(P02-08-26) Impact of (-)-Epicatechin on Metabolic, Gut Microbiome, Gut Permeability and Cognitive Outcomes in DB/DB Mice: Sex-Specific Responses

Objectives: Type 2 diabetes mellitus (T2DM) increases cardiometabolic risk and susceptibility to cognitive decline. (-)-Epicatechin (EC), however, sex-specific responses remain unknown. The aim of this study was to determine whether nutritionally relevant EC supplementation improves metabolic and behavioral outcomes in db/db mice and whether responses differ by sex.

Methods: Male and female db/db and C57BL/6J mice were fed AIN-93M diets with or without 0.04% EC (human equivalent ≈150 mg/day). Body weight, fasting glucose, total cholesterol (TC), triglycerides (TG), and glucagon-like peptide-1 (GLP-1) were measured. Body composition was assessed by EchoMRI. Behavioral performance was evaluated using Y-maze, open field, and novel object recognition tests. DNA was extracted from gut microbiome from cecum and RNA was isolated from colon tissue using the QIAGEN extraction kits. Gene expression in colon samples was measured by RT-PCR using primers targeting ZO1, CLDN2, CLDN3, and CLDN5 to assess gut permeability.

Results: EC did not significantly affect body weight or fasting glucose in db/db mice. TC was reduced in EC-treated female db/db mice compared with female controls, while no effect was observed in males. TG levels were modestly reduced independent of sex. GLP-1 concentrations increased significantly in EC-treated females but not in males. In behavioral testing, EC-treated females exhibited reduced anxiety-like behavior in the open field, whereas spatial working memory was not significantly improved in either sex. Female db/db mice treated with EC showed a significant elevation in tight junction markers, such an increase in ZO-1, while EC- treated male showed no change. Preliminary analysis showed changes in the gut microbiome

Conclusions: EC supplementation exerts sex-dependent metabolic and behavioral effects in diabetic mice, with females showing greater responsiveness, particularly in lipid profile, GLP-1, tight junctions, and anxiety-related behavior. These findings underscore the importance of biological sex in evaluating polyphenol efficacy and support further investigation into sex-specific mechanisms of EC action in T2DM.

Funding Sources: University of California, Davis and North Carolina State University