A ketogenic diet – which provides 99 percent of calories from fat and protein and only 1 percent from carbohydrates – produces health benefits in the short term, but negative effects after about a week, Yale researchers found in a study of mice.
The results offer early indications that the keto diet could, over limited time periods, improve human health by lowering diabetes risk and inflammation. They also represent an important first step toward possible clinical trials in humans.
The keto diet has become increasingly popular as celebrities, including Gwyneth Paltrow, Lebron James, and Kim Kardashian, have touted it as a weight-loss regimen.
In the Yale study, published in the Jan. 20 issue of Nature Metabolism, researchers found that the positive and negative effects of the diet both relate to immune cells called gamma delta T-cells, tissue-protective cells that lower diabetes risk and inflammation.
A keto diet tricks the body into burning fat, said lead author Vishwa Deep Dixit of the Yale School of Medicine.
When the body’s glucose level is reduced due to the diet’s low carbohydrate content, the body acts as if it is in a starvation state – although it is not – and begins burning fats instead of carbohydrates.
This process in turn yields chemicals called ketone bodies as an alternative source of fuel. When the body burns ketone bodies, tissue-protective gamma delta T-cells expand throughout the body.
This reduces diabetes risk and inflammation, and improves the body’s metabolism, said Dixit, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology. After a week on the keto diet, he said, mice show a reduction in blood sugar levels and inflammation.
But when the body is in this “starving-not-starving” mode, fat storage is also happening simultaneously with fat breakdown, the researchers found.
When mice continue to eat the high-fat, low-carb diet beyond one week, Dixit said, they consume more fat than they can burn, and develop diabetes and obesity.
“They lose the protective gamma delta T-cells in the fat,” he said.
Long-term clinical studies in humans are still necessary to validate the anecdotal claims of keto’s health benefits.
“Before such a diet can be prescribed, a large clinical trial in controlled conditions is necessary to understand the mechanism behind metabolic and immunological benefits or any potential harm to individuals who are overweight and pre-diabetic,” Dixit said.
There are good reasons to pursue further study: According to the Centers for Disease Control, approximately 84 million American adults – or more than one out of three – have prediabetes (increased blood sugar levels), putting them at higher risk of developing type 2 diabetes, heart disease, and stroke. More than 90 percent of people with this condition don’t know they have it.
“Obesity and type 2 diabetes are lifestyle diseases,” Dixit said. “Diet allows people a way to be in control.”
With the latest findings, researchers now better understand the mechanisms at work in bodies sustained on the keto diet, and why the diet may bring health benefits over limited time periods.
“Our findings highlight the interplay between metabolism and the immune system, and how it coordinates maintenance of healthy tissue function,” said Emily Goldberg, the postdoctoral fellow in comparative medicine who discovered that the keto diet expands gamma-delta T cells in mice.
If the ideal length of the diet for health benefits in humans is a subject for later studies, Dixit said, discovering that keto is better in small doses is good news, he said: “Who wants to be on a diet forever?”
Despite continuous advances in the medical world, obesity continues to remain a major worldwide health hazard with adult mortality as high as 2.8 million per year. The majority of chronic diseases like diabetes, hypertension, and heart disease are largely related to obesity which is usually a product of unhealthy lifestyle and poor dietary habits.
Appropriately tailored diet regimens for weight reduction can help manage the obesity epidemic to some extent. One diet regimen that has proven to be very effective for rapid weight loss is a very-low-carbohydrate and high-fat ketogenic diet.
A ketogenic diet primarily consists of high-fats, moderate-proteins, and very-low-carbohydrates. The dietary macronutrients are divided into approximately 55% to 60% fat, 30% to 35% protein and 5% to 10% carbohydrates. Specifically, in a 2000 kcal per day diet, carbohydrates amount up to 20 to 50 g per day.
History and Origin
Russel Wilder first used the ketogenic diet to treat epilepsy in 1921. He also coined the term “ketogenic diet.” For almost a decade, the ketogenic diet enjoyed a place in the medical world as a therapeutic diet for pediatric epilepsy and was widely used until its popularity ceased with the introduction of antiepileptic agents. The resurgence of the ketogenic diet as a rapid weight loss formula is a relatively new concept the has shown to be quite effective, at least in the short run.
Physiology and Biochemistry
Basically, carbohydrates are the primary source of energy production in body tissues. When the body is deprived of carbohydrates due to reducing intake to less than 50g per day, insulin secretion is significantly reduced and the body enters a catabolic state. Glycogen stores deplete, forcing the body to go through certain metabolic changes. Two metabolic processes come into action when there is low carbohydrate availability in body tissues: gluconeogenesis and ketogenesis.
Gluconeogenesis is the endogenous production of glucose in the body, especially in the liver primarily from lactic acid, glycerol, and the amino acids alanine and glutamine. When glucose availability drops further, the endogenous production of glucose is not able to keep up with the needs of the body and ketogenesis begins in order to provide an alternate source of energy in the form of ketone bodies. Ketone bodies replace glucose as a primary source of energy. During ketogenesis due to low blood glucose feedback, stimulus for insulin secretion is also low, which sharply reduces the stimulus for fat and glucose storage.
Other hormonal changes may contribute to the increased breakdown of fats that result in fatty acids. Fatty acids are metabolized to acetoacetate which is later converted to beta-hydroxybutyrate and acetone. These are the basic ketone bodies that accumulate in the body as a ketogenic diet is sustained. This metabolic state is referred to as “nutritional ketosis.” As long as the body is deprived of carbohydrates, metabolism remains in the ketotic state.
The nutritional ketosis state is considered quite safe, as ketone bodies are produced in small concentrations without any alterations in blood pH. It greatly differs from ketoacidosis, a life-threatening condition where ketone bodies are produced in extremely larger concentrations, altering blood ph to acidotic a state.
Ketone bodies synthesized in the body can be easily utilized for energy production by heart, muscle tissue, and the kidneys. Ketone bodies also can cross the blood-brain barrier to provide an alternative source of energy to the brain. RBCs and the liver do not utilize ketones due to lack of mitochondria and enzyme diaphorase respectively.
Ketone body production depends on several factors such as resting basal metabolic rate (BMR), body mass index (BMI), and body fat percentage. Ketone bodies produce more adenosine triphosphate in comparison to glucose, sometimes aptly called a “super fuel.”
One hundred grams of acetoacetate generates 9400 grams of ATP, and 100 g of beta-hydroxybutyrate yields 10,500 grams of ATP; whereas, 100 grams of glucose produces only 8,700 grams of ATP. This allows the body to maintain efficient fuel production even during a caloric deficit. Ketone bodies also decrease free radical damage and enhance antioxidant capacity.
Issues of Concern
The most common and relatively minor short-term side effects of ketogenic diet include a collection of symptoms like nausea, vomiting, headache, fatigue, dizziness, insomnia, difficulty in exercise tolerance, and constipation, sometimes referred to as keto flu. These symptoms resolve in a few days to few weeks. Ensuring adequate fluid and electrolyte intake can help counter some of these symptoms. Long-term adverse effects include hepatic steatosis, hypoproteinemia, kidney stones, and vitamin and mineral deficiencies.
Cautions and Contraindications
People suffering from diabetes and taking insulin or oral hypoglycemic agents suffer severe hypoglycemia if the medications are not appropriately adjusted before initiating this diet. The ketogenic diet is contraindicated in patients with pancreatitis, liver failure, disorders of fat metabolism, primary carnitine deficiency, carnitine palmitoyltransferase deficiency, carnitine translocase deficiency, porphyrias, or pyruvate kinase deficiency. People on a ketogenic diet rarely can have a false positive breath alcohol test. Due to ketonemia, acetone in the body can sometimes be reduced to isopropanol by hepatic alcohol dehydrogenase which can give a false positive alcohol breath test result.
The popular belief that high-fat diets cause obesity and several other diseases such as coronary heart disease, diabetes, and cancer has not been observed in recent epidemiological studies. Studies carried out in animals that were fed high-fat diets did not show a specific causal relationship between dietary fat and obesity. On the contrary, very-low-carbohydrate and high-fat diets such as the ketogenic diet have shown to beneficial to weight loss.
Evidence Behind The Ketogenic Diet
In relation to overall caloric intake, carbohydrates comprise around 55% of the typical American diet, ranging from 200 to 350 g/day. The vast potential of refined carbohydrates to cause harmful effects were relatively neglected until recently. A greater intake of sugar-laden food is associated with a 44% increased prevalence of metabolic syndrome and obesity and a 26% increase in the risk of developing diabetes mellitus. In a 2012 study of all cardiometabolic deaths (heart disease, stroke, and type 2 diabetes) in the United States, an estimated 45.4% were associated with suboptimal intakes of 10 dietary factors.
The largest estimated mortality was associated with high sodium intake (9.5%), followed by low intake of nuts and seeds (8.5%), high intake of processed meats (8.2%), low intake of omega-3 fats (7.8%), low intake of vegetables 7.6%), low intake of fruits (7.5%), and high intake of artificially sweetened beverages (7.4%). The lowest estimated mortality was associated with low polyunsaturated fats (2.3%) and unprocessed red meats (0.4%). In addition to this direct harm, excess consumption of low-quality carbohydrates may displace and leave no room in the diet for healthier foods like nuts, unprocessed grains, fruits, and vegetables.
A recent systemic review and meta-analysis of randomized controlled trials comparing the long-term effects (greater than 1 year) of dietary interventions on weight loss showed no sound evidence for recommending low-fat diets. In fact, low-carbohydrate diets led to significantly greater weight loss compared to low-fat interventions. It was observed that a carbohydrate-restricted diet is better than a low-fat diet for retaining an individual’s BMR. In other words, the quality of calories consumed may affect the number of calories burned. BMR dropped by more than 400 kcal/day on a low-fat diet when compared to a very low-carb diet.
A well-formulated ketogenic diet, besides limiting carbohydrates, also limits protein intake moderately to less than 1g/lb body weight, unless individuals are performing heavy exercise involving weight training when the protein intake can be increased to 1.5g/lb body weight. This is to prevent the endogenous production of glucose in the body via gluconeogenesis. However, it does not restrict fat or overall daily calories. People on a ketogenic diet initially experience rapid weight loss up to 10 lbs in 2 weeks or less. This diet has a diuretic effect, and some early weight loss is due to water weight loss followed by a fat loss. Interestingly with this diet plan, lean body muscle is largely spared. As a nutritional ketosis state sustains, hunger pangs subside, and an overall reduction in caloric intake helps to further weight loss.
Long-term compliance is low and can be a big issue with a ketogenic diet, but this is the case with any lifestyle change. Even though the ketogenic diet is significantly superior in the induction of weight loss in otherwise healthy patients with obesity and the induced weight loss is rapid, intense, and sustained until at least 2 year, the understanding of the clinical impacts, safety, tolerability, efficacy, duration of treatment, and prognosis after discontinuation of the diet is challenging and requires further studies to understand the disease-specific mechanisms.
A ketogenic diet may be followed for a minimum of 2 to 3 weeks up to 6 to 12 months. Close monitoring of renal functions while on a ketogenic diet is imperative, and the transition from a ketogenic diet to a standard diet should be gradual and well controlled.
Enhancing Healthcare Team Outcomes
To counter the obesity epidemic, some healthcare workers do recommend the ketogenic diet. However, the primary care provider, nurse practitioner, dietitian and internist need to be aware of a few facts.
Overweight individuals with metabolic syndrome, insulin resistance, and type 2 diabetes are likely to see improvements in the clinical markers of disease risk with a well-formulated very-low-carbohydrate diet. Glucose control improves due to less glucose introduction and improved insulin sensitivity. In addition to reducing weight, especially truncal obesity and insulin resistance, low-carb diets also may help improve blood pressure, blood glucose regulation, triglycerides, and HDL cholesterol levels. However, LDL cholesterol may increase on this diet.
Also, in various studies, the ketogenic diet has shown promising results in a variety of neurological disorders, like epilepsy, dementia, ALS, traumatic brain injury, acne, cancers, and metabolic disorders.
Due to the complexity of the mechanism and lack of long-term studies, a general recommendation of the ketogenic diet for prevention of type 2 diabetes mellitus or cardiovascular disease may seem premature but is, however, not farfetched for primary weight loss.
While in the short term the ketogenic diet may help one lose weight, this is not sustained over the long run. In addition, countless studies show that the diet is associated with many complications that often lead to emergency room visits and admissions for dehydration, electrolyte disturbances, and hypoglycemia. 
More information: Emily L. Goldberg et al. Ketogenesis activates metabolically protective γδ T cells in visceral adipose tissue, Nature Metabolism (2020). DOI: 10.1038/s42255-019-0160-6