A positive allosteric modulator that promotes insulin secretion in mice by selectively enhancing M3 muscarinic receptor signaling in beta-cells

– Poster Session IV
3:30 – 5:00 p.m.

FAES Terrace

NIDDK

PHARM-7

Authors

  • Lu Zhu
  • M Rossi
  • A Cohen
  • H Zheng
  • JL Langel
  • S Hattar
  • D Apella
  • NM Doliba
  • J Wess

Abstract

The inability of pancreatic beta-cells to secrete sufficient amounts of insulin is a key feature of type 2 diabetes. We previously showed that acetylcholine (ACh)-dependent activation of beta-cell M3 muscarinic receptors (M3Rs) strongly enhances glucose-stimulated insulin release. ACh and other classical muscarinic receptor agonists bind to the so-called orthosteric site on muscarinic receptors that is highly conserved among the five muscarinic receptor subtypes (M1-M5Rs). To more selectively enhance signaling through the M3R, we studied a positive allosteric modulator (PAM) that is known to enhance ACh-mediated activation of M3Rs in vitro (VU0119498). The potential therapeutic use of allosteric modulators has the advantage that such agents preserve the temporal-spatial pattern of endogenous M3R signaling. We initially demonstrated that VU0119498 greatly enhanced ACh-induced insulin secretion in cultured MIN6 cells and isolated mouse pancreatic islets. We obtained similar findings with isolated human islets. Acute treatment of mice with VU0119498 resulted in significant increases in plasma insulin levels, associated with improved glucose tolerance. This effect was observed independent of the diet on which the mice were maintained (regular chow vs. high fat diet). Importantly, the beneficial metabolic effects caused by VU0119498 treatment were absent in mice that selectively lacked M3Rs in pancreatic beta-cells. Administration of VU0119498 had no or little effect on other M3R-mediated physiological functions including regulation of pupil size and salivary secretion. Taken together, these data strongly suggest that selective M3R-PAMs may prove useful as novel antidiabetic drugs.

Scientific Focus Area: Molecular Pharmacology

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