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.

Epac2-deficiency leads to more severe retinal swelling, glial reactivity and oxidative stress in transient middle cerebral artery occlusion induced ischemic retinopathy

“…The Epac1  mice displayed neither developmental nor reproductive abnormalities, but they showed an impaired glucose tolerance and insulin secretion reduction after glucose challenge when compared with their Epac1 +/+ littermates [20]. Epac2  mice also have such insulin secretion dysfunction after glucose stimulation [26].…”

“… mice were generated previously [20], and they were backcrossed to C57BL/6N mice for more than 10 generations. Age-matched Epac1 +/+ littermates served as the control group.…”

Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions

“…Previous studies reported that the GEFs Epac1 and Epac2 attenuate cellular leptin signaling in cultured cells and brain slices (Fukuda et al, 2011; Sands et al, 2006). However, the biological significance of this effect remains controversial because while one study showed resistance to diet-induced obesity in Epac1-null mice (Yan et al, 2013), another reported augmented diet-induced obesity and glucose imbalance in the Epac1 global-knockout mice (Kai et al, 2013). In contrast to this conflicting data on the role of Epac1 in the control of whole-body energy and glucose balance, our findings suggest that brain Epac2 is likely involved in Rap1 activation and its effects on hypothalamic functions in HFD-induced obesity.…”

Role of Exchange Protein Activated by cAMP 1 in Regulating Rates of Microtubule Formation in Cystic Fibrosis Epithelial Cells

“…The implication of reduced EPAC1/ Rap1 functions in CF phenotypes needs to be further explored. For example, EPAC1 deficiency is associated with insulin resistance, and could be a factor in the development of CF-related diabetes (41).…”