Chronic hyperglycemia downregulates GLP-1 receptor signaling in pancreatic β-cells via protein kinase A.

ABSTRACT:

Objective

Glucagon-like peptide 1 (GLP-1) enhances insulin secretion and protects β-cell mass. Diabetes therapies targeting the GLP-1 receptor (GLP-1R), expressed in numerous tissues, have diminished dose-response in patients with type 2 diabetes compared with healthy human controls. The aim of this study was to determine the mechanistic causes underlying the reduced efficacy of GLP-1R ligands.

Methods

Using primary mouse islets and the β-cell line MIN6, outcomes downstream of the GLP-1R were analyzed: Insulin secretion; phosphorylation of the cAMP-response element binding protein (CREB); cAMP responses. Signaling systems were studied by immunoblotting and qRT-PCR, and PKA activity was assayed. Cell surface localization of the GLP-1R was studied by confocal microscopy using

SUBMITTER: Rajan S 

PROVIDER: S-EPMC4354925 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature