Allosteric modulation of β-cell M₃muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice

Abstract

Given the global epidemic in type 2 diabetes, novel antidiabetic drugs with increased efficacy and reduced side effects are urgently needed. Previous work has shown that M3muscarinic acetylcholine (ACh) receptors (M3Rs) expressed by pancreatic β cells play key roles in stimulating insulin secretion and maintaining physiological blood glucose levels. In the present study, we tested the hypothesis that a positive allosteric modulator (PAM) of M3R function can improve glucose homeostasis in mice by promoting insulin release. One major advantage of this approach is that allosteric agents respect the ACh-dependent spatiotemporal control of M3R activity. In this study, we first demonstrated that VU0119498, a drug known to act as a PAM at M3Rs, significantly augmented ACh-induced insulin release from cultured β cells and mouse and human pancreatic islets. This stimulatory effect was absent in islets prepared from mice lacking M3Rs, indicative of the involvement of M3Rs. VU0119498 treatment of wild-type mice caused a significant increase in plasma insulin levels, accompanied by a striking improvement in glucose tolerance. These effects were mediated by β-cell M3Rs, since they were absent in mutant mice selectively lacking M3Rs in β cells. Moreover, acute VU0119498 treatment of obese, glucose-intolerant mice triggered enhanced insulin release and restored normal glucose tolerance. Interestingly, doses of VU0119498 that led to pronounced improvements in glucose homeostasis did not cause any significant side effects due to activation of M3Rs expressed by other peripheral cell types. Taken together, the data from this proof-of-concept study strongly suggest that M3R PAMs may become clinically useful as novel antidiabetic agents.

Potentiation of Muscarinic M3Receptor Activation through a New Allosteric Site with a Novel Positive Allosteric Modulator ASP8302

“…The observed leftward shift by 51.2 times at 1 μmol/L ASP8302 suggests that ASP8302 is more potent than other functionally confirmed M 3 receptor PAMs (no shift with VU0119498 up to 1 μmol/L(Burger et al, 2018) or 10 times shift at 1 μmol/L for Compound 9(Tanaka et al, 2020)). In addition, ASP8302 produced no change in the E max of CCh-induced intracellular Ca 2+ mobilization whereas amiodarone(Stahl et al, 2011) and VU0119498(Zhu et al, 2019) increased it. These findings demonstrate a unique M 3 PAM profile of ASP8302.…”

Current Advances in Allosteric Modulation of Muscarinic Receptors

“…Effects of acetylcholine on insulin secretion are mediated by the M3 receptor [91]. In accordance, M3 PAM of acetylcholine VU0119498 ( Figure 10) has been shown to enhance glucose-stimulated insulin secretion and greatly improve glucose tolerance in lean and obese glucose-intolerant mice [92]. These effects were absent from mice lacking M3 receptors in their β cells.…”

ENDOCRINOLOGY IN PREGNANCY: Metabolic impact of bile acids in gestation

“…Muscarinic receptors are responsible for the physiological effects of acetylcholine, which acts as a neurotransmitter in the brain or neuromuscular junctions and also mediates the parasympathetic system (3). There is increasing evidence that positive allosteric modulation of M 3 muscarinic receptors improves glucose homeostasis and promotes insulin release (54,55), and mice lacking M 3 in pancreatic β-cells displayed impaired glucose control and reduced insulin release, producing a diabetic phenotype (54).…”