eNAMPT induces alpha-cell mass expansion but impaired glucagon counter regulatory response
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ID: 317093
2026
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Abstract
PURPOSE: 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 eNAMPT is elevated in T2D, that elevated eNAMPT levels promote beta-cell dysfunction. However, the effects of eNAMPT on beta-cell mass remains incompletely understood. METHODS: Islets isolated from CD1 and Ins1tm1.1(cre)Thor+/-; mTmGfl/- mice and human donors were exposed to eNAMPT (48-96 h). CD1 mice were administered eNAMPT for 14 days. Alpha-, beta- and delta-cell number was determined by glucagon, insulin, and somatostatin staining, respectively. Alpha-cell proliferation was assessed by BrDU uptake and Ki67 expression. Glucagon secretion was assessed via radioimmunoassay. Transdifferentiation 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. CONCLUSIONS: 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.
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| Authors | Sophie R. Sayers, Vesela S. Gesheva, Jithu James Varghese, Rebecca Beavil, Min Zhao, Yee Cheah, David Hopkins, Nicholas H F Fine, Annie Hasib, David J. Hodson, Paul Caton |
| Journal | american journal of physiology endocrinology and metabolism |
| Year | 2026 |
| DOI |
10.1210/endocr/bqag061
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| URL | |
| Keywords | Keywords not found |
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