Results from our work in rats and others findings from human epidemiologic studies demonstrate deficits in cognitive performance following chronic ingestion of high fat, high saturated fat, diets. Yet, the precise physiologic mechanism underlying these deficits is not well understood. We report that older adults with insulin resistance show remarkably similar deficits in cognitive function and respond to glucose ingestion in a comparable manner to rodents fed a high-fat diet, suggesting that insulin resistance is a probable mediator of these diet-induced deficits. As insulin resistance worsens to overt type 2 diabetes, profound deficits in cognitive functions, especially those dependent on the medial temporal lobes, are apparent in both obese Zucker rats and humans with type 2 diabetes. Unlike the older adult with insulin resistance, glucose ingestion further impairs medial temporal lobe function in adults with type 2 diabetes. Collectively, the human and rodent data point to a role of diet-induced endocrine abnormalities, including the development of insulin resistance, as mediating the cognitive deficits associated with high fat consumption.