Journal article
eNAMPT induces alpha-cell mass expansion but impaired glucagon counter regulatory response
- Abstract:
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Context
Loss of functional beta-cell mass, coupled with alpha-cell dysfunction are key factors in pathophysiology of type 1 and type 2 diabetes. We have reported that extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is elevated in type 2 diabetes and that elevated eNAMPT levels promote beta-cell dysfunction.
Objective
To further investigate the effects of eNAMPT on beta-cell mass.
Methods
Islets isolated from CD1 and Ins1tm1.1(cre)Thor+/−; mTmGfl/− mice and human donors were exposed to eNAMPT (48-96 hours). CD1 mice were administered eNAMPT for 14 days. Alpha-, beta-, and delta-cell numbers were determined by glucagon, insulin, and somatostatin staining, respectively. Alpha-cell proliferation was assessed by bromodeoxyuridine (BrDU) uptake and Ki67 expression. Glucagon secretion was assessed via radioimmunoassay. Trans-differentiation was assessed by determining changes in presence of bi-hormonal cells in CD1/human islets and using Ins1tm1.1(cre)Thor+/−; mTmGfl/− islets to determine changes in GLU+/GFP+ and GLU+/TdT+ cells.
Results
eNAMPT treatment reduced beta-cell number and induced corresponding increases in alpha-cell number. Indicative of beta- to alpha-cell trans-differentiation eNAMPT induced increased presence of bi-hormonal INS+/GLU+ cells and PDX1+/GLU+ cells, and increased GLU+/GFP+ cells in Ins1tm1.1(cre)Thor+/−; mTmGfl/− mouse islets. In addition, eNAMPT induced alpha-cell proliferation, indicated by increased BrDU uptake. Despite marked elevation in alpha-cell number, alpha-cell function was compromised following eNAMPT exposure, indicated by impaired glucagon counterregulatory response (CCR) to low glucose levels.
Conclusion
This data supports a role for elevated eNAMPT levels in driving increased alpha-cell mass via a combination of beta- to alpha-cell trans-differentiation and alpha-cell proliferation. When combined with observed impaired CCR, these data have implications for both type 1 and type 2 diabetes pathophysiology.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.1MB, Terms of use)
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- Publisher copy:
- 10.1210/endocr/bqag061
Authors
+ European Union
More from this funder
- Funder identifier:
- https://ror.org/019w4f821
- Grant:
- 715884
- Programme:
- Horizon 2020 research and innovation programme
+ Medical Research Council
More from this funder
- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/X502923/1
- MR/S025618/1
- APP23529
+ UK Research and Innovation
More from this funder
- Funder identifier:
- https://ror.org/001aqnf71
- Grant:
- EP/X026833/1
+ Diabetes UK
More from this funder
- Funder identifier:
- https://ror.org/050rgn017
- Grant:
- 25/0006885
- 24/0006744
- 22/0006389
- 23/0006627
- AMS5971128
- Publisher:
- Oxford University Press
- Journal:
- Endocrinology More from this journal
- Volume:
- 167
- Issue:
- 7
- Article number:
- bqag061
- Publication date:
- 2026-06-11
- Acceptance date:
- 2026-04-06
- DOI:
- EISSN:
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1945-7170
- ISSN:
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0013-7227
- Language:
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English
- Keywords:
- Pubs id:
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2434352
- Local pid:
-
pubs:2434352
- Deposit date:
-
2026-06-17
- ARK identifier:
Terms of use
- Copyright holder:
- Sayers et al.
- Copyright date:
- 2026
- Rights statement:
- © The Author(s) 2026. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. See the journal About page for additional terms.
- Licence:
- CC Attribution (CC BY)
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