Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice

Ryan Lafferty; Neil Tanday; Charlotte Moffett; Frank Reimann; Fiona Gribble; PR Flatt; Nigel Irwin

doi:10.3389/fendo.2021.633625

Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice

Ryan Lafferty, Neil Tanday, Charlotte Moffett, Frank Reimann, Fiona Gribble, PR Flatt, Nigel Irwin

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Abstract

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 Glu CreERT2 ; ROSA26-eYFP and Ins1 Cre/+; 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 Ins1 Cre/+; 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 Glu CreERT2 ; ROSA26-eYFP and Ins1 Cre/+; 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 Glu CreERT2 ; ROSA26-eYFP mice, together with increased loss of beta-cell identity in Ins1 Cre/+; 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 Ins1 Cre/+; Rosa26-eYFP mice and glucagon expressing alpha-cells in Glu CreERT2 ; 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.

Original language	English
Article number	633625
Pages (from-to)	633625
Number of pages	10
Journal	Frontiers in Endocrinology
Volume	12
DOIs	https://doi.org/10.3389/fendo.2021.633625
Publication status	Published (in print/issue) - 25 Feb 2021

Bibliographical note

Funding Information:
This work was supported by a PhD studentship (awarded to RL) from the Department for the Economy (DfE) Northern Ireland and University of Ulster strategic research funding. Work in the Reimann/Gribble laboratory is currently funded by the Welcome Trust (106262/Z/14/Z and 106263/Z/14/Z) and the MRC (MRC_MC_UU_12012/3).

Publisher Copyright:
© Copyright © 2021 Lafferty, Tanday, Moffett, Reimann, Gribble, Flatt and Irwin.

Keywords

peptide YY
sea lamprey PYY
diabetes
transdifferentiation
streptozotocin

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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fendo-12-633625 (1)Final published version, 2.4 MBLicence: CC BY

Cite this

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title = "Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice",

abstract = "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 Glu CreERT2 ; ROSA26-eYFP and Ins1 Cre/+; 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 Ins1 Cre/+; 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 Glu CreERT2 ; ROSA26-eYFP and Ins1 Cre/+; 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 Glu CreERT2 ; ROSA26-eYFP mice, together with increased loss of beta-cell identity in Ins1 Cre/+; 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 Ins1 Cre/+; Rosa26-eYFP mice and glucagon expressing alpha-cells in Glu CreERT2 ; 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. ",

keywords = "peptide YY, sea lamprey PYY, diabetes, transdifferentiation, streptozotocin",

author = "Ryan Lafferty and Neil Tanday and Charlotte Moffett and Frank Reimann and Fiona Gribble and PR Flatt and Nigel Irwin",

note = "Funding Information: This work was supported by a PhD studentship (awarded to RL) from the Department for the Economy (DfE) Northern Ireland and University of Ulster strategic research funding. Work in the Reimann/Gribble laboratory is currently funded by the Welcome Trust (106262/Z/14/Z and 106263/Z/14/Z) and the MRC (MRC_MC_UU_12012/3). Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2021 Lafferty, Tanday, Moffett, Reimann, Gribble, Flatt and Irwin.",

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AU - Moffett, Charlotte

AU - Reimann, Frank

AU - Gribble, Fiona

AU - Flatt, PR

AU - Irwin, Nigel

N1 - Funding Information: This work was supported by a PhD studentship (awarded to RL) from the Department for the Economy (DfE) Northern Ireland and University of Ulster strategic research funding. Work in the Reimann/Gribble laboratory is currently funded by the Welcome Trust (106262/Z/14/Z and 106263/Z/14/Z) and the MRC (MRC_MC_UU_12012/3). Publisher Copyright: © Copyright © 2021 Lafferty, Tanday, Moffett, Reimann, Gribble, Flatt and Irwin.

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N2 - 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 Glu CreERT2 ; ROSA26-eYFP and Ins1 Cre/+; 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 Ins1 Cre/+; 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 Glu CreERT2 ; ROSA26-eYFP and Ins1 Cre/+; 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 Glu CreERT2 ; ROSA26-eYFP mice, together with increased loss of beta-cell identity in Ins1 Cre/+; 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 Ins1 Cre/+; Rosa26-eYFP mice and glucagon expressing alpha-cells in Glu CreERT2 ; 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.

AB - 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 Glu CreERT2 ; ROSA26-eYFP and Ins1 Cre/+; 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 Ins1 Cre/+; 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 Glu CreERT2 ; ROSA26-eYFP and Ins1 Cre/+; 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 Glu CreERT2 ; ROSA26-eYFP mice, together with increased loss of beta-cell identity in Ins1 Cre/+; 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 Ins1 Cre/+; Rosa26-eYFP mice and glucagon expressing alpha-cells in Glu CreERT2 ; 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.

KW - peptide YY

KW - sea lamprey PYY

KW - diabetes

KW - transdifferentiation

KW - streptozotocin

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DO - 10.3389/fendo.2021.633625

M3 - Article

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SP - 633625

JO - Frontiers in Endocrinology

JF - Frontiers in Endocrinology

SN - 1664-2392

M1 - 633625

ER -

Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice

Abstract

Bibliographical note

Keywords

UN SDGs

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