The recent update on the traditional food pyramid emphasizes a greater reliance on wholesome, nutritious foods, placing refined sugars and highly processed foodstuffs further down in the pyramid in attempt to decrease the prevalence of obesity and its pathophysiologic sequelae, and improve human health outcomes. Overconsumption of refined carbohydrates has been linked to systemic inflammation including neuroinflammation in the CNS, and the pathophysiologic sequela of systemic inflammation is a common observation in obesity and T2DM, where it contributes to the stigmata of the comorbidities linked to the disorder. Multiple factors contribute to the systemic inflammation, including elements of lifestyle, dietary macronutrient, micronutrient, and caloric intake, genetic predisposition, and the magnitude of the excess body fat accretion, particularly excess central adiposity. The interaction between epigenetic metabolic factors and the above contributors remain unclear but appear to include the quantity, type and glycemic index of the carbohydrates consumed. Carbohydrates with a high glycemic index contribute to greater excursions in glycemic and insulinogenic parameters, increase the generation of reactive oxygen species (ROS) and have been reported to contribute to neuronal dysregulation, neurologic demise, and epigenetically mediated senescence and cognitive decline in man and animals.