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Pancreas. 2014 Jan;43(1):93-102. doi: 10.1097/MPA.0b013e3182a70bfb.

R-spondin1 deficiency enhances β-Cell neogenesis in a murine model of diabetes.

Author information

1
From the *Department of Physiology, University of Toronto, Toronto, Ontario, Canada; †Centre for Neuroscience, UC Davis, Davis, CA; ‡iBV, INSERM U1091, CNRS UMR7277, University of Nice Sophia-Antipolis, UFR Sciences, F-06108 Nice, France; and §Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada.

Abstract

OBJECTIVE:

The cWnt activator, R-spondin1 (Rspo1), regulates β-cell growth, function, and neogenesis, although its role in conditions such as streptozotocin (STZ)-induced diabetes is unknown. We hypothesized that Rspo1 deficiency enhances β-cell neogenesis in STZ-induced diabetes.

METHODS:

Wild-type (Rspo1) and knockout (Rspo1) mice were injected with STZ (40 mg/kg) for 5 days, followed by analysis of oral glucose and insulin tolerance, and were killed on day 6 (acute; 9-11 mice) or 32 (chronic; 11-16 mice). Immunohistochemistry was performed for β-cell apoptosis, proliferation, neogenesis, and markers of β-cell maturity.

RESULTS:

There was no difference in oral glucose handling between STZ-induced Rspo1 and Rspo1 mice, although Rspo1 mice demonstrated increased insulin sensitivity. β-cell mass, islet number, and islet size distribution did not differ between STZ-induced Rspo1 and Rspo1 mice, but Rspo1 animals had reduced β-cell apoptosis and increased numbers of insulin-positive ductal cells, indicating β-cell neogenesis. Furthermore, the increased β-cell regeneration observed in the Rspo1 animals was associated with a more differentiated/mature β-cell phenotype as assessed by increased immunopositivity for Nkx6.1, MafA, and GLUT2.

CONCLUSIONS:

These findings indicate that Rspo1 is a negative regulator of β-cell neogenesis, development, and survival in the face of STZ-induced diabetes, providing a therapeutic target for the enhancement of β-cell mass.

PMID:
24263108
DOI:
10.1097/MPA.0b013e3182a70bfb
[Indexed for MEDLINE]

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