Beneficial actions of a long-acting apelin analogue in diabetes are related to positive effects on islet cell turnover and transdifferentiation

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Abstract

Aim  The current study has tested the hypothesis that the positive effects of apelin receptor activation in diabetes are linked to benefits on islet cell apoptosis, proliferation and transdifferentiation using Ins1 Cre/+;Rosa26-eYFP transgenic mice and induction of diabetes-like syndromes by streptozotocin (STZ) or high-fat feeding. 

Materials and methods  Groups (n = 6–8) of streptozotocin (STZ)-induced diabetic and high-fat diet (HFD)-fed mice received once-daily injection (25 nmol/kg) of the long-acting acylated apelin-13 analogue, pGlu(Lys 8Glu-PAL)apelin-13 amide, for 10 or 12 days, respectively. 

Results  pGlu(Lys 8Glu-PAL)apelin-13 amide treatment partly reversed body weight loss induced by STZ and normalized circulating insulin. There was no effect of pGlu(Lys 8Glu-PAL)apelin-13 amide on these variables in HFD-fed mice, but an increase in pancreatic insulin content was observed. pGlu(Lys 8Glu-PAL)apelin-13 amide also fully, or partially, reversed the detrimental effects of STZ and HFD on plasma and pancreatic glucagon concentrations. In HFD-fed mice, the apelin analogue decreased dietary-induced elevations of islet, β- and α-cell areas, whilst reducing α-cell area in STZ-induced diabetic mice. In terms of islet cell lineage, pGlu(Lys 8Glu-PAL)apelin-13 amide effectively reduced β- to α-cell transdifferentiation and helped maintain β-cell identity, which was linked to elevated Pdx-1 expression. These islet effects were coupled with decreased β-cell apoptosis and α-cell proliferation in both models, and there was an accompanying increase of β-cell proliferation in STZ-induced diabetic mice. 

Conclusion  Taken together these data demonstrate, for the first time, that pancreatic islet benefits of sustained APJ receptor activation in diabetes are linked to favourable islet cell transition events, leading to maintenance of β-cell mass.

Original languageEnglish
Pages (from-to)2468-2478
Number of pages11
JournalDiabetes, Obesity and Metabolism
Volume22
Issue number12
Early online date26 Aug 2020
DOIs
Publication statusPublished - 31 Dec 2020

Bibliographical note

Funding Information:
These studies were supported by a Department for the Economy, Northern Ireland, PhD Research Scholarship (N.T.), an early career research award from Diabetes UK to R.C.M., an Invest Northern Ireland, Proof of Concept grant (F.O.H.) and Irish Endocrine Society funding (F.O.H.). Additional support (F.O.H., P.R.F. and N.I.) was provided by Ulster University selective research funding.

Publisher Copyright:
© 2020 John Wiley & Sons Ltd

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • apelin analogues
  • high-fat-fed mice
  • streptozotocin
  • transdifferentiation
  • α cell
  • β cell
  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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