Project ID CM-HD2024_46


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Cardiovascular and Metabolic Medicine & Sciences, Diabetes & Obesity themeWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Cardiovascular and Metabolic Medicine & Sciences, Diabetes & Obesity themeWebsite

Can over-the-counter NAD boosting supplements be used to prevent type 2 diabetes?

An estimated 13.6 million people in the UK are currently at high risk of developing type 2 diabetes (T2D). The overall cost of T2D in the UK is predicted to rise to £39.8 bn by 2036. Development of effective approaches to prevent individuals from developing T2D are urgently required to improve patient outcomes, relieve pressure on healthcare systems and reduce associated economic costs.

Nicotinamide adenine dinucleotide (NAD) boosting supplements are available as over-the-counter products, with a global market size of $532m, expected to rise to $1.72bn by 2032. These are typically marketed as anti-aging supplements, potentially capable of preventing onset of age-related metabolic disease, including T2D.
Therefore, NAD boosting supplements are a potentially valuable tool in the drive to prevent T2D onset. However, the impact of increasing NAD levels on pancreatic islets – the essential tissue for prevention of T2D – remains poorly understood and may not always be beneficial. For example, we have shown that activation of NAD-producing enzymes exacerbates inflammation-mediated pancreatic islet dysfunction, whilst inhibition of NAD-producing enzymes has the opposite effect.
Aim: This project will aim to develop a comprehensive evidence base by fully characterise the effects of NAD boosting supplements on pancreatic beta-cell functional mass. This is essential to elucidate with the precise effects of these supplements on progression of T2D.

Year 1) Determine the impact of NAD boosting supplements on pancreatic islet function and mass using isolated mouse and human islets.

Year 2) To utilise mouse models to determine whether NAD boosting supplements can prevent onset of T2D.

Year 3 and 4) Conduct in-depth metabolomic and transcriptomic analysis to determine the mechanisms of action NAD boosting supplements in pancreatic islets.

Techniques and skills: Pancreatic islet isolation, cell culture, qRT-PCR, microscopy/immunofluorescence, in vivo mouse phenotyping (glucose metabolism), FACS sorting, confocal imaging, NAD metabolomics (mass spectrometry), transcriptomics (RNAseq).

Representative Publications

Sayers SR, Beavil RL, Fine NHF, Huang GC, Choudhary P, Pacholarz KJ, Barran PE, Butterworth S, Mills CE, Cruickshank JK, Silvestre MP, Poppitt SD, McGill A, Lavery GG, Hodson DJ, Caton PW. Structure-functional changes in eNAMPT at high concentrations mediate mouse and human beta-cell dysfunction in type 2 diabetes. Diabetologia, 2020 63(2):313-323 doi: 10.1007/s00125-019-05029-y Kieswich J, Sayers SR, Silvestre MF, Harwood SM, Yaqoob MM, Caton PW (2016) Monomeric eNAMPT in the development of experimental diabetes in mice: a potential target for type 2 diabetes treatment. Diabetologia, 59(11):2477-86 doi: 10.1007/s00125-016-4076-3 Caton PW, Richardson SJ, Kieswich J, Bugliani M, Holland ML, Marchetti P, Morgan NG, Yaqoob MM, Holness MJ, Sugden MC (2013). SIRT3 regulates pancreatic beta-cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic subjects. Diabetologia 56; 1068-77 doi: 10.1007/s00125-013-2851-y
Franklin ZJ, Tsakmaki A, Fonseca Pedro P, King AJ, Huang GC, Amjad S, Persaud SJ, Bewick GA. Islet neuropeptide Y receptors are functionally conserved and novel targets for the preservation of beta-cell mass. Diabetes Obes Metab. 2018 Mar;20(3):599-609. doi: 10.1111/dom.13119. West JA, Tsakmaki A, Ghosh SS, Parkes DG, Grønlund RV, Pedersen PJ, Maggs D, Rajagopalan H, Bewick GA.PLoS One. 2021 Chronic peptide-based GIP receptor inhibition exhibits modest glucose metabolic changes in mice when administered either alone or combined with GLP-1 agonism. Mar 31;16(3):e0249239. doi: 10.1371/journal.pone.0249239 ISX-9 manipulates endocrine progenitor fate revealing conserved intestinal lineages in mouse and human organoids. Tsakmaki A, Fonseca Pedro P, Pavlidis P, Hayee B, Bewick GA.Mol Metab. 2020 Apr;34:157-173. doi: 10.1016/j.molmet.2020.01.012.