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

Abstract

ABSTRACTOf the β-cell signaling pathways altered by non-diabetic obesity and insulin resistance, some are adaptive while others actively contribute to β-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 β-cell cAMP during diabetes progression we utilized a β-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, normoglycemicLeptinOb, and hyperglycemicLeptinOb. Here, we report robust increases in β-cell cAMP and insulin secretion responses in normoglycemicLeptinobmice as compared to wild-type: an effect that was lost in islets from hyperglycemicLeptinobmice, 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 hyperglycemicLeptinObmice. Our results suggest alterations in beta-cell EP3 signaling may be both adaptive and maladaptive and define β-cell EP3 signaling as much more nuanced than previously understood.