Integrative Therapeutic Strategies for Diabetes-induced Cognitive Decline (DCI): Role of Mechanistic Targets and Nutritional Modulation

Introduction: Diabetes-induced cognitive impairment (DCI) has emerged as a significant yet underexplored complication of diabetes mellitus. Despite its growing prevalence, effective strategies for the prevention and management of DCI remain elusive. Thus, this paper aims to comprehensively evaluate molecular mechanisms underlying DCI, highlight potential therapeutic targets, and explore the role of dietary interventions as adjunctive strategies. Methods: An extensive literature review was conducted using PubMed, Scopus, and Web of Science, focusing on mechanistic studies, therapeutic strategies, and dietary interventions for DCI (keywords: diabetes, cognitive impairment, hippocampus, dietary interventions, therapeutic targets). Preclinical and clinical data were critically examined, with particular emphasis on endoplasmic reticulum (ER) stress, insulin/IGF-1 resistance, ferroptosis, sirtuin signalling, and tau hyperphosphorylation. Dietary patterns and nutraceuticals, including flavonoids, carotenoids, polyphenols, and probiotics, were also evaluated. Results: Emerging evidence highlights ER stress-mediated apoptosis, PI3K/Akt/CREB dysfunction, tau hyperphosphorylation via Cav-1-mTOR and PKC-α, and impaired sirtuin-1 activity as pivotal drivers of DCI. Novel therapeutic targets such as ferroptosis inhibition, BDNF modulation, and dopamine receptor regulation show translational potential. Discussion: Dietary interventions – including Mediterranean diet, polyphenol-rich foods, carotenoids, and gut–brain axis modulation – demonstrated neuroprotective effects by reducing oxidative stress, neuroinflammation, and synaptic dysfunction. Thus, DCI is a multifactorial neurometabolic complication requiring an integrated approach Conclusion: Targeted molecular therapies combined with dietary interventions hold promise for mitigating DCI. Future directions should focus on biomarker-driven clinical trials, precision nutrition, and multi-targeted drug development to achieve effective prevention and treatment strategies. DOI:10.2174/0115743624443205260226152634