High-Frequency Feeding With Late-Night Snacking Accelerates Type 2 Diabetes and Alters Diurnal Metabolic Gene Expression in Male KKAy Mice.

Meal frequency as an independent determinant of type 2 diabetes mellitus (T2DM) risk under strictly isocaloric conditions remains undefined. We investigated whether increasing meal frequency from three to six isocaloric meals per day alters T2DM incidence and diurnal metabolic and gene expression patterns in male KKAy mice. High-frequency feeding with late-night snacking significantly increased T2DM incidence (relative risk = 2.1), disrupted diurnal glucose and insulin rhythms, increased hepatic glycogen accumulation, and elevated hepatic metabolic gene expression, with altered diurnal coexpression patterns. These findings establish meal frequency as an independent modifier of metabolic health and provide preclinical evidence supporting chrononutrition-based strategies for T2DM prevention.