Carbonyl stress as the missing molecular link between diabetes and neurodegeneration: a unified mechanistic framework for type 3 diabetes.

Type 2 diabetes mellitus is associated with an increased risk of cognitive dysfunction and neurodegenerative changes, contributing to the emerging concept of "Type 3 Diabetes," characterized by impaired cerebral insulin signaling and altered brain glucose metabolism. However, the metabolic processes connecting systemic metabolic dysfunction with cerebral insulin resistance remain incompletely understood. This review examines carbonyl stress, particularly methylglyoxal and other reactive dicarbonyls, as potential links between dysregulated glucose metabolism and impaired cerebral insulin signaling. We evaluate MGO generation and glyoxalase-mediated detoxification, evidence linking carbonyl stress with insulin-signaling abnormalities and interactions among AGE-RAGE signaling, oxidative stress and neuroinflammation. Particular emphasis is placed on distinguishing evidence from peripheral insulin-responsive tissues, vascular compartments and neuronal models, given the limited direct in vivo evidence establishing MGO as a cause of cerebral insulin resistance. The review further considers potential consequences for neuronal metabolism, synaptic function, and neurodegenerative vulnerability, alongside emerging therapeutic strategies targeting carbonyl metabolism and related pathways, including intranasal nanocarrier-mediated delivery. Overall, carbonyl stress represents a biologically plausible but not yet established molecular link between diabetes-associated metabolic dysfunction and neurodegenerative vulnerability, warranting brain-specific studies to determine its causal and therapeutic relevance.