Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 18, Pages 6614-6619Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0710402105
Keywords
CREB; IRS-2
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Funding
- NICHD NIH HHS [U54 HD012303] Funding Source: Medline
- NIDDK NIH HHS [DK 074868, R01 DK033651, DK 033651, P01 DK074868, R37 DK033651] Funding Source: Medline
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Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone secreted from enteroendocrine L cells and potentiates glucose-dependent insulin secretion in pancreatic beta cells. Recently the GLP-1 receptor (GLP-1 R) has been a focus for new anti-diabetic therapy with the introduction of GLP-1 analogues and DPP-IV inhibitors, and this has stimulated additional interest in the mechanisms of GLP-1 signaling. Here we identify a mechanism for GLP-1 action, showing that the scaffold protein beta-arrestin-1 mediates the effects of GLP-1 to stimulate CAMP production and insulin secretion in P cells. Using a coimmunoprecipitation technique, we also found a physical association between the GLP-1 R and beta-arrestin-1 in cultured INS-1 pancreatic beta cells. beta-Arrestin-1 knockdown broadly attenuated GLP-1 signaling, causing decreased ERK and CREB activation and IRS-2 expression as well as reduced cAMP levels and impaired insulin secretion. However, beta-arrestin-1 knockdown did not affect GLP-1 R surface expression and ligand-induced GLP-1 R internalization/desensitization. Taken together, these studies indicate that beta-arrestin-1 plays a role in GLP-1 signaling leading to insulin secretion, defining a previously undescribed mechanism for GLP-1 action.
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