Effects of long-acting GIP, xenin and oxyntomodulin peptide analogues on alpha-cell transdifferentiation in insulin-deficient diabetic GluCreERT2;ROSA26-eYFP mice

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Abstract

Enzyme-resistant long-acting forms of the gut-derived peptide hormones, glucose-dependent insulinotropic polypeptide (GIP), xenin and oxyntomodulin (Oxm) have been generated, and exert beneficial effects on diabetes control and pancreatic islet architecture. The current study has employed alpha-cell lineage tracing in GluCreERT2;ROSA26-eYFP transgenic mice to investigate the extent to which these positive pancreatic effects are associated with alpha- to beta-cell transdifferentiation. Twice-daily administration of (D-Ala2)GIP, xenin-25[Lys13PAL] or (D-Ser2)-Oxm[Lys38PAL] for 10 days to streptozotocin (STZ)-induced diabetic mice did not affect body weight, food intake or blood glucose levels, but (D-Ser2)-Oxm[Lys38PAL] reduced (P<0.05 to P<0.001) fluid intake and circulating glucagon. (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] also augmented (P<0.05 and P<0.01, respectively) pancreatic insulin content. Detrimental changes of pancreatic morphology induced by STZ in GluCreERT2;ROSA26-eYFP mice were partially reversed by all treatment interventions. This was associated with reduced (P<0.05) apoptosis and increased (P<0.05 to P<0.01) proliferation of beta-cells, alongside opposing effects on alpha-cells, with (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] being particularly effective in this regard. Alpha-cell lineage tracing revealed that induction of diabetes was accompanied by increased (P<0.01) transdifferentiation of glucagon positive alpha-cells to insulin positive beta-cells. This islet cell transitioning process was augmented (P<0.01 and P<0.001, respectively) by (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL]. (D-Ser2)-Oxm[Lys38PAL] also significantly (P<0.05) promoted loss of alpha-cell identity in favour of other endocrine islet cells. These data highlight intra-islet benefits of (D-Ala2)GIP, xenin-25[Lys13PAL] and (D-Ser2)-Oxm[Lys38PAL] in diabetes with beta-cell loss induced by STZ. The effects appear to be independent of glycaemic change, and associated with alpha- to beta-cell transdifferentiation for the GIP and Oxm analogues.
LanguageEnglish
Pagesxx
JournalPeptides
Volumexx
Issue numberxx
Publication statusAccepted/In press - 13 Nov 2019

Fingerprint

Oxyntomodulin
Cell Transdifferentiation
Insulin
Glucose
Peptides
Streptozocin
Islets of Langerhans
Medical problems
Cell Lineage
Glucagon
Endocrine Cells
Peptide Hormones
D-Ser2-oxyntomodulin
xenin 25
Transgenic Mice
Blood Glucose
Eating
Body Weight
Cell Proliferation
Apoptosis

Keywords

  • Alpha-cell
  • GIP
  • GluCreERT2;ROSA26-eYFP mice
  • oxyntomodulin (Oxm)
  • transdifferentiation
  • xenin

Cite this

@article{ddbc95f4d08f496c813ffc71537f5f9c,
title = "Effects of long-acting GIP, xenin and oxyntomodulin peptide analogues on alpha-cell transdifferentiation in insulin-deficient diabetic GluCreERT2;ROSA26-eYFP mice",
abstract = "Enzyme-resistant long-acting forms of the gut-derived peptide hormones, glucose-dependent insulinotropic polypeptide (GIP), xenin and oxyntomodulin (Oxm) have been generated, and exert beneficial effects on diabetes control and pancreatic islet architecture. The current study has employed alpha-cell lineage tracing in GluCreERT2;ROSA26-eYFP transgenic mice to investigate the extent to which these positive pancreatic effects are associated with alpha- to beta-cell transdifferentiation. Twice-daily administration of (D-Ala2)GIP, xenin-25[Lys13PAL] or (D-Ser2)-Oxm[Lys38PAL] for 10 days to streptozotocin (STZ)-induced diabetic mice did not affect body weight, food intake or blood glucose levels, but (D-Ser2)-Oxm[Lys38PAL] reduced (P<0.05 to P<0.001) fluid intake and circulating glucagon. (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] also augmented (P<0.05 and P<0.01, respectively) pancreatic insulin content. Detrimental changes of pancreatic morphology induced by STZ in GluCreERT2;ROSA26-eYFP mice were partially reversed by all treatment interventions. This was associated with reduced (P<0.05) apoptosis and increased (P<0.05 to P<0.01) proliferation of beta-cells, alongside opposing effects on alpha-cells, with (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] being particularly effective in this regard. Alpha-cell lineage tracing revealed that induction of diabetes was accompanied by increased (P<0.01) transdifferentiation of glucagon positive alpha-cells to insulin positive beta-cells. This islet cell transitioning process was augmented (P<0.01 and P<0.001, respectively) by (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL]. (D-Ser2)-Oxm[Lys38PAL] also significantly (P<0.05) promoted loss of alpha-cell identity in favour of other endocrine islet cells. These data highlight intra-islet benefits of (D-Ala2)GIP, xenin-25[Lys13PAL] and (D-Ser2)-Oxm[Lys38PAL] in diabetes with beta-cell loss induced by STZ. The effects appear to be independent of glycaemic change, and associated with alpha- to beta-cell transdifferentiation for the GIP and Oxm analogues.",
keywords = "Alpha-cell, GIP, GluCreERT2;ROSA26-eYFP mice, oxyntomodulin (Oxm), transdifferentiation, xenin",
author = "Sarnobat, {Dipak Sadashiv} and Charlotte Moffett and Gault, {Victor A} and Neil Tanday and Frank Reimann and Fiona Gribble and PR Flatt and Nigel Irwin",
year = "2019",
month = "11",
day = "13",
language = "English",
volume = "xx",
pages = "xx",
journal = "Peptides",
issn = "0196-9781",
publisher = "Elsevier",
number = "xx",

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TY - JOUR

T1 - Effects of long-acting GIP, xenin and oxyntomodulin peptide analogues on alpha-cell transdifferentiation in insulin-deficient diabetic GluCreERT2;ROSA26-eYFP mice

AU - Sarnobat, Dipak Sadashiv

AU - Moffett, Charlotte

AU - Gault, Victor A

AU - Tanday, Neil

AU - Reimann, Frank

AU - Gribble, Fiona

AU - Flatt, PR

AU - Irwin, Nigel

PY - 2019/11/13

Y1 - 2019/11/13

N2 - Enzyme-resistant long-acting forms of the gut-derived peptide hormones, glucose-dependent insulinotropic polypeptide (GIP), xenin and oxyntomodulin (Oxm) have been generated, and exert beneficial effects on diabetes control and pancreatic islet architecture. The current study has employed alpha-cell lineage tracing in GluCreERT2;ROSA26-eYFP transgenic mice to investigate the extent to which these positive pancreatic effects are associated with alpha- to beta-cell transdifferentiation. Twice-daily administration of (D-Ala2)GIP, xenin-25[Lys13PAL] or (D-Ser2)-Oxm[Lys38PAL] for 10 days to streptozotocin (STZ)-induced diabetic mice did not affect body weight, food intake or blood glucose levels, but (D-Ser2)-Oxm[Lys38PAL] reduced (P<0.05 to P<0.001) fluid intake and circulating glucagon. (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] also augmented (P<0.05 and P<0.01, respectively) pancreatic insulin content. Detrimental changes of pancreatic morphology induced by STZ in GluCreERT2;ROSA26-eYFP mice were partially reversed by all treatment interventions. This was associated with reduced (P<0.05) apoptosis and increased (P<0.05 to P<0.01) proliferation of beta-cells, alongside opposing effects on alpha-cells, with (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] being particularly effective in this regard. Alpha-cell lineage tracing revealed that induction of diabetes was accompanied by increased (P<0.01) transdifferentiation of glucagon positive alpha-cells to insulin positive beta-cells. This islet cell transitioning process was augmented (P<0.01 and P<0.001, respectively) by (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL]. (D-Ser2)-Oxm[Lys38PAL] also significantly (P<0.05) promoted loss of alpha-cell identity in favour of other endocrine islet cells. These data highlight intra-islet benefits of (D-Ala2)GIP, xenin-25[Lys13PAL] and (D-Ser2)-Oxm[Lys38PAL] in diabetes with beta-cell loss induced by STZ. The effects appear to be independent of glycaemic change, and associated with alpha- to beta-cell transdifferentiation for the GIP and Oxm analogues.

AB - Enzyme-resistant long-acting forms of the gut-derived peptide hormones, glucose-dependent insulinotropic polypeptide (GIP), xenin and oxyntomodulin (Oxm) have been generated, and exert beneficial effects on diabetes control and pancreatic islet architecture. The current study has employed alpha-cell lineage tracing in GluCreERT2;ROSA26-eYFP transgenic mice to investigate the extent to which these positive pancreatic effects are associated with alpha- to beta-cell transdifferentiation. Twice-daily administration of (D-Ala2)GIP, xenin-25[Lys13PAL] or (D-Ser2)-Oxm[Lys38PAL] for 10 days to streptozotocin (STZ)-induced diabetic mice did not affect body weight, food intake or blood glucose levels, but (D-Ser2)-Oxm[Lys38PAL] reduced (P<0.05 to P<0.001) fluid intake and circulating glucagon. (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] also augmented (P<0.05 and P<0.01, respectively) pancreatic insulin content. Detrimental changes of pancreatic morphology induced by STZ in GluCreERT2;ROSA26-eYFP mice were partially reversed by all treatment interventions. This was associated with reduced (P<0.05) apoptosis and increased (P<0.05 to P<0.01) proliferation of beta-cells, alongside opposing effects on alpha-cells, with (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] being particularly effective in this regard. Alpha-cell lineage tracing revealed that induction of diabetes was accompanied by increased (P<0.01) transdifferentiation of glucagon positive alpha-cells to insulin positive beta-cells. This islet cell transitioning process was augmented (P<0.01 and P<0.001, respectively) by (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL]. (D-Ser2)-Oxm[Lys38PAL] also significantly (P<0.05) promoted loss of alpha-cell identity in favour of other endocrine islet cells. These data highlight intra-islet benefits of (D-Ala2)GIP, xenin-25[Lys13PAL] and (D-Ser2)-Oxm[Lys38PAL] in diabetes with beta-cell loss induced by STZ. The effects appear to be independent of glycaemic change, and associated with alpha- to beta-cell transdifferentiation for the GIP and Oxm analogues.

KW - Alpha-cell

KW - GIP

KW - GluCreERT2;ROSA26-eYFP mice

KW - oxyntomodulin (Oxm)

KW - transdifferentiation

KW - xenin

M3 - Article

VL - xx

SP - xx

JO - Peptides

T2 - Peptides

JF - Peptides

SN - 0196-9781

IS - xx

ER -