Peripheral metabolic dysfunction is associated with cognitive frailty in a mouse model of type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder increasingly associated with cognitive impairment and neurodegeneration. Peripheral metabolic dysfunction, particularly insulin resistance and glycation stress, represents a critical link between diabetes and brain pathology. This study investigated the relationship between metabolic alterations and cognitive frailty using a murine T2DM model induced by a high-fat diet (HFD) combined with low-dose streptozotocin (STZ). Male C57BL/6J mice were longitudinally followed from adulthood to senescence and subjected to HFD alone or HFD plus STZ. Metabolic parameters, including fasting glycemia, oral glucose tolerance, insulin resistance (HOMA-IR), glycated albumin (GA), and methylglyoxal (MGO), were assessed over time. Cognitive function was evaluated using spontaneous behavioral tests of recognition memory (Novel Object Recognition, Object Location, and Y-maze), integrated into a cognitive frailty index. Post-mortem histological and immunohistochemical analyses were performed on pancreatic and hippocampal tissues. While HFD alone induced mild alterations, HFD/STZ mice developed a stable diabetic phenotype with severe hyperglycemia, pancreatic β-cell damage, elevated HOMA-IR, and increased GA and MGO levels. Notably, HFD/STZ mice exhibited a marked decline in recognition memory, affecting both knowledge and remembering components. At the central level, diabetic mice showed hippocampal cytoarchitectural alterations, increased tau hyperphosphorylation, and amyloid accumulation. Crucially, both insulin resistance and glycation stress (GA) directly correlated with recognition memory deficits. These findings demonstrate that peripheral metabolic dysfunction, i.e. insulin resistance and advanced glycation, directly correlates with hippocampal pathology and cognitive decline, supporting the translational relevance of the HFD/STZ model for diabetes-related cognitive frailty.