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Egbase, D.* ; Sayers, S.R.* ; Haq, N.* ; Gesheva, V.S.* ; Varghese, J.J.* ; Bhattacharya, S. ; Kynaston, J.* ; Hubber, E.L.* ; Smith, L.I.F.* ; Pullen, T.J.* ; Gerdes, H.* ; Lee, V.K.* ; Hopkins, D.* ; Zhao, M.* ; Cheah, Y.* ; Greally, J.* ; Butterworth, S.* ; Pearson, J.A.* ; Bewick, G.A.* ; Persaud, S.J.* ; Caton, P.W.*

NAMPT activity plays a key role in driving autoimmune processes that mediate beta-cell death and type 1 diabetes development in mice.

Cell Death Dis. 17:713 (2026)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
Type 1 diabetes (T1D) is characterised by destruction of pancreatic beta-cells by islet-infiltrating cytotoxic lymphocytes and elevated intra-islet secretion of pro-inflammatory cytokines. However, the underlying pathophysiological mechanisms remain incompletely understood. We hypothesised that abnormal elevation of islet NAD, via activation of NAMPT, plays a key role in driving islet autoimmune processes, leading to beta-cell death in T1D. Here, we report that NAMPT inhibition protects against pro-inflammatory cytokine (IL-1β, TNFα and IFNγ) mediated beta-cell dysfunction and apoptosis in isolated mouse and human islets. RNAseq revealed that NAMPT inhibition blocked cytokine-mediated gene expression linked to pro-inflammatory responses and leukocyte migration. In vivo, diabetes was induced in CD1 mice via multiple low-dose streptozotocin (MLDS) injections. MLDS mice were administered the NAMPT inhibitor FK866 (10 mg/kg; IP) or saline equivalent for 16 days. These experiments demonstrated that NAMPT inhibition improved glycaemic control and beta-cell survival and function in MLDS mice. FK866 also reduced proportions of islet-residing TNFα-producing CD4+T-cells and F4/80+macrophages, proliferation of spleen-derived CD4+ and CD8+T-cells and proliferation of islet-derived CD4+T-cells and F4/80+macrophages. Finally, we report that NAMPT inhibition was able to block pro-inflammatory cytokine-mediated migration of cytotoxic CD8+T-cells into isolated islets, using an in vitro transwell platform. This data supports a key immunomodulatory role for NAMPT in islet autoimmunity. NAMPT inhibition may be able to prevent beta-cell death and thus represent a novel therapeutic approach for T1D. The effects of increased NAD levels on islet inflammation require in-depth characterisation and caution should be exercised with regard to the use of NAD boosting supplements, particularly in individuals at risk of developing T1D.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 2041-4889
e-ISSN 2041-4889
Journal Cell Death & Disease
Quellenangaben Volume: 17, Issue: 1, Pages: , Article Number: 713 Supplement: ,
Publisher Springer
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Regeneration Research (IDR)