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Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis
Yazhou Li1, Tanya Hansotia, Bernardo Yusta
1Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Ontario M5G 2C4, Canada.
Abstract:
Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and augments beta cell mass via activation of beta cell proliferation and islet neogenesis. We examined whether GLP-1 receptor signaling modifies the cellular susceptibility to apoptosis. Mice administered streptozotocin (STZ), an agent known to induce beta cell apoptosis, exhibit sustained improvement in glycemic control and increased levels of plasma insulin with concomitant administration of the GLP-1 agonist exendin-4 (Ex-4). Blood glucose remained significantly lower for weeks after cessation of exendin-4. STZ induced beta cell apoptosis, which was significantly reduced by co-administration of Ex-4. Conversely, mice with a targeted disruption of the GLP-1 receptor gene exhibited increased beta cell apoptosis after STZ administration. Exendin-4 directly reduced cytokine-induced apoptosis in purified rat beta cells exposed to interleukin 1beta, tumor necrosis fator alpha, and interferon gamma in vitro. Furthermore, Ex-4-treated BHK-GLP-1R cells exhibited significantly increased cell viability, reduced caspase activity, and decreased cleavage of beta-catenin after treatment with cycloheximide in vitro. These findings demonstrate that GLP-1 receptor signaling directly modifies the susceptibility to apoptotic injury, and provides a new potential mechanism linking GLP-1 receptor activation to preservation or enhancement of beta cell mass in vivo.
Insights
Glucagon-like peptide-1 (GLP-1) receptor signaling protects against beta cell apoptosis. Exendin-4, a GLP-1 agonist, reduced STZ-induced beta cell death and improved glycemic control in mice.
Area of Science:
- Endocrinology and Metabolism
- Cell Biology
- Diabetes Research
Background:
- Glucagon-like peptide-1 (GLP-1) is known to stimulate insulin secretion and enhance beta cell mass.
- The role of GLP-1 receptor signaling in modulating beta cell susceptibility to apoptosis remains to be fully elucidated.
- Streptozotocin (STZ) is a diabetogenic agent that induces beta cell apoptosis.
Purpose of the Study:
- To investigate whether GLP-1 receptor signaling influences cellular susceptibility to apoptosis.
- To determine the protective effects of GLP-1 receptor activation on beta cells in vivo and in vitro.
Main Methods:
- Mice were administered streptozotocin (STZ) with or without the GLP-1 agonist exendin-4 (Ex-4).
- GLP-1 receptor knockout mice were subjected to STZ administration.
- Purified rat beta cells and BHK-GLP-1R cells were treated with Ex-4 and apoptotic stimuli in vitro.
Main Results:
- Co-administration of Ex-4 with STZ significantly reduced beta cell apoptosis and improved glycemic control in mice.
- Mice lacking the GLP-1 receptor exhibited increased beta cell apoptosis following STZ treatment.
- Exendin-4 demonstrated direct protection against cytokine-induced apoptosis in isolated beta cells and reduced caspase activity in vitro.
Conclusions:
- GLP-1 receptor signaling directly modulates beta cell susceptibility to apoptotic injury.
- Activation of the GLP-1 receptor offers a protective mechanism against beta cell loss.
- These findings suggest a novel pathway linking GLP-1 receptor activation to the preservation or enhancement of beta cell mass.