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

7 Citations (Scopus)

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.
LanguageEnglish
Pages2486-2502
Number of pages17
JournalEndocrinology
Volume158
Issue number8
Early online date2 Jun 2017
DOIs
Publication statusPublished - 1 Aug 2017

Fingerprint

Calcium-Sensing Receptors
Hyperglycemia
Glucose Intolerance
Islets of Langerhans
Glucose
KATP Channels
Therapeutics
Glucagon
Homeostasis
Cell Proliferation
Insulin
Hypocalcemia
Electrophysiology
G-Protein-Coupled Receptors
Flecks
Oral Administration
Cell Count
Adenosine Triphosphate
Cell Membrane
Calcium

Keywords

  • dopamine
  • melatonin
  • myopia

Cite this

Babinsky, V. N., Hannan, F. M., Ramracheya, R., Zhang, Q., Nesbit, M. A., Hugill, A., ... Thakker, R. V. (2017). Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy. Endocrinology, 158(8), 2486-2502. https://doi.org/10.1210/en.2017-00111
Babinsky, Valerie N. ; Hannan, Fadil M. ; Ramracheya, Reshna ; Zhang, Quan ; Nesbit, M. Andrew ; Hugill, Alison ; Bentley, Liz ; Hough, Tertius A ; Joynson, Elizabeth ; Stewart, Michelle ; Aggarwal, Abhishek ; Priz-Wohigenannt, Maximilian ; Gorvin, Caroline M ; Kallay, Enikö ; Wells, Sara ; Cox, Roger D ; Richards, Duncan ; Rorsman, Patrik ; Thakker, Rajesh V. / Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy. In: Endocrinology. 2017 ; Vol. 158, No. 8. pp. 2486-2502.
@article{ea397da0db324fec86ff2c0de204d4f5,
title = "Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy",
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.",
keywords = "dopamine, melatonin, myopia",
author = "Babinsky, {Valerie N.} and Hannan, {Fadil M.} and Reshna Ramracheya and Quan Zhang and Nesbit, {M. Andrew} and Alison Hugill and Liz Bentley and Hough, {Tertius A} and Elizabeth Joynson and Michelle Stewart and Abhishek Aggarwal and Maximilian Priz-Wohigenannt and Gorvin, {Caroline M} and Enik{\"o} Kallay and Sara Wells and Cox, {Roger D} and Duncan Richards and Patrik Rorsman and Thakker, {Rajesh V.}",
year = "2017",
month = "8",
day = "1",
doi = "10.1210/en.2017-00111",
language = "English",
volume = "158",
pages = "2486--2502",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "Endocrine Society",
number = "8",

}

Babinsky, VN, Hannan, FM, Ramracheya, R, Zhang, Q, Nesbit, MA, Hugill, A, Bentley, L, Hough, TA, Joynson, E, Stewart, M, Aggarwal, A, Priz-Wohigenannt, M, Gorvin, CM, Kallay, E, Wells, S, Cox, RD, Richards, D, Rorsman, P & Thakker, RV 2017, 'Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy', Endocrinology, vol. 158, no. 8, pp. 2486-2502. https://doi.org/10.1210/en.2017-00111

Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy. / Babinsky, Valerie N.; Hannan, Fadil M.; Ramracheya, Reshna; Zhang, Quan; Nesbit, M. Andrew; Hugill, Alison; Bentley, Liz; Hough, Tertius A; Joynson, Elizabeth; Stewart, Michelle; Aggarwal, Abhishek; Priz-Wohigenannt, Maximilian; Gorvin, Caroline M; Kallay, Enikö; Wells, Sara; Cox, Roger D; Richards, Duncan; Rorsman, Patrik; Thakker, Rajesh V.

In: Endocrinology, Vol. 158, No. 8, 01.08.2017, p. 2486-2502.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy

AU - Babinsky, Valerie N.

AU - Hannan, Fadil M.

AU - Ramracheya, Reshna

AU - Zhang, Quan

AU - Nesbit, M. Andrew

AU - Hugill, Alison

AU - Bentley, Liz

AU - Hough, Tertius A

AU - Joynson, Elizabeth

AU - Stewart, Michelle

AU - Aggarwal, Abhishek

AU - Priz-Wohigenannt, Maximilian

AU - Gorvin, Caroline M

AU - Kallay, Enikö

AU - Wells, Sara

AU - Cox, Roger D

AU - Richards, Duncan

AU - Rorsman, Patrik

AU - Thakker, Rajesh V.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

KW - dopamine

KW - melatonin

KW - myopia

UR - https://pure.ulster.ac.uk/en/publications/mutant-mice-with-calcium-sensing-receptor-activation-have-hypergl

U2 - 10.1210/en.2017-00111

DO - 10.1210/en.2017-00111

M3 - Article

VL - 158

SP - 2486

EP - 2502

JO - Endocrinology

T2 - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 8

ER -