Does a ketogenic diet impair metabolic health?

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Project Summary Since the 1960s, a ketogenic diet (KD) has been touted as a potential treatment for diabetes and obesity. A KD is a very low carbohydrate, high fat, and moderate protein diet that has been used since the 1910s to treat epilepsy and was designed to mimic the benefits that fasting had on seizure control. Noting metabolic similarities between a KD and fasting — namely a switch from burning glucose to burning fat — a KD was hypothesized to lower fasting glucose and insulin, leading to consequent inhibition of lipogenesis, thereby favoring burning rather than storage of fat. However, the efficacy and metabolic effects of a KD have been largely underexplored. As obesity raises the risk for the development of many health conditions, including diabetes, heart disease, and multiple types of cancer, the long-term goal of this work is to develop rigorously tested and efficacious weight control therapeutics. The overall objective of this proposal is to determine whether a KD is a safe and effective treatment to control weight and blood glucose. The driving hypothesis of this proposed work is that a KD suppresses weight gain and causes weight loss but impairs glucose homeostasis. The rationale for carrying out the proposed studies is that the efficacy of a KD as a weight control diet, and the overall effects that KD has on metabolic health are unclear. Since KD is now a commonly used diet, it is critical to understand the effects of a KD on metabolic health so that we do not make health conditions worse by prescribing a KD. In humans who have obesity, some studies report greater weight loss when participants were prescribed a KD versus a control weight loss diet. However, other studies have reported that a KD produces similar effects to other weight loss diets, making the effects of KD on weight regulation unclear and necessitating further study. Conversely, while studies in both rodents and humans have shown that a KD intervention lowered fasting glucose and HbA1c, several studies have suggested that glucose tolerance is impaired on a KD. This proposed work is of crucial importance since a KD is prescribed to people who may already have diabetes or obesity, so it is imperative to understand if a KD worsens blood glucose regulation. Thus, to ascertain whether a KD is a metabolically safe and beneficial intervention for people with diabetes and/or obesity, we will elucidate the mechanisms by which a KD controls body weight (Aim 1) and establish the effects of a KD on beta cell function (Aim 2). The proposed studies are innovative as the mechanistic effects of KD on weight and blood glucose regulation have been largely under-investigated. Ultimately, these studies will determine whether a KD is a safe and effective treatment for weight control and glucose homeostasis. Furthermore, mechanistic insights gained from elucidating the effects of a KD on weight control will pave the way for the development of future weight control therapies.