Glucagon-like peptide 1 receptor (GLP-1R) is a G protein-coupled receptor that is highly expressed on pancreatic beta-cells and activated by endogenous incretins or antidiabetic GLP-1R agonist drugs. GLP-1R function is important in maintaining glucose homeostasis and involves stimulation of glucose-induced beta-cell insulin secretion via cAMP generation. While GLP-1R expression has been shown to be downregulated in diabetes, the molecular mechanisms have not been fully elucidated. In this study, we have discovered that miR-204, a highly beta-cell-enriched microRNA that is upregulated in diabetes, directly targets the 3’ UTR of GLP-1R and decreases its expression in INS-1 cells as well as primary mouse and human islets. Moreover, genetic knockout of miR-204 in vivo increased islet GLP-1R expression and enhanced GLP-1R agonist-induced cAMP production and insulin secretion, resulting in improved glucose tolerance as well as protection against diabetes. In addition, miR-204 antagomir administration was able to mimic the effects of genetic miR-204 deletion and resulted again in GLP-1R agonist-induced insulin secretion as well as improved glucose tolerance. Thus, these results indicate for the first time that GLP-1R is under the control of a micro RNA and suggest that antagomir-mediated inhibition of miR-204 represents a potential novel therapeutic approach to promote the actions of GLP-1R agonist drugs in a beta-cell-specific manner and thereby help treat diabetes.
S. Jo: None. J. Chen: None. G. Xu: None. T. Grayson: None. L. Thielen: None. A. Shalev: None.