Exchange protein activated by cAMP 1 (Epac1)-deficient mice develop β-cell dysfunction and metabolic syndrome

FASEB J. 2013 Oct;27(10):4122-35. doi: 10.1096/fj.13-230433. Epub 2013 Jun 27.


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 Epac1(-/-) 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.

Keywords: glucose transporter type 2; glucose-stimulated insulin secretion; high-fat-diet-induced obesity; hyperglycemia; multiple low-dose streptozotocin-induced diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose
  • Diabetes Mellitus, Experimental
  • Dietary Fats / adverse effects
  • Embryonic Stem Cells
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Insulin-Secreting Cells / metabolism*
  • Metabolic Syndrome / metabolism*
  • Mice
  • Mice, Knockout
  • Obesity / etiology
  • Obesity / genetics


  • Blood Glucose
  • Dietary Fats
  • Epac protein, mouse
  • Guanine Nucleotide Exchange Factors