Previously, exchange protein directly activated by cAMP 2 (Epac2) and PKA were known to play a role in glucose-stimulated insulin secretion (GSIS) by pancreatic β cells. The present study shows that Epac1 mRNA is also expressed by β cells. Therefore, we generated mice and embryonic stem (ES) cells with deletion of the Epac1 gene to define its role in β-cell biology and metabolism. The homozygous Epac1-knockout (Epac1-) mice developed impaired glucose tolerance and GSIS with deranged islet cytoarchitecture, which was confirmed by isolated islets from adult Epac1-/- mice. Moreover, Epac1-/- mice developed more severe hyperglycemia with increased β-cell apoptosis and insulitis after multiple low-dose streptozotocin (MLDS; 40 mg/kg) treatment than Epac1+/+ mice. Interestingly, Epac1- mice also showed metabolic defects, including increased respiratory exchange ratio (RER) and plasma triglyceride (TG), and more severe diet-induced obesity with insulin resistance, which may contributed to β-cell dysfunction. However, islets differentiated from Epac-1- ES cells showed insulin secretion defect, reduced Glut2 and PDX-1 expression, and abolished GLP-1-stimulated PCNA induction, suggesting a role of Epac1 in β-cell function. The current study provides in vitro and in vivo evidence that Epac1 has an important role in GSIS of β cells and phenotype resembling metabolic syndrome. © FASEB.
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