Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice
Enzymatically stable and specific neuropeptide Y1 receptor (NPYR1) agonists, such as sea lamprey PYY(1-36) (SL-PYY(1-36)), are believed to improve glucose regulation in diabetes by targeting pancreatic islets. In this study, streptozotocin (STZ) diabetic transgenic GluCreERT2;ROSA26-eYFP and Ins1Cre...
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doaj-ff3f9ed79ae042faab83503d27504daa2021-02-25T13:30:43ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922021-02-011210.3389/fendo.2021.633625633625Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic MiceRyan A. Lafferty0Neil Tanday1R. Charlotte Moffett2Frank Reimann3Fiona M. Gribble4Peter R. Flatt5Nigel Irwin6SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, United KingdomSAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, United KingdomSAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, United KingdomWellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United KingdomWellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United KingdomSAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, United KingdomSAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, United KingdomEnzymatically stable and specific neuropeptide Y1 receptor (NPYR1) agonists, such as sea lamprey PYY(1-36) (SL-PYY(1-36)), are believed to improve glucose regulation in diabetes by targeting pancreatic islets. In this study, streptozotocin (STZ) diabetic transgenic GluCreERT2;ROSA26-eYFP and Ins1Cre/+;Rosa26-eYFP mouse models have been used to study effects of sustained NPYR1 activation on islet cell composition and alpha- and beta-cell lineage transitioning. STZ induced a particularly severe form of diabetes in Ins1Cre/+;Rosa26-eYFP mice, but twice-daily administration (25 nmol/kg) of SL-PYY(1-36) for 11 days consistently improved metabolic status. Blood glucose was decreased (p < 0.05 - p < 0.001) and both fasted plasma and pancreatic insulin significantly increased by SL-PYY(1-36). In both GluCreERT2;ROSA26-eYFP and Ins1Cre/+; Rosa26-eYFP mice, STZ provoked characteristic losses (p < 0.05 - p < 0.001) of islet numbers, beta-cell and pancreatic islet areas together with increases in area and central islet location of alpha-cells. With exception of alpha-cell area, these morphological changes were fully, or partially, returned to non-diabetic control levels by SL-PYY(1-36). Interestingly, STZ apparently triggered decreased (p < 0.001) alpha- to beta-cell transition in GluCreERT2;ROSA26-eYFP mice, together with increased loss of beta-cell identity in Ins1Cre/+;Rosa26-eYFP mice, but both effects were significantly (p < 0.001) reversed by SL-PYY(1-36). SL-PYY(1-36) also apparently reduced (p < 0.05) beta- to alpha-cell conversion in Ins1Cre/+;Rosa26-eYFP mice and glucagon expressing alpha-cells in GluCreERT2;ROSA26-eYFP mice. These data indicate that islet benefits of prolonged NPY1R activation, and especially restoration of beta-cell mass, are observed irrespective of diabetes status, being linked to cell lineage alterations including transdifferentiation of alpha- to beta-cells.https://www.frontiersin.org/articles/10.3389/fendo.2021.633625/fullpeptide YYsea lamprey PYYdiabetestransdifferentiationstreptozotocin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ryan A. Lafferty Neil Tanday R. Charlotte Moffett Frank Reimann Fiona M. Gribble Peter R. Flatt Nigel Irwin |
spellingShingle |
Ryan A. Lafferty Neil Tanday R. Charlotte Moffett Frank Reimann Fiona M. Gribble Peter R. Flatt Nigel Irwin Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice Frontiers in Endocrinology peptide YY sea lamprey PYY diabetes transdifferentiation streptozotocin |
author_facet |
Ryan A. Lafferty Neil Tanday R. Charlotte Moffett Frank Reimann Fiona M. Gribble Peter R. Flatt Nigel Irwin |
author_sort |
Ryan A. Lafferty |
title |
Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice |
title_short |
Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice |
title_full |
Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice |
title_fullStr |
Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice |
title_full_unstemmed |
Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice |
title_sort |
positive effects of npy1 receptor activation on islet structure are driven by pancreatic alpha- and beta-cell transdifferentiation in diabetic mice |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Endocrinology |
issn |
1664-2392 |
publishDate |
2021-02-01 |
description |
Enzymatically stable and specific neuropeptide Y1 receptor (NPYR1) agonists, such as sea lamprey PYY(1-36) (SL-PYY(1-36)), are believed to improve glucose regulation in diabetes by targeting pancreatic islets. In this study, streptozotocin (STZ) diabetic transgenic GluCreERT2;ROSA26-eYFP and Ins1Cre/+;Rosa26-eYFP mouse models have been used to study effects of sustained NPYR1 activation on islet cell composition and alpha- and beta-cell lineage transitioning. STZ induced a particularly severe form of diabetes in Ins1Cre/+;Rosa26-eYFP mice, but twice-daily administration (25 nmol/kg) of SL-PYY(1-36) for 11 days consistently improved metabolic status. Blood glucose was decreased (p < 0.05 - p < 0.001) and both fasted plasma and pancreatic insulin significantly increased by SL-PYY(1-36). In both GluCreERT2;ROSA26-eYFP and Ins1Cre/+; Rosa26-eYFP mice, STZ provoked characteristic losses (p < 0.05 - p < 0.001) of islet numbers, beta-cell and pancreatic islet areas together with increases in area and central islet location of alpha-cells. With exception of alpha-cell area, these morphological changes were fully, or partially, returned to non-diabetic control levels by SL-PYY(1-36). Interestingly, STZ apparently triggered decreased (p < 0.001) alpha- to beta-cell transition in GluCreERT2;ROSA26-eYFP mice, together with increased loss of beta-cell identity in Ins1Cre/+;Rosa26-eYFP mice, but both effects were significantly (p < 0.001) reversed by SL-PYY(1-36). SL-PYY(1-36) also apparently reduced (p < 0.05) beta- to alpha-cell conversion in Ins1Cre/+;Rosa26-eYFP mice and glucagon expressing alpha-cells in GluCreERT2;ROSA26-eYFP mice. These data indicate that islet benefits of prolonged NPY1R activation, and especially restoration of beta-cell mass, are observed irrespective of diabetes status, being linked to cell lineage alterations including transdifferentiation of alpha- to beta-cells. |
topic |
peptide YY sea lamprey PYY diabetes transdifferentiation streptozotocin |
url |
https://www.frontiersin.org/articles/10.3389/fendo.2021.633625/full |
work_keys_str_mv |
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