Several studies have shown that activation of M3 muscarinic acetylcholine (ACh) receptors (M3Rs) expressed by pancreatic beta-cells leads to striking increases in glucose-stimulated insulin release. As a result, we hypothesized that agents that can promote signaling through beta-cell M3Rs might become useful in the treatment of type 2 diabetes. The M3R is a prototypic class A GPCR that is selectively coupled to G proteins of the Gq family. At present, selective M3R agonists that bind to the orthosteric ACh binding site are not available. However, the lab of Craig Lindsley (Bridges et al., 2010) recently described a compound (VU0119498) that binds to an allosteric site on the M3R, thus enhancing ACh-induced signaling through M3Rs. In this study, we tested the ability of this positive allosteric modulator (PAM) to stimulate insulin release in vitro and in vivo. The use of PAMs has the great advantage that it respects the spatio-temporal control of receptor activation, i.e., the PAM is only active upon receptor occupation by an endogenous orthosteric agonist. Studies with cultured MIN6 cells showed that VU0119498 enhanced ACh-induced insulin secretion in an M3R-dependent fashion. In vivo studies demonstrated that PAM treatment of WT mice caused a significant increase in plasma insulin levels, accompanied by a striking improvement in glucose tolerance. These VU0119498 effects were mediated by beta-cell M3Rs since they were absent in mutant mice selectively lacking M3Rs in beta-cells. In future studies, we will use mouse models of diabetes to examine whether this M3R-PAM is endowed with antidiabetic activity. This approach may lead to the development of a novel generation of antidiabetic drugs.


L. Zhu: None. J. Wess: None.

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