The prevalence of both Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is increasing worldwide, and the trends are unfortunately expected to continue. AD has recently been tied with mitochondrial dysfunction and insulin resistance, creating a mechanistic tie between AD and T2DM. Unfortunately, insulin resistance is often increased with aging and therefore, all individuals are at risk of brain mitochondrial dysfunction. Without proper mitochondrial function, the brain will degenerate, causing impaired cognitive function and reduced quality of life. The purpose of this study is two-fold: first, to understand the role of ceramides in insulin-induced brain mitochondrial dysfunction, and; second, to understand how ketones can restore brain mitochondrial function in aged brains. To evaluate the role of insulin resistance and ceramides in brain mitochondrial function, we induced hyperinsulinemia in ApoE4 mice. In addition to insulin, one group received myriocin injections to inhibit ceramide biosynthesis. We observed significant increases in brain ceramides in the insulin-treated group, which correlated with disrupted brain mitochondrial function. However, the group receiving myriocin alone, and, importantly, myriocin with insulin, had normal lipid profiles and normal mitochondrial bioenergetics. Altogether, these findings support the hypothesis of the key role of ceramides in insulin resistance-induced mitochondrial dysfunction within the brain. Next, young adult (5 months old) and old (28 months old) rats were assigned to either standard chow diets or very-low-carbohydrate, high-fat, ketogenic diets for 4 weeks. Following the treatment period, we analyzed brain mitochondrial function and oxidative stress. We found that the old rats fed the ketogenic diet had improved mitochondrial function in comparison to the old rats consuming standard rodent chow. In addition, the old rats fed a standard diet had significantly higher levels of oxidative stress than the aged rats on the very-low-carbohydrate, high-fat diet. These findings revealed that ketones can protect brain mitochondrial function in aging. Collectively, these results suggest that insulin resistance has a role in the development of brain mitochondrial dysfunction due to ceramide accumulation, while ketones can help mitigate some of the negative consequences of aging, perhaps some due to insulin resistance, on brain mitochondrial function.



College and Department

Life Sciences; Physiology and Developmental Biology



Date Submitted


Document Type





type 2 diabetes, alzheimer's disease, mitochondria, insulin, ketones, ceramide



Included in

Physiology Commons