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.
Highlights
To establish whether the gain-of-function calcium-sensing receptor (CaSR) mutation in Nuclear flecks (Nuf) mice may be associated with alterations in glucose homeostasis, IP glucose tolerance testing (IPGTT) was performed on WT (Casr+/+), heterozygous- (CasrNuf/+), and homozygous-affected (CasrNuf/Nuf) mice aged 20 to 28 weeks that had been fasted for 16 hours
To test whether the impaired glucose tolerance of Nuf mice may be associated with abnormalities of insulin secretion in vivo, an IPGTT was conducted with plasma samples collected for insulin measurement at 0, 10, 20, and 30 minutes
These findings indicate that ADHcausing mutations of the CaSR, which lead to a gain-offunction [14], may perturb systemic glucose homeostasis, and this contrasts with familial hypocalciuric hypercalcemia (FHH)-causing loss-of-function CaSR mutations, which have been shown to not influence glucose tolerance or insulin secretion [13]
Summary
It may be that gain-of-function CaSR mutations, which cause autosomal dominant hypocalcemia (ADH) [14], are associated with abnormalities of glucose homeostasis and not FHH-associated loss-of-function CaSR mutations To investigate this possibility, we have evaluated glucose tolerance and pancreatic islet function in a mouse model for ADH due to a germline gain-of-function CaSR mutation, Leu723Gln, referred to as Nuclear flecks (Nuf) because the mouse was initially identified to have cataracts [15, 16]. We have evaluated glucose tolerance and pancreatic islet function in a mouse model for ADH due to a germline gain-of-function CaSR mutation, Leu723Gln, referred to as Nuclear flecks (Nuf) because the mouse was initially identified to have cataracts [15, 16] Our analysis of these Nuf mice has demonstrated a role for the CaSR in glucose homeostasis
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