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

Research output: Contribution to journalArticlepeer-review

Authors

  • Valerie N Babinsky
  • Fadil M Hannan
  • Reshma D Ramracheya
  • Quan Zhang
  • M Andrew Nesbit
  • Alison Hugill
  • Liz Bentley
  • Tertius A Hough
  • Elizabeth Joynson
  • Michelle Stewart
  • Abhishek Aggarwal
  • Maximilian Prinz-Wohlgenannt
  • Enikö Kallay
  • Sara Wells
  • Roger D Cox
  • Duncan Richards
  • Patrik Rorsman
  • Rajesh V Thakker

Colleges, School and Institutes

External organisations

  • Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, United Kingdom.
  • University of Liverpool
  • Biomedical Sciences Research Institute, Ulster University, Coleraine BT52 1SA, United Kingdom.
  • Medical Research Council Mammalian Genetics Unit and Mary Lyon Centre, Medical Research Council Harwell Institute, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, United Kingdom.
  • Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna A-1090, Austria.
  • GlaxoSmithKline Clinical Unit, Cambridge CB2 0GG, United Kingdom.

Abstract

The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor 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 adenosine triphosphate (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.

Details

Original languageEnglish
Pages (from-to)2486-2502
Number of pages17
JournalEndocrinology
Volume158
Issue number8
Early online date2 Jun 2017
Publication statusPublished - 1 Aug 2017

Keywords

  • Animals, Body Composition, Calcium, Cell Proliferation, Glucose Intolerance, HEK293 Cells, Humans, Hyperglycemia, Indans, Islets of Langerhans, Mice, Mice, Knockout, Mutation, Phenylpropionates, Receptors, Calcium-Sensing, Receptors, G-Protein-Coupled, Journal Article