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R-spondin1 deficiency in mice improves glycaemic control in association with increased beta cell mass
V S C Wong1, A H Oh, A A Chassot
1Department of Physiology, Room 3366 Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, ON, Canada, M5S 1A8.
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.
Insights
Roof plate-specific spondin 1 (RSPO1) deficiency unexpectedly increased beta cell mass and improved glucose control in mice. This highlights RSPO1
Area of Science:
- Endocrinology and Metabolism
- Developmental Biology
- Molecular Signaling
Background:
- Roof plate-specific spondin 1 (RSPO1) modulates canonical Wnt/β-catenin signaling, crucial for various developmental processes.
- RSPO1 is expressed in murine beta cells and influences their function, including proliferation, insulin secretion, and apoptosis resistance.
- Investigating RSPO1's in vivo role in beta cells is essential for understanding pancreatic islet biology.
Purpose of the Study:
- To elucidate the in vivo function of RSPO1 in pancreatic beta cells.
- To determine the impact of RSPO1 deficiency on beta cell mass, function, and glucose homeostasis.
- To assess the role of RSPO1 in regulating canonical Wnt/β-catenin signaling within pancreatic islets.
Main Methods:
- Generation and analysis of Rspo1 knockout (Rspo1-/-) mice.
- Assessment of canonical Wnt/β-catenin signaling pathway activity in islets.
- Evaluation of glucose tolerance, insulin sensitivity, and insulin/glucagon responses.
- Quantification of beta cell mass, proliferation (Ki67+ cells), and neogenesis (insulin+ ductal cells).
- Analysis of beta cell apoptosis using TUNEL staining.
Main Results:
- Rspo1 deficiency led to significantly reduced RSPO1 transcripts and protein levels, with decreased islet Wnt/β-catenin signaling.
- Rspo1-/- mice exhibited improved glucose tolerance and an enhanced insulin response, despite normal fasting glucose and insulin levels.
- Beta cell mass was doubled in Rspo1-/- mice, associated with increased beta cell proliferation and insulin-positive ductal cells, indicating enhanced neogenesis.
- No differences in apoptosis or isolated islet function (glucose-stimulated insulin secretion) were observed.
Conclusions:
- RSPO1 acts as a novel regulator of beta cell proliferation and neogenesis in vivo.
- Canonical Wnt/β-catenin signaling is critical for maintaining normal pancreatic beta cell behavior and mass.
- Targeting RSPO1 or Wnt/β-catenin signaling may offer therapeutic strategies for diabetes by modulating beta cell regeneration.
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