia of CasrNuf/+ mice, and ameliorated glucose intolerance in CasrNuf/Nuf mice. Ex vivo studies showed CasrNuf/+ and CasrNuf/Nuf mice to have reduced pancreatic islet mass and β-cell proliferation. Electrophysiological analysis of isolated CasrNuf/Nuf islets showed CaSR activation to increase the basal electrical activity of β-cells independently of effects on the activity of the ATP-sensitive K+ (KATP) channel. CasrNuf/Nuf mice also had impaired glucose-mediated suppression of glucagon secretion, which was associated with increased numbers of α-cells and a higher α-cell proliferation rate. Moreover, CasrNuf/Nuf islet electrophysiology demonstrated an impairment of α-cell membrane depolarization in association with attenuated α-cell basal KATP channel activity. These studies indicate that the CaSR activation impairs glucose tolerance by a combination of α- and β-cell defects and also influences pancreatic islet mass. Moreover, our findings highlight a potential application of targeted CaSR compounds for modulating glucose metabolism.

Item Type: Article
Uncontrolled Keywords: Islets of Langerhans, Animals, Mice, Knockout, Humans, Mice, Hyperglycemia, Glucose Intolerance, Calcium, Phenylpropionates, Indans, Receptors, G-Protein-Coupled, Receptors, Calcium-Sensing, Cell Proliferation, Body Composition, Mutation, HEK293 Cells
Depositing User: Symplectic Admin
Date Deposited: 15 Jun 2017 10:55
Last Modified: 19 Jan 2023 07:02
DOI: 10.1210/en.2017-00111
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3008000
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