The canonical pathway of GPCR activation postulates increases in the second messenger cAMP following the receptor activation that rapidly attenuates with the receptor internalization and desensitization. The activation of the receptor propels a cellular signaling cascade that eventually potentiates glucose-stimulated insulin secretion (GSIS) ( Drucker, 2006). In each instance, the receptor stabilizes in an active conformation suitable for the association with heterotrimeric G-protein subunit Gα s and subsequent activation of the adenylate cyclase. Incretin receptors can be activated by orthosteric peptide-based agonists ( Drucker et al., 2010), dual agonists ( Finan et al., 2013), and small-molecule allosteric modulators ( Knudsen et al., 2007 Bueno et al., 2016). The unmet medical need warrants additional complementary mechanisms to incretin action ( Tschöp and DiMarchi, 2017) or a novel approach to supplement incretin pharmacology. Unfortunately, not all patients achieve normal glucose control, and even fewer show reversal of obesity ( Amori et al., 2007). Incretin-based therapy and specifically glucagon-like peptide 1 receptor (GLP-1R) agonists provide sizable glycemic benefit and modest improvement in the body weight ( Astrup et al., 2009).

Type 2 diabetes (T2D) and obesity have reached global epidemic levels and required a therapeutic intervention to reduce the burden of the disease. Source Data Figure 3K: Relative GLUT2 mRNA expression the quantification was carried out using the 2 -ΔΔC T method and the data normalized using 18S rRNA as reference Source Data Figure 3L: Effect of MS-275 on Basal Glucose uptake in BRIN-BD11 pancreatic beta cells. Source Data Figure 3H: Effect of chemical uncoupling of mitochondrial oxidative phosphorylation by CCCP (10 μM) on GLP-1R-mediated cAMP generation in control and MS-275-treated cultured pancreatic beta cells. Source Data Figure 3D and Figure 3E: Relative beta arrestin1 mRNA and beta-arrestin 2 mRNA expression the quantification was carried out using the 2 -ΔΔC T method and the data normalized using GAPDH as reference. Source Data Figure 3G: Relative Adcy8 mRNA expression the quantification was carried out using the 2 -ΔΔC T method and the data normalized using GAPDH as reference. Figure 3-source data 2: Source Data Figure 3B: Relative GLP-1R mRNA expression the quantification was carried out using the 2 -ΔΔC T method and the data normalized using GAPDH as reference.

Blood in blood out 5 hour version