Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy

Valerie N. Babinsky, Fadil M. Hannan, Reshna Ramracheya, Quan Zhang, M. Andrew Nesbit, Alison Hugill, Liz Bentley, Tertius A Hough, Elizabeth Joynson, Michelle Stewart, Abhishek Aggarwal, Maximilian Priz-Wohigenannt, Caroline M Gorvin, Enikö Kallay, Sara Wells, Roger D Cox, Duncan Richards, Patrik Rorsman, Rajesh V. Thakker

Research output: Contribution to journalArticle

13 Citations (Scopus)
13 Downloads (Pure)

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

Keywords

  • dopamine
  • melatonin
  • myopia

Fingerprint Dive into the research topics of 'Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy'. Together they form a unique fingerprint.

Cite this