Allosteric modulation of β-cell M 3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice
| Autor: | James E. Melvin, Diptadip Dattaroy, Jürgen Wess, Mario Rossi, Jennifer Langel, Nicolai M. Doliba, Hongchao Zheng, Taro Mukaibo, Franz M. Matschinsky, Lu Zhu, Daniel H. Appella, Samer Hattar, Jonathan Pham, Amanda Cohen |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Multidisciplinary Allosteric modulator Chemistry Insulin medicine.medical_treatment Pancreatic islets Allosteric regulation 030209 endocrinology & metabolism 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Endocrinology medicine.anatomical_structure Internal medicine Muscarinic acetylcholine receptor medicine Glucose homeostasis Receptor Acetylcholine medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 116:18684-18690 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1904943116 |
| Popis: | 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 M3 muscarinic 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. |
| Databáze: | OpenAIRE |
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