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

Egbase, Daniel, Sayers, Sophie R., Haq, Naila, Gesheva, Vesela S., Varghese, Jithu J. and Pearson, James A. ORCID: https://orcid.org/0000-0002-2867-2269 2026. NAMPT activity plays a key role in driving autoimmune processes that mediate beta-cell death and type 1 diabetes development in mice. Cell Death & Disease 17 , 713. 10.1038/s41419-026-08700-6

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Abstract

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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Publisher:	Springer Nature [academic journals on nature.com]
Date of First Compliant Deposit:	4 September 2026
Date of Acceptance:	24 March 2026
Last Modified:	04 Sep 2026 14:45
URI:	https://orca.cardiff.ac.uk/id/eprint/189405

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