The Ketogenic Diet and Its Physiological Effects on the Human Body

In this interview, Benjamin Bikman, Ph.D., obesity and diabetes scientist and associate professor of physiology and developmental biology at Brigham Young University (BYU) in Utah,¹ reveals how the ketogenic diet affects your physiology and supports optimal health.

“My main interest early on was looking at how the body adapts to obesity,” he says. “That was my master’s thesis. My master’s degree was exercise science here at BYU … I ended up pursuing a Ph.D. in bioenergetics at East Carolina University, under this wonderful scientist named Lynis Dohm, Ph.D.

His focus had been looking at how lipids cause insulin resistance. That was an interest of mine because I thought this was starting to explain why and how the body becomes insulin-resistant in the midst of obesity … Insulin resistance is that connection.

During my Ph.D., we were looking at inflammation in people who were losing weight following gastric bypass procedures and how improved inflammation is likely part of the improvements in insulin sensitivity that people see post-bypass.

I followed that up with a post-doctoral fellowship at … the Duke-National University of Singapore. They had this focus on cardiometabolic disorders. I … looked at inflammation as a particular mediator there … Then in 2011, my alma mater, BYU, came knocking. They wanted to do more diabetes research, and I fit the requirements … That got me, essentially, to where I am now …

If I really am getting this conviction, based on my own research, that insulin is key to not only diabetes but to almost every chronic disease, what is the best way to control insulin? That was when I insisted on only looking at published human clinical data — not rodents, not cells, not epidemiology, just clinical data.

The low-carb diet was just this very effective way to do that. That then got me interested in asking questions about ketones, which is what my lab is doing … how ketones are regulated by insulin.”

Bikman’s conviction that insulin is a key to health and disease prevention, and that controlling carbohydrate intake is the most effective way to control insulin, led him to start practicing what he’d learned. He went on a low-carb diet about eight years ago. “Sure enough, at middle age, it’s helped me stay healthy,” he says.

Most Americans Are Insulin Resistant

Unfortunately, many, including doctors, still do not understand the influence of insulin on health and disease. The late Dr. Joseph Kraft, former chairman of the department of clinical pathology and nuclear medicine at St. Joseph’s Hospital in Chicago, wrote the book “Diabetes Epidemic and You: Should Everyone Be Tested?”

In it, he presents data that suggests 80 percent of Americans are in fact insulin resistant or have “diabetes in situ.” Based on data from 14,000 patients,² Kraft developed a powerfully predictive test for diabetes.³ He would have the patient drink 75 grams of glucose, and then measure their insulin response over time, at half-hour intervals for up to five hours.

He noticed five distinctive patterns suggesting that a vast majority of people were already diabetic, even though their fasting glucose was normal. Only 20 percent of patients had healthy post-prandial insulin sensitivity and low diabetes risk. According to Kraft, “Those with cardiovascular disease not identified with diabetes … are simply undiagnosed.”

One of the take-home messages here is that insulin resistance and hyperinsulinemia (a condition marked by excess insulin in your blood relative to your level of glucose) are two sides of the same coin, as they drive and promote each other. In other words, if you have hyperinsulinemia, you are essentially insulin resistant and on your way toward developing Type 2 diabetes.

High Insulin Is a Key Disease Promoter

Both insulin resistance and hyperinsulinemia promote fatty liver and high blood glucose, and both of those, in turn, promote atherosclerosis. High blood pressure is another side effect of insulin resistance that drives atherosclerosis by placing stress on your arteries.

The effects of insulin resistance are really at the heart of most if not all chronic degenerative diseases. Diabetes, heart disease, cancer and Alzheimer’s are just a few of the most obvious ones. The logical conclusion then would be that addressing insulin resistance is a foundational component of effective health care. Bikman says:

“When I teach this to my students … I put insulin resistance in the core. Around it, I have all these chronic diseases. It’s what I call the ‘wheel of misfortune.’ Really, the most common cancers, prostate and breast cancers, almost always … will heavily express — by six or seven times — the number of insulin receptors. So, insulin is promoting the growth of the tumor.

With dementia, the connection between insulin resistance and Alzheimer’s is so tight that people refer to it as Type 3 diabetes. With sarcopenia, we know that if a muscle becomes insulin-resistant, that actually diminishes insulin’s ability to promote the anabolic production of proteins within the muscle …

We have to have our medical practitioners start appreciating … the utility [of] measuring insulin, because our focus on measuring glucose misses the mark. As someone’s becoming insulin-resistant, their insulin is climbing, but it’s enough to keep their glucose in check.

And because we always look at glucose, we don’t catch the disease until they become so insulin-resistant that no amount of their own insulin is enough to keep the glucose in check. Now, the glucose starts to climb — 10 years later, perhaps — and that’s when we detect the problem. We’re looking at the wrong marker.”

How the Ketogenic Diet Improves Insulin Sensitivity

The question then becomes, how do we treat insulin resistance? As Bikman’s research reveals, the ketogenic diet is part and parcel of the “cure” for this condition.

“For me, the benefit of a low-carb ketogenic diet is that it addresses the endocrine aspect of metabolic health,” Bikman says. “For too long … the message has been completely focused on calorie number.

It is this idea that if you can simply put a person into caloric deficiency, they will lose weight — problem solved … But we know that has long-term consequences … There’s a lasting metabolic damage …

Nevertheless, the power of the low-carbohydrate diet is that it addresses the endocrine component. As important as calorie number is, and I can appreciate the laws of thermodynamics … we cannot ignore the relevance of hormones, especially insulin.”

As explained by Bikman, it’s important to realize that insulin is what dictates what your body does with the energy it has — the energy you consume and the energy you have stored. “Insulin has its strong, capable hands right on the steering wheel of what the body does with the energy that it has available,” he says.

Importantly, research shows your metabolic rate increases as insulin decreases. “To me, that’s the power of the low-carb diet. You’re controlling insulin, and that can start to address all of those chronic diseases,” Bikman says.

The Importance of Cycling High and Low Carbohydrate Intake

For all its benefits though, there are drawbacks to staying in chronic nutritional ketosis. Based on the evidence, I’m convinced one needs to pulse or cycle in and out of nutritional ketosis. Bikman, who is in general agreement with this idea, explains:

“As a scientist, I wish there were longer-term studies to be able to conclusively say you can’t do this long-term or you can. What I’m comfortable saying, with a little bit of speculation, is that … the avoidance of carbohydrates for a prolonged period will create this situation of a relative glucose intolerance.

Now, I’m not going to say that causes insulin resistance. Some people say low-carb [diet] causes physiological insulin resistance … To me, a low-carb diet can create a situation of carbohydrate intolerance. That is reflective of a general and very substantial shift in energy use.

Insulin is down — that means the body is in fat-burning mode. That is the absolute bioenergetic fuel. If insulin is low, you are fueled with fat. That can create a shift where the body becomes almost reluctant to fuel itself with carbohydrates.

That’s where you have instances of someone adopting a low-carbohydrate diet, and then they’ll eat a carbohydrate load and they’ll say, ‘Wow, my glucose levels; it’s like I’ve become diabetic.’ That’s not the same thing. They become glucose-intolerant.

If that’s something someone wants to avoid for whatever reason, then cyclical [keto] is probably the way to go. You kind of spike the glucose from time to time, maybe weekly, whatever would work best for the person … The idea [is] you have that frequent-enough exposure to carbohydrates so that you can maintain that tolerance to the carbohydrates …”

Insulin also suppresses the liver’s ability to produce glucose. It impairs gluconeogenesis. What this means is that if your insulin level is too low for too long, your glucose level can start to rise. While this is not universally true for everyone, it can occur, as it did for me. Cycling in and out of ketosis will help you avoid this paradoxical side effect as well. Bikman notes:

“I’ve heard enough people say that. I think it has to be taken seriously. Nevertheless, glucagon [hormone] starts to climb. Insulin’s main effect is to take glucose from the blood (or any fuel) and push it into the cells. Glucagon does the opposite. Glucagon wants to mobilize fuel from tissues and push it into the blood.

One of glucagon’s main actions is to promote the breakdown of stored glycogen to promote the production of glucose in the liver. In that instance, where insulin has gone too low then, theoretically, glucagon could go too high, and that could increase glucose too much … That’s kind of reflective, perhaps, of that intolerance I mentioned …

With regards to the context of low-carb [causing] glucose to climb over time, it could be due to the lack of insulin, and thus an absence of the inhibition of glucagon production from the pancreas. The pancreas is making too much glucagon. That could potentially be driving up glucose levels.”

The Connection Between Gut Bacteria and Liver Health

Bikman also summarizes how a high-fiber diet helps combat fatty liver disease, which it does by way of influencing your gut microbiome.

“While the human body doesn’t get any energetic benefit from the fiber, the bacteria do. The bacteria are able to use the fiber as fuel. One of the products of that is short-chain fatty acids, [such as] butyrate.

What’s interesting is that as the fiber is being digested by the bacteria to create butyrate, that short-chain fat can get absorbed into the body … [I]t goes right into the portal vein from the gut, right to the liver …

Short-chain fatty acids are so stimulatory with regards to mitochondrial biogenesis … that it actually can combat fatty liver disease. It’s kind of a fun little paradox of using a fat to fight the fat that’s stored in the liver, in the case of fatty liver disease. Nevertheless, that’s an odd little connection between gut bacteria and liver health.”

Butyric acid (butyrate, a short-chain fatty acid produced by bacteria in your gut) is really similar to the ketone hydroxybutyrate, produced by your liver during the conversion of fat into energy.

The primary difference between the two is that hydroxybutyrate isn’t as absorbable. Most of it is used locally by colonocytes (epithelial cells of your colon). In other words, hydroxybutyrate is used for fuel in your gut, while butyrate benefits your liver.

The Mechanistic Target of Rapamycin — A Driver of Ill Health

The mammalian target of rapamycin (mTOR), also known as the mechanistic target of rapamycin, is an incredibly important pathway, as it controls autophagy — your body’s natural clean-up process in which old, damaged cells are eliminated and replaced with new, healthy ones. As such, it also plays an important role in aging and cancer.

In short, to slow aging and reduce your risk of cancer, you want to inhibit mTOR, as this triggers autophagy. When mTOR is activated, autophagy is deactivated, which prevents the recycling of proteins. Alas, chronic suppression of mTOR is not ideal either. Bikman explains:

“What’s important with regards to mTOR … is that because it inhibits autophagy, it is thought to allow proteins and just organelles, parts of the cells, to get old due to things like oxidative damage. As those proteins get damaged, they get old, and then the cell, by extension, gets old.

As the cells get old, so too is the organ, and then the whole body … But … the body has been designed with far too clever a scheme to have something that shouldn’t be there; mTOR is so fundamental to life that you can’t just go in and just slam the breaks on it, because that is death. We have to grow. We have to allow a cell to grow, and tissue to grow.

This idea [is to] optimize or strategically focus on boosting mTOR and letting it come back down to keep the body young, to keep the cells cleaning themselves out through autophagy … Then you inhibit that and allow the body to grow with this cyclical spike of mTOR.

A lot of the focus … among vegetarians … is this idea that you’ve got to avoid animal protein because it spikes mTOR. That’s the wrong way of looking at it … What spikes mTOR the most and the longest? Insulin spikes mTOR far more than amino acids do.”

Insulin Activates mTOR to a Far Greater Degree Than Protein

In other words, sugar/carbohydrates are the No. 1 enemy when it comes to activating mTOR and driving the aging and disease processes. According to Bikman, a direct comparison in tissue shows insulin spikes mTOR three to four times higher than leucine, the amino acid that has the greatest impact on mTOR, raising it the most.

Importantly, while amino acids such as leucine, or protein in general, will spike mTOR for 45 to 90 minutes, after which mTOR dials back down if you eat lots of starchy, sugary foods, you have chronically elevated insulin and hence chronically activated mTOR, and that’s what’s causing problems.

“If you look at the global breakfast trends, it’s going to be something starchy and sugary. Insulin will come up, depending on the person, [and stay elevated for] two to even four hours; mTOR is active that whole time. Then, right as the insulin is coming down, they have a mid-morning snack.

Of course, it’s another starch and it’s another sugar. Insulin comes up again and it’s up for hours. Of course, as insulin is up, so too is mTOR. That, I submit, is far more pathological — this chronic, every-waking-moment mTOR activation because of insulin, rather than these intermittent spikes of mTOR because of the ingestion of protein.”

The Benefits of Intermittent Fasting

Aside from a ketogenic diet, intermittent fasting — where you do not eat for 16 to 18 hours a day; 12 hours being the absolute minimum — is another effective way to regain your insulin sensitivity and control mTOR.

Basically, while you’re fasting, your insulin will dramatically drop, allowing your body to enter into autophagy and clean itself out. Then, when you refeed, your body deactivates autophagy and starts to rebuild itself.

Dr. Jason Fung, a nephrologist, recently published a case series paper⁴ on three diabetic patients — all of whom were on high doses of insulin — detailing how intermittent fasting can be used as a therapeutic alternative for Type 2 diabetes.

Of the three patients, two did alternating-day 24-hour fasts, while one fasted for 24 hours three times a week over a period of several months. On nonfasting days, they were allowed both lunch and dinner, but all meals were low in sugar and refined carbohydrates throughout. (The complete manual of the fasting regimen used is described in Fung’s book, “The Complete Guide to Fasting.”⁵)

Two of the patients were able to discontinue all of their diabetes medications while the third was able to discontinue three of his four drugs. All three also lost between 10 and 18 percent of their body weight. Incredibly, all were able to discontinue their insulin in just five to 18 days. Bikman comments:

“From the context of controlling insulin, there are studies on insulin-resistant people where they are on isocaloric diets, so the same amount of calories, but one is eating them frequently in smaller amounts and one is packing them in a smaller window …

Those on the time-restricted eating schedule … had greater drops in glucose and insulin. That, to me, is the beginning and end. As a guy who sees the relevance of insulin in any chronic disease … I just simply ask, what controls insulin?

Simply give your body a break from eating. Twelve hours should be what everyone does every night of the week, even if they’re eating three full meals. At least get that 12-hour break, for heaven’s sake.

As a professor, I see kids who live on cold cereal. They’re eating three bowls of cereal at midnight. [Then] they have the same three bowls of cereal at 7 or 8 a.m. I hear them, of course. They’re smug, ‘I can eat whatever I want.’ I say, ‘Let’s see how you’re doing in 10 years.’”

The reason you want to avoid eating for 16 to 18 hours is because you cannot effectively deplete the glycogen stores in your liver otherwise. As noted by Bikman, your liver will hold, on average, 100 grams of glycogen, and it takes anywhere between 24 and 48 hours to burn that up.

What this means is that if you’re eating a high-carb diet and want to get into ketosis, you’ll need to totally restrict carbohydrates or fast for at least 24 hours. Once you start running out of glycogen, your ketones will start to rise to take its place as a fuel for your body. Around 48 hours, you’re solidly in ketosis as the glycogen in your liver has been cleared.

On a side note, fasting will also release fat-bound toxins and facilitate detoxification. As noted by Bikman, “as insulin comes down, your urine production starts to increase,” as your kidneys start to flush out toxins.

Industrial Seed Oils — Another Culprit That Drives Disease

The devil’s in the details, of course, and the main problems are caused not only by refined carbohydrates in the Western processed food diet but also by processed seed oils, which Bikman describe as “surprisingly pathogenic.”

“We’ve just started a project in my lab. I’ve got a really sharp undergraduate who’s focusing on the main oxidized product of seed oils,” he says. “When you look at that main omega-6 and how it gets oxidized through this molecule called 4-hydroxynonenal (4-HNE), we’re looking at how it accumulates in muscle cells.

It is forcing these changes in the way the mitochondria are physically put together. Mitochondria love to be very dynamic. They’re long and stringy. They’ll separate often to small pieces then come back together. Not all have a very relevant physiological purpose with regards to cell growth and division.

Yet, in the case of 4-HNE accumulation, that process gets stopped. Now you’ve forced this sustained static state of the mitochondria, which is not healthy for them or the cell. I can’t say anything more about it yet just because we don’t have all the data yet, but it’s coming.”

Ketones — A Surrogate Marker for Insulin

While measuring insulin is really valuable, you need a doctor’s order to test it. Fortunately, there’s a good surrogate marker for insulin, namely your ketone level, because you cannot have high insulin if you have high ketones. In other words, ketones are an inverse indicator of what your insulin is. (One of the best ketone devices I know of is Keto-Mojo, as the strips are only $1 each.)

“That was my initial interest in ketones, because it provided that immediate marker of what insulin is, even in a way that glucose cannot. You can have normal glucose levels and have insulin be elevated. If you’re insulin-resistant, you just need more insulin to keep your glucose normal, so you can’t rely on glucose.

In a way, ketones then become more sensitive as a marker, a surrogate for insulin, than even glucose is. Over time, if someone’s had their insulin levels in control for a sufficient period, their liver is basically burning fat at such a high rate that it’s burning more fat than it needs, and so the body has this very kind of clever release or exhaust valve, which is the production of ketones,” Bikman says.

“We have to account for how energy is consumed, how it is used in the form of creating ATP or just body heat — even that’s relevant in ketosis — but then third, for lack of a better word, this energy wasting, because ketones provide this kind of exhaust valve where the body is burning fat so high that it has more than it needs, and it just starts moving it out of the body, in the breath and in the urine.

That needs to be considered, or at least acknowledged … Once again, insulin dictates what the body does with the energy that it has, including producing ketones and having them basically be wasted from the body.”

When and What to Eat When Exercising

Clearly, your diet is far more important than exercise when it comes to controlling your insulin and overall health. That said, I don’t think you can achieve optimal health unless you integrate exercise. The practical question is, “What and when should you eat when you exercise?” My conclusion is that protein is a necessary component of a post-workout meal, and that it’s best to exercise in a fasted state. Bikman agrees, saying:

“With regards to protein, it is without a doubt relevant to someone doing endurance or resistance exercise. You need to make sure you get enough protein. But it appears to be no magic window with that. Basically, you don’t have to get it 45 minutes or an hour after your workout. Essentially, within a 24-hour window, if you’ve eaten sufficient protein, then you’re okay.

Now, with regards to carbohydrate, there was a very neat study done with college students, where they had them exercise and then their next meal was a carbohydrate-rich meal in one group. In the other group, they fasted through that next meal … The group that ate the high-carb diet … did not have an improvement in insulin sensitivity.

By ending their exercise and then having the next meal be a high-carb meal, that undid the improvements in insulin sensitivity from the exercise itself. That has ramifications because so often someone gets done exercising and they reward themselves with something like juice at some smoothie joint, or they indulge themselves.

They treat themselves with some carbohydrates thinking, ‘I spent it, so I need to eat it.’ What a shame. They are directly preventing some of the insulin-sensitizing benefits of the exercise, because of what they ate …

Like you, I prefer to exercise fasted … I don’t like having something in my gut when I’m trying to push my blood to my muscles … That blood has to come from the gut.

You basically are creating this little war, this hemodynamic war where during exercise and yet having eaten something, your body is thinking, ‘Wait a minute. I need to be sending blood into my guts to help move this food through the intestines and digest it. But now, my muscles are active, so I’ve got to push the blood to my muscles.’

You’re creating this split, forcing the body to prioritize where the blood wants to go. But if you leave the food in the gut, that’s going to start to develop some gastrointestinal discomfort.”

The Importance of Leucine Post-Exercise

One of the most important protein sources, when you’re exercising, is the amino acid leucine. Interestingly, and paradoxically, leucine actually activates autophagy, even though it also activates mTOR, which logically says would result in autophagy being inhibited. This paradox likely has to do with the fact that leucine is ketogenic, meaning it can turn into a ketone, and ketones activate autophagy.

Leucine is so effective for muscle building, research cited by Bikman shows just 5 grams of leucine is enough to maximize muscle protein synthesis in people on an otherwise protein-deficient diet. When it comes to leucine supplements, hydroxymethylbutyrate (HBM) is a breakdown product of leucine that you can take. However, it’s more expensive, and according to Bikman’s reading of the literature, it has no added benefits over leucine itself.

“Just leave it on the store shelf. Don’t spend that higher amount. It is more money than leucine. Just stick with the leucine,” he says. “Leucine is one of the so-called ketogenic amino acids. It can, in fact, take that carbon skeleton of the leucine and turn it into a ketone.

Some amino acids are referred to as glycolytic, where they can come in and basically turn into alanine. They can readily turn into glucose as needed. Leucine is one of the ketogenic ones, [which] can turn into ketones, beta-hydroxybutyrate in particular. I’d say that if there’s any benefit to HMB, you’re going to get that anyway, because the leucine is going to become HMB.”

Collagen Does Not Count as a Protein Source

As a general rule, to optimize mTOR, you’ll want to restrict your protein intake to about 0.5 grams of protein per pound of lean body mass (not total body weight), or 1 gram of protein per kilo of lean mass. The elderly may need up to 25 percent more.

When calculating your protein intake, keep in mind you do not need to include collagen in your calculations, as it does not have the full complement of amino acids to be considered a complete protein. Collagen — provided it’s a high-quality, organic grass fed source — is important for the health of your connective tissue, and will help prevent injuries. So, while you don’t want to have excess protein, you almost get a free pass with collagen.

“Collagen [contains] a different bunch of amino acids,” Bikman explains. “One in particular is hydroxyproline, one of the main building blocks for collagen in the body. I’ve had people kind of challenge that idea and say, ‘Well, but when you eat these proteins, even in the form of collagen, it will degrade into the amino acids. The body will just kind of choose whatever amino acids it wants to put back together to make whatever proteins it wants.’

That’s generally true. There is a very neat rat study. We just have to assume the same thing holds in humans. I think it’s a safe assumption here. They had the rats eat a radio-labelled hydroxyproline, so they could basically follow that hydroxyproline around.

Sure enough, it went to the skin and to the connective tissue. They could detect where it was enriched. It was all this connective tissue-rich or collagen-rich tissue in the body. I am an advocate of collagen. The evidence supports it. It’s especially relevant to someone who adheres to a low-carb diet. Vitamin C is called C for collagen.

What’s important is that if you’re eating less vitamin C, it’s comforting to know that you’re fulfilling that need essentially by getting not only the collagen itself from the meat that you’re eating, that connective tissue and that hydroxyproline and the other amino acids relevant to collagen, but also carnitine, which is relevant to the function and production of collagen within the body.

Even a low-carb person, who’s avoiding vitamin C, can rest assured their joints and connective tissues are going to be OK, because they’re actually directly eating what they need rather than having the body make what they need with the help of vitamin C.”

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