title: Exchange protein activated by cAMP 1 (Epac1)-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.
authors.affiliation: 2Department of Anatomy, 1/F, Laboratory Block, Faculty of Medicine Bldg., 21 Sassoon Rd., Hong Kong, China. skchung@hkucc.hku.hk.
authors.forename: Alan K L
authors.initials: AK
authors.lastname: Kai
authors.forename: Amy K M
authors.initials: AK
authors.lastname: Lam
authors.forename: Yingxian
authors.initials: Y
authors.lastname: Chen
authors.forename: Andrew C P
authors.initials: AC
authors.lastname: Tai
authors.forename: Xinmei
authors.initials: X
authors.lastname: Zhang
authors.forename: Angela K W
authors.initials: AK
authors.lastname: Lai
authors.forename: Patrick K K
authors.initials: PK
authors.lastname: Yeung
authors.forename: Sidney
authors.initials: S
authors.lastname: Tam
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Karen S
authors.initials: KS
authors.lastname: Lam
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Bos
authors.forename: Stephen S M
authors.initials: SS
authors.lastname: Chung
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Sookja K
authors.initials: SK
authors.lastname: Chung
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental; D004041:Dietary Fats / Q000009:adverse effects; D053595:Embryonic Stem Cells; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000235:genetics
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors
keywords: glucose transporter type 2; glucose-stimulated insulin secretion; high-fat-diet-induced obesity; hyperglycemia; multiple low-dose streptozotocin-induced diabetes