Endocrine Abstracts

The calcium-sensing receptor (CaSR) is a G protein coupled receptor that is expressed widely, including pancreatic beta cells where it has been shown to modulate insulin secretion in vitro. However, the role of the CaSR in regulating in vivo insulin secretion and glucose homeostasis remains unknown. We have therefore investigated the Nuf mouse, which has an activating CaSR mutation (Leu723Gln), to determine whether abnormal CaSR function in vivo affects glucose tolerance and plasma insulin concentrations. Mice were kept in accordance with UK Home Office welfare guidelines and project license restrictions. A glucose tolerance test was performed by fasting mice overnight and administering an intraperitoneal 2 g/kg glucose bolus. Blood samples were obtained at 0 and 120 min. Plasma glucose concentrations were measured using an analox glucose analyser and fasting plasma insulin concentrations determined using a milliplex mouse endocrine immunoassay. The glucose tolerance tests revealed that male and female homozygous Nuf mice (Nuf/Nuf) had significantly raised plasma glucose concentrations at 120 min when compared to wild-type litter-mates (male glucose=25.4±1.7 vs 20.5±2.1 mmol/l, P<0.05; female glucose=13.0±0.6 vs 10.6±0.3 mmol/l, P<0.01). In addition, male and female Nuf/Nuf mice had significantly reduced fasting plasma insulin concentrations, when compared to wild-type litter-mates (male insulin=65.4±9.1 vs 200.0±49.5 pmol/l, P<0.01; female insulin=63.6±9.5 mmol/l vs 100.4±17.0 pmol/l, P<0.05). Thus, our finding demonstrate that CaSR activation impairs insulin secretion and glucose tolerance and highlights that the CaSR is an in vivo determinant of glucose homeostasis.