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 gl...

Familial juvenile hyperuricaemic nephropathy (FJHN), an autosomal dominant disorder characterised by raised serum urate, reduced fractional excretion of uric acid (FEUA), a urine concentrating defect, and progressive renal failure, is caused by mutations in the UMOD gene, encoding uromodulin (Tamm–Horsfall glycoprotein). The FJHN-causing UMOD mutations are missense mutations (>90%) or inframe deletions (<10%), and none result in prematurely truncated...

Inbred laboratory mice are widely used to generate, by homologous recombination, transgenic and chemical mutagenesis routes, genetic models of human disease. However, physiological studies of such models are hampered by the lack of normal ranges for serum and urinary biochemistry, particularly in relation to acclimatisation following placement in metabolic cages. To establish such values, we investigated urinary and serum parameters in forty, 24–30 week-old C3H/HeH, BALB/...

The calcium-sensing-receptor (CaSR) is a G-protein-coupled receptor that plays a fundamental role in extracellular calcium homeostasis, but is also implicated in non-calcitropic disorders including colon cancer and asthma. In addition, CaSR is highly expressed in pancreatic islets where it has a role in insulin secretion. Patients with gain-of-function CaSR mutations, and mice (referred to as Nuf) with a gain-of-function CaSR mutation (Leu723Gln), develop autosomal dominant hy...

Transient receptor potential cation channel, subfamily Vanilloid, member 5 (TRPV5) is a member of the TRP superfamily. TRPV5, which functions as a tetramer, is localized to apical membranes of distal convoluted tubules (DCT) and connecting tubules (CNT) of the kidney, and is involved in vitamin D-regulated calcium reabsorption. Mice with a targeted deletion of Trpv5 (Trpv5−/−) develop severe hypercalciuria, compensatory hyperabsorption of dietary ...

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 c...

Renal calcification (nephrocalcinosis), which has a multi-factorial etiology involving environmental and genetic determinants, affects ~8% of adults by 70 years. Nephrocalcinosis may occur as a familial disorder in ~65% of patients, and in 70% of patients, nephrocalcinosis may be associated with endocrine and metabolic disorders that include primary hyperparathyroidism, renal tubular acidosis, hypercalciuria, cystinuria, and hyperoxaluria. Investigations of families with hered...

Cushing’s syndrome, which is characterised by excessive circulating glucocorticoid (GC) concentrations, may be due to ACTH-dependent or -independent causes that include anterior pituitary and adrenal cortical tumours, respectively. In the course of our phenotype-driven screens of mouse mutants induced by the chemical mutagen N-ethyl-N-nitrosourea (ENU), we observed a mutant mouse with obesity, hyperglycaemia and low bone mineral density, features that ar...

Calcium-containing renal stones, which affect 7% of adults, may be associated with endocrine and metabolic disorders that include primary hyperparathyroidism, renal tubular acidosis, hypercalciuria and hyperoxaluria. In addition, ∼40% of patients with stones have a familial history, although the genetic defects remain to be elucidated. To facilitate this, we have established a mouse model for renal calcification, designated Rcalc1, and determined its chromosomal l...

Kidney stones, which affect 5% of adults, are most frequently associated with hypercalciuria or hypercalcaemia. Furthermore, kidney stones may occur in families in ∼40% of patients, thereby implicating the involvement of genetic mechanisms. To further elucidate these, we have established a mouse model for renal calcification, designated Rcalc2, and determined its chromosomal localisation. Mice were kept in accordance with UK Home Office welfare guidelines and proj...