EP3 signaling is decoupled from regulation of glucose-stimulated insulin secretion in β-cells compensating for obesity and insulin resistance

Abstract

Of the {beta}-cell signaling pathways altered by non-diabetic obesity and insulin resistance, some are adaptive while others actively contribute to {beta}-cell failure and demise. Cytoplasmic calcium (Ca2+) and cyclic AMP (cAMP), which control the timing and amplitude of insulin secretion, are two important signaling intermediates that can be controlled by stimulatory and inhibitory G protein-coupled receptors. Previous work has shown the importance of the cAMP-inhibitory EP3 receptor in the beta-cell dysfunction of type 2 diabetes. To examine alterations in {beta}-cell cAMP during diabetes progression we utilized a {beta}-cell specific cAMP biosensor in tandem with islet Ca2+ recordings and insulin secretion assays. Three groups of C57BL/6J mice were used as a model of the progression from metabolic health to type 2 diabetes: wildtype, normoglycemic LeptinOb, and hyperglycemic LeptinOb. Here, we report robust increases in {beta}-cell cAMP and insulin secretion responses in normoglycemic Leptinob mice as compared to wild-type: an effect that was lost in islets from hyperglycemic Leptinob mice, despite elevated Ca2+ duty cycle. Yet, the correlation of EP3 expression and activity to reduce cAMP levels and Ca2+ duty cycle with reduced insulin secretion only held true in hyperglycemic LeptinOb mice. Our results suggest alterations in beta-cell EP3 signaling may be both adaptive and maladaptive and define {beta}-cell EP3 signaling as much more nuanced than previously understood.