title: Pancreatic β-cell response to increased metabolic demand and to pharmacologic secretagogues requires EPAC2A.
abstract: Incretin hormone action on β-cells stimulates in parallel two different intracellular cyclic AMP-dependent signaling branches mediated by protein kinase A and exchange protein activated by cAMP islet/brain isoform 2A (EPAC2A). Both pathways contribute toward potentiation of glucose-stimulated insulin secretion (GSIS). However, the overall functional role of EPAC2A in β-cells as it relates to in vivo glucose homeostasis remains incompletely understood. Therefore, we have examined in vivo GSIS in global EPAC2A knockout mice. Additionally, we have conducted in vitro studies of GSIS and calcium dynamics in isolated EPAC2A-deficient islets. EPAC2A deficiency does not impact GSIS in mice under basal conditions. However, when mice are exposed to diet-induced insulin resistance, pharmacologic secretagogue stimulation of β-cells with an incretin hormone glucagon-like peptide-1 analog or with a fatty acid receptor 1/G protein-coupled receptor 40 selective activator, EPAC2A is required for the increased β-cell response to secretory demand. Under these circumstances, EPAC2A is required for potentiating the early dynamic increase in islet calcium levels after glucose stimulation, which is reflected in potentiated first-phase insulin secretion. These studies broaden our understanding of EPAC2A function and highlight its significance during increased secretory demand or drive on β-cells. Our findings advance the rationale for developing EPAC2A-selective pharmacologic activators for β-cell-targeted pharmacotherapy in type 2 diabetes.
authors.affiliation: Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Woo-Jin
authors.initials: WJ
authors.lastname: Song
authors.forename: Prosenjit
authors.initials: P
authors.lastname: Mondal
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.forename: Suh Eun
authors.initials: SE
authors.lastname: Lee
authors.forename: Mehboob A
authors.initials: MA
authors.lastname: Hussain
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005951:Glucose Tolerance Test; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; C486707:Rapgef4 protein, mouse; D005947:Glucose; D002118:Calcium