R-spondin1 deficiency in mice improves glycaemic control in association with increased beta cell mass.

AIMS/HYPOTHESIS: Roof plate-specific spondin (R-spondin1; RSPO1) is a modulator of canonical Wg (wingless) plus Int1 (chromosomal integration site of mouse mammary tumour virus on mouse chromosome 15) (cWNT) signalling that induces cWNT target genes. We have demonstrated that Rspo1 is expressed in murine beta cells, and that it stimulates proliferation and insulin secretion, and inhibits cytokine-induced apoptosis, in mouse insulinoma (MIN6) and beta cells. We thus investigated the role of RSPO1 in beta cells in vivo using Rspo1 ( -/- ) mice. METHODS: The effects of Rspo1 deficiency were assessed by determination of cWNT signalling, glucose tolerance and beta cell mass. RESULTS: Rspo1 ( -/- ) mice demonstrated an 82% reduction in RSPO1 transcripts and a 61% reduction in the signal detected by an RSPO1 antibody, as well as a 47% decrease in islet cWNT signalling. Despite no differences in body and pancreatic weights or in fasting glycaemia and insulinaemia compared with Rspo1 (+/+) mice, Rspo1 ( -/- ) animals had improved glycaemic control after oral glucose challenge (p < 0.05), with no difference in insulin sensitivity, but an enhanced insulin response over 30 min (p < 0.05); glucagon responses were normal. Rspo1 deficiency also resulted in a twofold increase in beta cell mass (p < 0.05) in association with 2- and 12-fold increases in the number of beta cells positive for antigen identified by monoclonal antibody Ki67 (Ki67) (p < 0.01) and insulin-positive ductal cells (p < 0.05), respectively. No change in the number of TUNEL-positive beta cells was detected. Islets isolated from Rspo1 ( -/- ) animals displayed no differences in glucose-induced insulin secretion or in glucose suppression of glucagon. CONCLUSIONS/INTERPRETATION: The present study reveals an unexpected role for RSPO1 as a regulator of both beta cell proliferation and neogenesis in vivo, and reinforces the importance of cWNT signalling for the maintenance of normal pancreatic beta cell behaviour.

From cradle to grave: pancreatic beta-cell mass and glucagon-like peptide-1.

Type 2 diabetes mellitus and its clinical correlates, including impaired fasting blood glucose, obesity and insulin resistance, represent a significant public health issue worldwide, with the prevalence of these metabolic conditions increasing exponentially. Given the staggering financial costs and human suffering incurred by diabetes and its co-morbid conditions, any safe new therapeutic interventions that prove to have a beneficial effect in reducing the incidence of diabetes in susceptible individuals or in preventing progression of the disease would have major public health benefits. Studies on the regulation of beta-cell mass have demonstrated a remarkable plasticity, from fetal through adult life, as well as in response to a variety of stresses. These findings are considered in this review in the context of newer studies on the intestinal hormone, glucagon-like peptide-1, which not only enhances beta-cell function, but also stimulates beta-cell growth, neogenesis and survival.