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Here, we review and support a key mechanistic role for nitric oxide (\u2022NO), a pleiotropic diffusible messenger that integrates vascular, neuronal, and metabolic functions within the neurovascular unit (NVU). Under physiological conditions, \u2022NO integrates vascular and metabolic responses by coupling blood supply to neuronal activity and fine-tuning cellular energy metabolism. In T2DM, chronic hyperglycemia and insulin resistance converge to reduce \u2022NO bioavailability through multiple mechanisms: mitochondrial and NADPH oxidase-derived superoxide production, endothelial nitric oxide synthases (eNOS) uncoupling via BH4 oxidation, and impaired PI3K-Akt-dependent eNOS activation. The resulting redox imbalance shifts the cerebrovascular environment towards oxidant-mediated damage, compromising the functional and structural integrity of the NVU. This translates into impaired cerebral blood flow regulation and maladaptive remodelling of the cerebrovascular network, ultimately disrupting neurovascular coupling (NVC) and reducing regional cerebral perfusion. Together, impaired perfusion and disrupted NVC result in a sustained mismatch between energy supply and neuronal demand, particularly in metabolically vulnerable regions such as the hippocampus, ultimately leading to progressive cognitive impairment. In sum, the present review integrates current mechanistic evidence positioning \u2022NO dysregulation as a central driver of neurovascular and metabolic dysfunction in T2DM, linking impaired cerebral perfusion, disrupted NVC, and structural vascular remodelling to cognitive decline.<\/jats:p>","DOI":"10.1042\/bst20250325","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:53:53Z","timestamp":1789545233000},"page":"1239-1250","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nitric oxide as a mechanistic link between metabolic dysfunction and cognitive decline in type 2 diabetes"],"prefix":"10.1042","volume":"54","author":[{"given":"Ana\u00a0L.","family":"Mar\u00e7al","sequence":"first","affiliation":[{"name":"1Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal"},{"name":"2Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal"},{"name":"3Centre for Innovative Biomedicine and Biotechnology, Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o","family":"Laranjinha","sequence":"additional","affiliation":[{"name":"1Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal"},{"name":"2Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal"},{"name":"3Centre for Innovative Biomedicine and Biotechnology, Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0514-0198","authenticated-orcid":false,"given":"C\u00e1tia\u00a0F.","family":"Louren\u00e7o","sequence":"additional","affiliation":[{"name":"1Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal"},{"name":"2Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal"},{"name":"3Centre for Innovative Biomedicine and Biotechnology, Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"2026091603534733700_B1","volume-title":"IDF Diabetes Atlas","author":"International Diabetes Federation","year":"2025","edition":"11th edition"},{"key":"2026091603534733700_B2","doi-asserted-by":"publisher","first-page":"105775","DOI":"10.1016\/j.neubiorev.2024.105775","article-title":"Diabetes and brain disorders, a new role for insulin?","volume":"163","author":"de Galan","year":"2024","journal-title":"Neurosci. 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