Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion
As an incretin hormone, glucagon-like peptide 1 (GLP-1) lowers blood glucose levels by enhancing glucose-stimulated insulin secretion from pancreatic beta-cells. Therapies targeting the GLP-1 receptor (GLP-1R) use the classical incretin model as a physiological framework in which GLP-1 secreted from...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.934775/full |
| _version_ | 1818042125595443200 |
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| author | Marlena M. Holter Mridusmita Saikia Mridusmita Saikia Bethany P. Cummings |
| author_facet | Marlena M. Holter Mridusmita Saikia Mridusmita Saikia Bethany P. Cummings |
| author_sort | Marlena M. Holter |
| collection | DOAJ |
| description | As an incretin hormone, glucagon-like peptide 1 (GLP-1) lowers blood glucose levels by enhancing glucose-stimulated insulin secretion from pancreatic beta-cells. Therapies targeting the GLP-1 receptor (GLP-1R) use the classical incretin model as a physiological framework in which GLP-1 secreted from enteroendocrine L-cells acts on the beta-cell GLP-1R. However, this model has come into question, as evidence demonstrating local, intra-islet GLP-1 production has advanced the competing hypothesis that the incretin activity of GLP-1 may reflect paracrine signaling of GLP-1 from alpha-cells on GLP-1Rs on beta-cells. Additionally, recent studies suggest that alpha-cell-derived glucagon can serve as an additional, albeit less potent, ligand for the beta-cell GLP-1R, thereby expanding the role of alpha-cells beyond that of a counterregulatory cell type. Efforts to understand the role of the alpha-cell in the regulation of islet function have revealed both transcriptional and functional heterogeneity within the alpha-cell population. Further analysis of this heterogeneity suggests that functionally distinct alpha-cell subpopulations display alterations in islet hormone profile. Thus, the role of the alpha-cell in glucose homeostasis has evolved in recent years, such that alpha-cell to beta-cell communication now presents a critical axis regulating the functional capacity of beta-cells. Herein, we describe and integrate recent advances in our understanding of the impact of alpha-cell paracrine signaling on insulin secretory dynamics and how this intra-islet crosstalk more broadly contributes to whole-body glucose regulation in health and under metabolic stress. Moreover, we explore how these conceptual changes in our understanding of intra-islet GLP-1 biology may impact our understanding of the mechanisms of incretin-based therapeutics. |
| first_indexed | 2024-12-10T08:41:21Z |
| format | Article |
| id | doaj.art-2cd53a8838c742bdbd5a056e2f5d1475 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-12-10T08:41:21Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-2cd53a8838c742bdbd5a056e2f5d14752022-12-22T01:55:51ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-07-011310.3389/fendo.2022.934775934775Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretionMarlena M. Holter0Mridusmita Saikia1Mridusmita Saikia2Bethany P. Cummings3Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesDepartment of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesNancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United StatesSchool of Medicine, Department of Surgery, Center for Alimentary and Metabolic Sciences, University of California, Davis, Sacramento, CA, United StatesAs an incretin hormone, glucagon-like peptide 1 (GLP-1) lowers blood glucose levels by enhancing glucose-stimulated insulin secretion from pancreatic beta-cells. Therapies targeting the GLP-1 receptor (GLP-1R) use the classical incretin model as a physiological framework in which GLP-1 secreted from enteroendocrine L-cells acts on the beta-cell GLP-1R. However, this model has come into question, as evidence demonstrating local, intra-islet GLP-1 production has advanced the competing hypothesis that the incretin activity of GLP-1 may reflect paracrine signaling of GLP-1 from alpha-cells on GLP-1Rs on beta-cells. Additionally, recent studies suggest that alpha-cell-derived glucagon can serve as an additional, albeit less potent, ligand for the beta-cell GLP-1R, thereby expanding the role of alpha-cells beyond that of a counterregulatory cell type. Efforts to understand the role of the alpha-cell in the regulation of islet function have revealed both transcriptional and functional heterogeneity within the alpha-cell population. Further analysis of this heterogeneity suggests that functionally distinct alpha-cell subpopulations display alterations in islet hormone profile. Thus, the role of the alpha-cell in glucose homeostasis has evolved in recent years, such that alpha-cell to beta-cell communication now presents a critical axis regulating the functional capacity of beta-cells. Herein, we describe and integrate recent advances in our understanding of the impact of alpha-cell paracrine signaling on insulin secretory dynamics and how this intra-islet crosstalk more broadly contributes to whole-body glucose regulation in health and under metabolic stress. Moreover, we explore how these conceptual changes in our understanding of intra-islet GLP-1 biology may impact our understanding of the mechanisms of incretin-based therapeutics.https://www.frontiersin.org/articles/10.3389/fendo.2022.934775/fullalpha-cellbeta-cellparacrine signalingGLP-1glucagoninsulin |
| spellingShingle | Marlena M. Holter Mridusmita Saikia Mridusmita Saikia Bethany P. Cummings Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion Frontiers in Endocrinology alpha-cell beta-cell paracrine signaling GLP-1 glucagon insulin |
| title | Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion |
| title_full | Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion |
| title_fullStr | Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion |
| title_full_unstemmed | Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion |
| title_short | Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion |
| title_sort | alpha cell paracrine signaling in the regulation of beta cell insulin secretion |
| topic | alpha-cell beta-cell paracrine signaling GLP-1 glucagon insulin |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.934775/full |
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