The ketogenic diet was first proposed by Russell M. Wilder at the Mayo Clinic in 1921. The goal was to mimic the the physiology of fasting in a way that was more sustainable over time than completely abstaining from food. The application was to treat epilepsy. The use of fasting to treat epilepsy dates back …
Why were the Inuit never in ketosis, despite their traditional high-fat diet? That question is answered in this lesson. The answer provides a stunning example of human evolution and makes it clear that evolution does not “want” us in a constant state of ketosis. CPT-1a deficiency is a genetic disorder in the ability to make …
Ketones have a dark side: ketoacidosis. And it does NOT only happen in diabetes. Ketoacidosis is a serious and life-threatening medical condition wherein ketones accumulate to such high levels that they overwhelm the body’s natural buffering capacity and sink the pH of the blood to dangerous and possibly fatal levels. Ketoacidosis is most often associated …
Ketone homeostasis has two central objectives: 1) keep ketone levels high enough to feed the brain, and 2) keep ketone levels low enough to avoid the serious and life-threatening condition of ketoacidosis. While proportion of circulating ketones taken up by skeletal muscle, heart, and other tissues during fasting is initially high, these tissues limit their …
The physiological purpose of ketogenesis is to spare the loss of lean mass that would otherwise occur during prolonged fasting. Meeting the glucose requirement of the brain entirely by gluconeogenesis from amino acids would cause us to lose 2.2 pounds of lean mass every day. This would cause us to die much more quickly from …
The production of ketones in the liver frees up coenzyme A (CoA) that would otherwise be captured in the accumulating acetyl CoA, and the conversion of acetoacetate to beta-hydroxybutyrate frees up NAD+ that would otherwise be trapped as NADH as the production of NADH in beta-oxidation exceeds that oxidized in the electron transport chain. This …
In conditions of glucose deprivation, such as fasting or carbohydrate restriction, ketogenesis serves to reduce our needs for glucose. This reduces the need to engage in the energetically wasteful process of gluconeogenesis, which would otherwise be extremely taxing on our skeletal muscle if dietary protein were inadequate. Ketogenesis mainly occurs in the liver. The biochemical …
The last lesson covered how insulin, glucagon, and allosteric regulators from within the liver ensure that the liver only engages in gluconeogenesis when it can and when it needs to. This lesson focuses on an additional layer of regulation: cortisol. Cortisol is the principal glucocorticoid in humans. Glucocorticoids are steroid hormones produced by the adrenal …
Since gluconeogenesis is extremely expensive, it has to be tightly regulated so that it only occurs when both of two conditions are met: 1) the liver has enough energy to invest a portion into synthesizing glucose, and 2) the rest of the body is in need of that glucose. Since the liver is the metabolic …
Gluconeogenesis is extremely expensive. Three steps of glycolysis are so energetically favorable that they are irreversible. Getting around them requires four gluconeogenesis-specific enzymes and the investment of a much larger amount of energy. Overall, six ATP worth of energy are invested to yield glucose, a molecule that only yields 2 ATP when broken down in …