| First Author | Kai AK | Year | 2013 |
| Journal | FASEB J | Volume | 27 |
| Issue | 10 | Pages | 4122-35 |
| PubMed ID | 23825225 | Mgi Jnum | J:201171 |
| Mgi Id | MGI:5511109 | Doi | 10.1096/fj.13-230433 |
| Citation | Kai AK, et al. (2013) Exchange protein activated by cAMP 1 (Epac1)-deficient mice develop beta-cell dysfunction and metabolic syndrome. FASEB J 27(10):4122-4135 |
| abstractText | 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 beta cells. The present study shows that Epac1 mRNA is also expressed by beta cells. Therefore, we generated mice and embryonic stem (ES) cells with deletion of the Epac1 gene to define its role in beta-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 beta-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 beta-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 beta-cell function. The current study provides in vitro and in vivo evidence that Epac1 has an important role in GSIS of beta 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 beta-cell dysfunction and metabolic syndrome. |
