Circa mid-19th century, ketones were discovered in the urine of patients with uncontrolled diabetes. This led to the negative connotation of ketones being indicative of metabolic dysfunction, a sentiment that persisted for the next 150 years. Despite pioneering work published more than 4 decades ago showing that ketones were highly functional metabolites, these fat-derived molecules are still considered by many doctors, dietitians, and nutritionists as toxic byproducts of fat metabolism. Adding to this, the concurrent misunderstanding and vilification of dietary fat, from which ketones are derived, has further perpetuated this negative perspective around ketones and nutritional ketosis.
Even to the present, the objective information on the science of ketones has been absent from most academic nutrition or medical curricula, resulting in an abundance of misinformation. To help the reader overcome this, we will strive to explain key terms and concepts related to ketones to give you a solid foundation with which to distinguish fact from fallacy.
During total fasting when there is complete absence of any caloric intake for several days, the resulting increase in ketones is referred to as starvation ketosis. The absence of any dietary carbohydrate and protein over a week or more raises ketone concentrations to between 5 and 10 mmol/L, significantly higher than nutritional ketosis, but lower than concentrations in keto-acidosis. Starvation ketosis is an important physiologic process that evolved millions of years ago, enabling humans to survive for prolonged periods on body fat when food was not available.4 Obviously starvation ketosis is not sustainable long term, nor is it advisable to intentionally induce it for shorter periods (i.e., intermittent fasting) because of essential nutrient deprivation, lean tissue loss, and other potentially dangerous side effects.5
This is a distinct pathologic state that happens when insulin levels are extremely low, such as in a person with type 1 diabetes who cannot produce insulin. It is often called diabetic keto-acidosis or DKA. In this case ketone production redlines, resulting in dangerously high ketone concentrations that can exceed 20 mmol/L, an order of magnitude higher than typical values in nutritional ketosis. Except for type 1 diabetes or other conditions associated with insulin insufficiency (e.g., people with advanced type 2 diabetes who have lost most or all of their capacity for insulin production), a well-formulated ketogenic diet is associated with a built-in safety mechanism thanks to negative feedback inhibition that prevents ketones from exceeding 5 mmol/L.6
When maintained for several consecutive weeks, nutritional ketosis fundamentally changes the way cells work.7 This includes switching the mix of fuels they use, as well as awakening genes that are silenced by high-carb diets. Over time the body refines its metabolism to run on fat and ketones, ultimately manifested by two-fold higher rates of whole body fatty acid oxidation. Meanwhile glycolysis, insulin concentrations, constituitive inflammation, and oxidative stress are all decreased. As a result, keto-adaptation can have prompt and potent therapeutic effects; most notable reversal of clinical signs of metabolic syndrome and type-2 diabetes. Many other disorders/diseases may be amenable to keto-adaptation. This is an early-stage but burgeoning area of scientific investigation.
This term is often used synonymously with keto-adaptation, and commonly used to describe low-carb adapted athletes. If you are fat-adapted, it implies you have restricted carbs enough to induce an increase in fat burning. Fat-adapted athletes, and sedentary folks, can derive up to twice as much of their energy needs from fat, while decreasing their dependency on carbs.2,8 Whereas fat adaptation can occur to different degrees and across a spectrum dependent on the degree of carb restriction, keto-adaptation represents a more comprehensive reshaping of many physiologic systems. Keto-adaptation only happens when carbs are restricted to a point that induces sustained nutritional ketosis. The nuances here are subtle, but meaningful. For example, moderately restricting carbs (e.g., adaptation to a Paleo diet) may induce some degree of fat-adaptation and perceived benefits, but falls short of maximizing fat oxidation and producing positive health outcomes specifically linked to nutritional ketosis.9 A keto-adapted person is by definition fully fat-adapted, but a fat-adapted person may not be keto-adapted.
In the opinion of most physicians and nutrition scientists, carbohydrate must constitute a major component of one's daily energy intake if optimum physical performance is to be maintained [1]. This consensus view is based upon a long list of published studies performed over the last century that links muscle glycogen stores to high intensity exercise. It has also been reinforced by the clinical experience of many physicians, whose patients following low carbohydrate formula or food diets frequently complain of lightheadedness, weakness, and ease of fatigue.
During the time that this consensus view of the necessity of carbohydrate for vigorous exercise was forming, the last pure hunting cultures among the peoples of North America finally lost out in competition with expanding European cultural influences. Between 1850 and 1930, the routine consumption of carbohydrates spread north from the U.S. Plains States through central Canada, where the indigenous peoples had heretofore made at most seasonal use of this nutrient class. However the last of these groups to practice their traditional diet, the Inuit people of the Canadian and Alaskan Arctic regions, were luckily observed by modern scientists before their traditional dietary practices were substantially altered. The reports of these early scientists imply that the Inuit people were physically unhampered despite consuming a diet that was essentially free of identifiable carbohydrate.
Given this juxtaposition of clinical research results favoring carbohydrate against observed functional well-being in traditional cultures consuming none, it is an interesting challenge to understand how these opposing perspectives can be explained. This paper will review the observations of early explorer scientists among the Inuit, track the controversy that they stimulated among nutritionists in the last century, and utilize some of the forgotten lessons from the Inuit culture to explain how well-being and physical performance can be maintained in the absence of significant dietary carbohydrate.
Until the development of agriculture over last few millennia, our human ancestors' consumption of dietary carbohydrate was opportunistic. As some groups adapted to hunting and fishing for their sustenance, they were able to move into temperate and then arctic regions, where limited access to wild grain, nuts, and fruit dictated sustained dependence upon fat and protein as primary sources of dietary energy.
With the development of agriculture came the ability to grow and store grain, allowing societies to remain in a stable physical location, build permanent dwellings, and potentially stimulating the development of written language (those early stone tablets would have been difficult to transport from camp to camp on a dog sled). Starting from locations in the Middle East and Asia, cultures based upon agricultural wheat and rice spread over 5 millennia to dominate Europe, Africa, and the Americas.
With its ability to support a non-nomadic life style, greater population density, and permanent communities; there were clear advantages of agriculture-based societies over those based upon hunting and fishing, particularly as agricultural communities built the infrastructure to support trade and transport. Given its success in this competition of cultures (and by implication, the competition of their diets), it is an easy assumption that a grain-based diet is functionally superior to one based upon the meat and fish (fat and protein) of the hunting societies that they superseded.
As the science of nutrition developed in the early 20th Century, numerous comparative studies were undertaken to assess differences between diets. Although there were some advocates of low carbohydrate diets (eg, the Banting diet of the 19th Century, promoted for weight loss and diabetes control), the prevailing premise for these studies was that carbohydrate was a necessary nutrient for optimum human health and function. Among studies confirming this view, a classic was the 1939 study by two Danish scientists, Christensen and Hansen [2]. They did a crossover study of low carbohydrate, moderate carbohydrate, and high carbohydrate diets, each lasting one week. At the end of each diet, the subjects' endurance time to exhaustion on a stationary bicycle was assessed. Compared to the mean endurance time on the low carb diet of 81 minutes, the subjects were able to ride for 206 minutes after the high carb diet.
During the Second World War, another oft-cited study was performed, this time examining the practicality of pemmican (a mixture of dried meat and fat) as a light-weight emergency ration for soldiers. This experiment by Kark et al [3] involved abruptly switching soldiers in winter training in the Canadian Arctic from standard carbohydrate-containing rations to pemmican. This study only lasted 3 days, as the soldiers rapidly became unable to complete their assigned tasks, which included pulling loaded sleds 25-miles per day through deep snow.
With the resurgence of biomedical science in the 1960's came development of the percutaneous needle biopsy, facilitating assessment of intra-muscular fuel stores and metabolism. This led to the concept of muscle glycogen as the limiting fuel for high intensity exercise [4] and to the nutritional strategy of carbohydrate loading [5]. The clear consensus that developed from this research was that fat had limited utility as a fuel for vigorous exercise, and that humans are physically impaired if given a low carbohydrate diet.
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