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Low-carbohydrate diets were first introduced in medicine as the Atkins diet during the 1970s, where Dr. Robert Coleman Atkins (October 17, 1930 – April 17, 2003), an American physician and cardiologist, recommended a diet based primarily on fat and protein sources, and limited the carbohydrate intake only from vegetables. After the rise and fall of Atkins diet, now, an even stricter version of low-carb eating, called the ketogenic (Keto) diet, is gaining attention, which has started a fierce scientific debate about its potential risks and benefits.
Keto places firm limits on carbs and protein. This way of eating depletes the body of glucose to a point where the metabolism is pushed to a state known as physiologic ketosis; different from ketoacidosis, an uncontrolled over-production of ketones that occurs in pathologic states and causes a metabolic acidosis, which is a medical emergency.
{Ketoacidosis results due to complete insulin deficiency in type 1 diabetes or late-stage type 2 diabetes. Ketone levels can be measured in blood, urine, or breath, and are generally between 0.5-3.0 mM in physiologic ketosis, while ketoacidosis may cause blood concentrations >10 mM.}
Biochemistry of ketosis
In a typical Keto diet, high glucagon and low insulin results due to low glucose availability from carbs. Fatty acids attach to coenzyme A to allow penetration into mitochondria. Once inside the mitochondrion, the bound fatty acids are used as fuel in cells mainly through β-oxidation, which breaks two carbons from the acyl-CoA molecule in every cycle to form acetyl-CoA. Acetyl-CoA enters the citric acid cycle, where it undergoes an aldol condensation with oxaloacetate to form citric acid; citric acid then enters the tricarboxylic acid cycle (TCA), which gives a very high energy yield per carbon in the original fatty acid.
Acetyl-CoA can be metabolized through the TCA cycle in any cell, but it can also undergo ketogenesis in the mitochondria of liver cells. When glucose availability is low, oxaloacetate is deflected away from the TCA cycle and is instead used to produce glucose by the process of gluconeogenesis. This utilization of oxaloacetate in gluconeogenesis can make it unavailable to acetyl-CoA for condensation, preventing entrance into the TCA cycle. In this case, energy can be stored from acetyl-CoA through ketone production.
In ketogenesis, two acetyl-CoA molecules combine to form acetoacetyl-CoA via thiolase. Acetoacetyl-CoA briefly combines with another acetyl-CoA via HMG-CoA synthase to form hydroxy-β-methylglutaryl-CoA. Hydroxy-β-methylglutaryl-CoA form the ketone body acetoacetate via HMG-CoA lyase. Acetoacetate can then reversibly convert to another ketone body—D-β-hydroxybutyrate—via D-β-hydroxybutyrate dehydrogenase. Alternatively, acetoacetate can spontaneously degrade to a third ketone body (acetone) and carbon dioxide, which generates much greater concentrations of acetoacetate and D-β-hydroxybutyrate. The resulting ketone bodies cannot be used for energy by the liver, so are exported from the liver to supply energy to the brain and peripheral tissues. Deaminated ketogenic amino acids can also be converted into intermediates in the citric acid cycle and produce ketone bodies.
A typical ketogenic diet restricts carbs to less than 10 percent of calories, and limits protein to 20 percent, while fat makes up the rest.
The Keto diet is popularized among best-selling books, promoted by celebrities and advertised on social media as an antidote to various diseases. Proponents say it causes substantial weight loss and can help those with type 2 diabetes dramatically improve their blood sugar levels, which fall when people avoid carbs. There have been many studies of the ketogenic diet over the years, but most have been small and of fairly short duration. A federal registry of clinical research of United States of America shows that more than 70 trials looking at the diet’s impact on brain, cardiovascular, and metabolic health are either underway, or in the beginning stages, and many others are being conducted all over the world, including Japan, China, India, and South Korea.
While the ketogenic diet can seem like the latest in an endless stream of fad diets, it has a long history of therapeutic uses. Diabetics routinely practiced carb restriction before the discovery of insulin in the 1920s, and doctors at Johns Hopkins and other hospitals have used the diet for almost a century to reduce seizures in patients with epilepsy. Ketosis is also being investigated in other neurological diseases due to its proposed neuro-protective effects, including Alzheimer’s disease amyotrophic lateral sclerosis (ALS), autism, headache, neurotrauma, pain, Parkinson’s disease, and sleep disorders. Other established uses include type 2 diabetes, obesity, and metabolic syndromes, mainly by reduction in serum triglycerides and elevation in high-density lipoprotein, as well as increased size and volume of low-density lipoprotein particles. These changes are consistent with an improved lipid profile, despite potential increases in total cholesterol level.
But, the ketogenic diet has no shortage of its dark side. In June 2019, three doctors published an essay in JAMA Internal Medicine warning that the enthusiasm for the diet as a treatment for obesity and diabetes “outpaces” the evidence. They pointed to studies suggesting that it had little advantage over lower fat diets for blood sugar control, and that it could cause adverse effects like constipation, fatigue, and in some people, an increase in LDL cholesterol particles, a risk factor for heart disease.
“The greatest risk, however, of the ketogenic diet, may be the one most overlooked—the opportunity cost of not eating high-fiber, unrefined carbohydrates,” the authors wrote. “Whole grains, fruits, and legumes are some of the most health-promoting foods on the planet. They are not responsible for the epidemics of Type 2 diabetes or obesity, and their avoidance may do harm.” Dr. Shivam Joshi, a co-author of the piece, and attending physician at NYC Health + Hospitals/Bellevue, as well as a clinical assistant professor at New York University Medical School, has mentioned that it generated a flood of emails from people all across the globe. Some expressed praise and support, while others offered condemnation, a sign of just how polarizing the diet can be.
Dr. David Ludwig, an endocrinologist at Harvard Medical School, and the author of a best-selling book on low-carb diets, on the other hand, comments that one of the benefits of carb restriction is that blood sugar levels remain stable after a meal, resulting in lower levels of insulin, a hormone that causes weight gain. He quotes “Insulin is like a Miracle-Gro for cells; by lowering insulin levels, fewer calories from the meal may get stored in fat cells, leaving more to fuel metabolism and feed the brain. As a result, you may feel fuller longer after eating.” In a series of studies over the years, Dr. Ludwig has found that low carb diets cause people to burn more calories and lose more weight compared to lower fat diets. According to the carb and insulin theory of obesity, whole grains, starchy vegetables, and tropical fruits are more healthful than processed carbs. But, they can still cause swings in blood sugar and insulin after a meal, and that can be particularly problematic for people with diabetes.
In May 2019, the American Diabetes Association published a consensus statement on nutrition strategies for people with diabetes. It found that a variety of diets rich in unprocessed foods, like the Mediterranean and vegetarian diets, could help people prevent and manage the disease. But it also concluded that reducing overall carb intake “has demonstrated the most evidence” for improving blood sugar control. Nevertheless, the carb and insulin explanation for obesity is the subject of much debate. Scientists at the National Institutes of Health have published research showing that people actually burn more calories on low-fat diets, and many experts contend that, in the end, people will lose weight on any diet, so long as they consume fewer calories.
Ultimately, it is very hard to get specific answers on any diet, because nutrition studies tend to be short-term and not very rigorous, and there is tremendous variation in how people respond to different diets. Dr. Steven B. Heymsfield, President of the Obesity Society, and Director of the Body Composition-Metabolism Laboratory at the Pennington Biomedical Research Center in Baton Rouge, LA, has conducted studies showing that some people who adopt a very low-carb diet experience a significant increase in their LDL cholesterol levels, while others see little or no change at all.
Lastly, my advice to people who try the ketogenic diet would be to limit foods high in saturated fat like butter, meat, and cheese, and focus on foods with unsaturated fats like olive oil, seafood, nuts, chicken, and avocado. Consult a dietitian or doctor for their guidance and ask yourself if you are willing to commit to the diet for the long term. I personally think we must set down a lifestyle and a healthy eating plan that we can adhere to for the rest of our lives, because these things only work while we’re doing them.
References: Harper’s illustrated biochemistry 31st edition Dr. Atkins New Diet revolution Annual report Federal Registry of clinical research, USA 2018 Ketogenic diet therapy for Epilepsy, Johns Hopkins Medicine Journal JAMA Internal Medicine Journal June/July 2019 “Always hungry?” by Dr. David Ludwig American Diabetes Association Journal 2019 / www.Diabetes.org National Institute of Health publications 2019/ www.nih.gov ,USA Pennington Biomedical Research Center/ www.pbrc.edu
