From validation to innovation: TALLYHO/JngJ mouse model for T2D-related cognitive impairments and lipid-based therapeutic testing

Type 2 diabetes (T2D) frequently co-occurs with neurological conditions and impairments in executive functions, driven by shared pathophysiology such as altered insulin signalling. Evaluating this overlap requires preclinical models with robust translational validity. In this talk, we systematically evaluated the TALLYHO/JngJ (TH) mouse model across three axes of translational validity (construct, face, and predictive) to subsequently test a novel lipid-based pharmacological intervention. Across three sequential studies, we assessed cognitive performance (attention, memory, cognitive flexibility via ASST, Barnes maze, T-maze) and general metabolism (glucose tolerance, insulin resistance). We showed that TH mice exhibited early-onset, sex-dependent impairments in cognitive flexibility, attention, and memory co-occurring with hyperglycaemia, insulin resistance, and altered energy metabolism, establishing robust face and construct validity. We then confirmed predictive validity: subchronic oral metformin (300 mg/kg/day, 4 weeks) significantly improved hyperglycaemia, spatial memory, and cognitive flexibility. Building on this validation, we evaluated a novel therapeutic strategy: an intranasal nanoemulsion of two N-acylethanolamines (oleoylethanolamide [OEA] and palmitoylethanolamide [PEA]; 0.2 µL/day, 6 weeks). This intervention successfully reduced basal hyperglycaemia and improved attentional performance. These findings validate the TH mouse as a translational model for comorbid T2D and comorbid cognitive impairments. Furthermore, the efficacy of a novel OEA/PEA intranasal formulation highlights a promising dual-target pharmacological avenue for addressing both the metabolic disorders and cognitive impairments of T2D.