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, Elizabeth Joynson, Michelle Stewart, Abhishek Aggarwal, Maximilian Priz-Wohigenannt, 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

6 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
JournalEndocrinology
Volume158
Issue number8
Early online date2 Jun 2017
DOIs
Publication statusPublished - 1 Aug 2017

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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

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 ; Joynson, Elizabeth ; Stewart, Michelle ; Aggarwal, Abhishek ; Priz-Wohigenannt, Maximilian ; 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.
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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.",
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Babinsky, VN, Hannan, FM, Ramracheya, R, Zhang, Q, Nesbit, MA, Hugill, A, Joynson, E, Stewart, M, Aggarwal, A, Priz-Wohigenannt, M, 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; Joynson, Elizabeth; Stewart, Michelle; Aggarwal, Abhishek; Priz-Wohigenannt, Maximilian; 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

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AU - Babinsky, Valerie N.

AU - Hannan, Fadil M.

AU - Ramracheya, Reshna

AU - Zhang, Quan

AU - Nesbit, M. Andrew

AU - Hugill, Alison

AU - Joynson, Elizabeth

AU - Stewart, Michelle

AU - Aggarwal, Abhishek

AU - Priz-Wohigenannt, Maximilian

AU - Priz-Wohigenannt, Maximilian

AU - Gorvin, Caroline M

AU - Kallay, Enikö

AU - Wells, Sara

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AU - Thakker, Rajesh V.

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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.

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DO - 10.1210/en.2017-00111

M3 - Article

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