Our results revealed the dual effect of peripheral-specific Y1 receptor antagonism as a potential therapeutic strategy for T2D: 1) during the early pathogenesis of diabetes, whereby compensatory β-cell function is present driven by obesity and insulin resistance, we found that the inhibition of peripheral Y1 receptor signaling led to decreased adiposity, increased insulin sensitivity and, to a lesser extent, enhanced insulin-stimulated glucose uptake in the skeletal muscle. Here, INS is linked to diabetes mellitus.