Exchange protein activated by cAMP 1 <i>(Epac1)</i> ‐deficient mice develop β‐cell dysfunction and metabolic syndrome

Abstract

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. Kai, A. K. L., Lam, A. K. M., Chen, Y., Tai, A. C. P., Zhang, X., Lai, A. K. W., Yeung, P. K. K., Tam, S., Wang, J., Lam, K. S., Vanhoutte, P. M., Bos, J. L., Chung, S. S. M., Xu, A., Chung, S. K. Exchange protein activated by cAMP 1 ( Epac1 )‐deficient mice develop β‐cell dysfunction and metabolic syndrome. FASEBJ. 27, 4122–4135 (2013). www.fasebj.org