eNAMPT induces alpha-cell mass expansion but impaired glucagon counter regulatory response

Journal article

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.

Authors: Sayers, SR; Gesheva, VS; Varghese, JJ; Beavil, R; Zhao, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Oxford University Press
• Journal: Endocrinology
• Volume: 167
• Issue: 7
• Article number: bqag061
• Publication date: 2026-06-11
• Acceptance date: 2026-04-06
• DOI: 10.1210/endocr/bqag061
• EISSN: 1945-7170
• ISSN: 0013-7227
• Language: English
• Keywords: NAMPT; type 1 diabetes; type 2 diabetes; alpha-cells; glucagon; beta-cells