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

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.