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Due to the high oxygen and energy demands required for insulin secretion, hypoxia has been shown to play a critical role in pancreatic \u03b2-cell dysfunction. Lipid metabolism abnormalities, a common metabolic feature in type 2 diabetic patients, are often accompanied by tissue hypoxia caused by metabolic overload and lead to increased free fatty acid (FFA) levels. However, the specific mechanisms underlying FFA-induced \u03b2-cell dysfunction remain unclear. Nicotinamide mononucleotide (NMN), a naturally occurring bioactive nucleotide, has garnered significant attention in recent years for its effectiveness in replenishing NAD+ and alleviating various diseases. Nevertheless, studies exploring the mechanisms through which NMN influences \u03b2-cell dysfunction remain scarce. In this study, we established an in vitro \u03b2-cell dysfunction model by treating INS-1 cells with palmitate (PA), including control, PA-treated, and PA combined with NMN or activator\/inhibitor groups. Compared to the control group, cells treated with PA alone showed significantly reduced insulin secretion capacity and decreased expression of proteins related to the NAD+\/AMPK\/SIRT1\/HIF-1\u03b1 pathway. In contrast, NMN supplementation significantly restored the expression of pathway-related proteins by activating NAD+ and effectively improved insulin secretion. Results obtained using HIF-1\u03b1 and AMPK inhibitors\/activators further supported these findings. In conclusion, our study demonstrates that NMN reversed the PA-induced downregulation of the NAD+\/AMPK\/SIRT1\/HIF-1\u03b1 pathway, thereby alleviating \u03b2-cell dysfunction. Our study investigated the mechanisms underlying PA-induced \u03b2-cell dysfunction, examined how NMN mitigates this dysfunction and offered new insights into the therapeutic potential of NMN for treating \u03b2-cell dysfunction and T2DM.<\/jats:p>","DOI":"10.3390\/ijms251910534","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T04:00:04Z","timestamp":1727668804000},"page":"10534","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Nicotinamide Mononucleotide (NMN) Ameliorates Free Fatty Acid-Induced Pancreatic \u03b2-Cell Dysfunction via the NAD+\/AMPK\/SIRT1\/HIF-1\u03b1 Pathway"],"prefix":"10.3390","volume":"25","author":[{"given":"Yan","family":"Wang","sequence":"first","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si","family":"Liu","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linyao","family":"Ying","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Li","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Liang","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4940-4423","authenticated-orcid":false,"given":"Lin","family":"Xiao","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7899-4154","authenticated-orcid":false,"given":"Gang","family":"Luo","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1016\/j.cell.2020.02.048","article-title":"Long-Term Expansion of Pancreatic Islet Organoids from Resident Procr+ Progenitors","volume":"180","author":"Wang","year":"2020","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"eaba9112","DOI":"10.1126\/scitranslmed.aba9112","article-title":"HIF-1\u03b1 inhibitor PX-478 preserves pancreatic \u03b2 cell function in diabetes","volume":"14","author":"Ilegems","year":"2022","journal-title":"Sci. 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