SFEBES2015 Poster Presentations Obesity, diabetes, metabolism and cardiovascular (108 abstracts)
Studies of Nuf mice with an activating calcium-sensing receptor (CaSR) mutation demonstrate the CaSR to regulate pancreatic beta-cell mass and glucose homeostasis
Valerie N Babinsky 1 , Fadil M Hannan 1 , M Andrew Nesbit 1 , Alison Hough 2 , Michelle Stewart 2 , Elizabeth Joynson 2 , Tertius A Hough 2 , Liz Bentley 2 , Abhishek Aggarwal 3 , Enikö Kallay 3 , Sara Wells 2 , Roger D Cox 2 , Duncan Richards 4 & Rajesh V Thakker 1
1University of Oxford, Oxford, UK; 2Medical Research Council, Harwell, Oxfordshire, UK; 3Medical University of Vienna, Vienna, Austria; 4GlaxoSmithKline Clinical Unit, Cambridge, UK.
The modulation of pancreatic islet mass represents a novel therapeutic approach for the management of diabetes mellitus. G-protein coupled receptors (GPCRs) regulate beta-cell expansion and proliferation, and the objective of this study was to assess whether the calcium-sensing receptor (CaSR), which is an abundantly expressed beta-cell GPCR, may influence islet mass and systemic glucose homeostasis, and thus represent an exploitable drug target in some forms of diabetes. We characterised the islet mass, glucose tolerance and insulin secretory capacity of Nuf mice, which harbour an activating CaSR mutation, and evaluated whether a targeted negative allosteric modulator, known as ronacaleret, may rectify any disturbances of glucose homeostasis. All studies were conducted using WT and homozygous affected (Nuf/Nuf) mice aged 20–28 weeks and in accordance with institutional welfare guidelines. Islet mass and beta-cell proliferation rates were measured by pancreas histology and immunofluorescent labelling for insulin and KI-67. I.p. glucose tolerance and insulin secretion were assessed in mice that received either 90 mg/kg ronacaleret or drug vehicle by oral gavage over 5-days. These studies revealed Nuf/Nuf mice to have a 31% reduction in islet mass and 39% reduction in beta-cell proliferation rates when compared to wild-type littermates (P<0.05), with no derangement of islet architecture. Nuf/Nuf mice also displayed significantly impaired glucose tolerance (P<0.001) compared to wild-types and an almost complete absence of insulin secretion in response to an i.p. 2 g/kg glucose bolus injection. Administration of ronacaleret significantly (P<0.05) lowered plasma glucose concentrations in Nuf/Nuf mice, but did not increase insulin secretion, and had no significant effect on beta-cell mass or proliferation rates. These findings demonstrate that the CaSR is a determinant of pancreatic islet mass and novel target for the modulation of plasma glucose concentrations, and also highlight that this GPCR may have additional insulin-independent effects on glucose homeostasis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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