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However, the GLP-1 [736] amide accounts for 80% of circulating GLP-1 ( FIGURE 1 Notably, the insulinotropic actions of circulating GLP-1 are facilitated through a two-domain binding interaction with GLP-1R (Figure 2), a structurally well-characterized prototypical class B GPCR, which recruits the G s -subunit of the heterotrimeric G-protein for cAMP-mediated downstream signaling, involving protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), leading to insulin exocytosis