Impaired adrenergic stimulation of cardiac function in hyperinsulinemic states is mediated in part by increased PDE4D expression. a) Insulin treatment (100 nM, 12hrs) impairs adrenergic stimulation of cAMP in mouse AVMs, which is rescued by pretreating cells with the PDE4 specific inhibitor rolipram (100 nM, n=6). &&& p <0.001 by two-way ANOVA, * p< 0.05, ** p < 0.01, and *** p < 0.001 by one-way ANOVA followed by post hoc Tukey's test. b and c) HFD leads to reduced PKA phosphorylation of PLB (S16) and TnI (S23/24), calcium signaling, and contractility in mouse AVMs in response to β adrenergic stimulation (ISO, 100 nM for AVM stimulation, n=6), which are rescued by the PDE4 inhibitor rolipram (100 nM). ** p < 0.01, and *** p < 0.001 by one-way ANOVA followed by post hoc Tukey's test