Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action.
Pancreatic islet β-cell dysfunction is characterized by defective glucose-stimulated insulin secretion (GSIS) and is a predominant component of the pathophysiology of diabetes. Imeglimin, a novel first-in-class small molecule tetrahydrotriazine drug candidate, improves glycemia and GSIS in preclinic...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0241651 |
| _version_ | 1819012623726804992 |
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| author | Sophie Hallakou-Bozec Micheline Kergoat Pascale Fouqueray Sébastien Bolze David E Moller |
| author_facet | Sophie Hallakou-Bozec Micheline Kergoat Pascale Fouqueray Sébastien Bolze David E Moller |
| author_sort | Sophie Hallakou-Bozec |
| collection | DOAJ |
| description | Pancreatic islet β-cell dysfunction is characterized by defective glucose-stimulated insulin secretion (GSIS) and is a predominant component of the pathophysiology of diabetes. Imeglimin, a novel first-in-class small molecule tetrahydrotriazine drug candidate, improves glycemia and GSIS in preclinical models and clinical trials in patients with Type 2 diabetes; however, the mechanism by which it restores β-cell function is unknown. Here, we show that imeglimin acutely and directly amplifies GSIS in islets isolated from rodents with Type 2 diabetes via a mode of action that is distinct from other known therapeutic approaches. The underlying mechanism involves increases in the cellular nicotinamide adenine dinucleotide (NAD+) pool-potentially via the salvage pathway and induction of nicotinamide phosphoribosyltransferase (NAMPT) along with augmentation of glucose-induced ATP levels. Further, additional results suggest that NAD+ conversion to a second messenger, cyclic ADP ribose (cADPR), via ADP ribosyl cyclase/cADPR hydrolase (CD38) is required for imeglimin's effects in islets, thus representing a potential link between increased NAD+ and enhanced glucose-induced Ca2+ mobilization which-in turn-is known to drive insulin granule exocytosis. Collectively, these findings implicate a novel mode of action for imeglimin that explains its ability to effectively restore-β-cell function and provides for a new approach to treat patients suffering from Type 2 diabetes. |
| first_indexed | 2024-12-21T01:47:00Z |
| format | Article |
| id | doaj.art-252dbd8ec96f47f7ab59bc8d28490a5c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T01:47:00Z |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-252dbd8ec96f47f7ab59bc8d28490a5c2022-12-21T19:20:00ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01162e024165110.1371/journal.pone.0241651Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action.Sophie Hallakou-BozecMicheline KergoatPascale FouqueraySébastien BolzeDavid E MollerPancreatic islet β-cell dysfunction is characterized by defective glucose-stimulated insulin secretion (GSIS) and is a predominant component of the pathophysiology of diabetes. Imeglimin, a novel first-in-class small molecule tetrahydrotriazine drug candidate, improves glycemia and GSIS in preclinical models and clinical trials in patients with Type 2 diabetes; however, the mechanism by which it restores β-cell function is unknown. Here, we show that imeglimin acutely and directly amplifies GSIS in islets isolated from rodents with Type 2 diabetes via a mode of action that is distinct from other known therapeutic approaches. The underlying mechanism involves increases in the cellular nicotinamide adenine dinucleotide (NAD+) pool-potentially via the salvage pathway and induction of nicotinamide phosphoribosyltransferase (NAMPT) along with augmentation of glucose-induced ATP levels. Further, additional results suggest that NAD+ conversion to a second messenger, cyclic ADP ribose (cADPR), via ADP ribosyl cyclase/cADPR hydrolase (CD38) is required for imeglimin's effects in islets, thus representing a potential link between increased NAD+ and enhanced glucose-induced Ca2+ mobilization which-in turn-is known to drive insulin granule exocytosis. Collectively, these findings implicate a novel mode of action for imeglimin that explains its ability to effectively restore-β-cell function and provides for a new approach to treat patients suffering from Type 2 diabetes.https://doi.org/10.1371/journal.pone.0241651 |
| spellingShingle | Sophie Hallakou-Bozec Micheline Kergoat Pascale Fouqueray Sébastien Bolze David E Moller Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action. PLoS ONE |
| title | Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action. |
| title_full | Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action. |
| title_fullStr | Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action. |
| title_full_unstemmed | Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action. |
| title_short | Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action. |
| title_sort | imeglimin amplifies glucose stimulated insulin release from diabetic islets via a distinct mechanism of action |
| url | https://doi.org/10.1371/journal.pone.0241651 |
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