True Metabolic Flexibility: Beyond Permanent Ketosis

# True Metabolic Flexibility: Staying in Ketosis All Day Is Not Flexibility

**by Laurent Glatz – for Athletic Carnivore**

“Metabolic flexibility” has become one of the favorite buzzwords on YouTube, keto circles, and carnivore communities.

The usual narrative is simple: you’ve spent your life burning glucose, you cut out carbs, your body learns to burn fats and ketones, and voilà—you’re finally “metabolically flexible.”

But biologically, this definition misses the point.

Switching from a metabolism primarily fueled by glucose to one mainly fueled by lipids and ketones does not necessarily mean becoming flexible.

**It first means you have changed your dominant fuel source.**

True metabolic flexibility is the body's ability to adjust substrate utilization depending on the situation: fed state, fasting, sleep, exercise, rest, glycogen availability, insulin levels, exercise intensity, and energy demands.

This is exactly how Goodpaster and Sparks define the concept in their landmark review published in *Cell Metabolism*: the capacity to respond and adapt to changes in metabolic demand and fuel availability.

In other words, being flexible is not about choosing a permanent side.

**Being flexible means knowing how to switch.**

Your Body Doesn’t Work with an On-Off Switch

Human metabolism doesn’t have a button labeled “glucose” on one side and “ketones” on the other.

We simultaneously use multiple substrates, but their proportions continuously shift.

After a meal, nutrient availability rises. Insulin increases to varying degrees, lipolysis is suppressed, and glucose utilization rises.

A few hours later, as insulin falls and the post-absorptive state sets in, fatty acid contribution gradually increases.

If the energy-free period extends long enough, liver glycogen decreases further, fat mobilization increases, and the liver produces more ketone bodies.

Anton, Mattson, and colleagues precisely described this transition as the **metabolic switch**: the gradual shift from a glucose-dependent state toward increased fat and ketone mobilization during prolonged fasting, typically beyond about twelve hours depending on initial reserves and energy expenditure.

Then you eat again.

And the metabolic signal changes once more.

That’s exactly what matters.

Flexibility Is an Oscillation, Not a Destination

This is probably the fundamental error in some keto discourse.

They present the transition to fat burning as an arrival:

“Before, you ran on sugar. Now, you run on fat.”

No.

A truly flexible organism should not aim to remain fixed at either extreme.

It must be able to increase fat utilization when fats become the relevant fuel, then rapidly increase glucose utilization when it becomes available or when energy demand justifies it.

Metabolic flexibility is therefore not:

**“I used to burn carbs, now I burn ketones.”**

It is:

**“My body shifts its metabolism according to the situation.”**

And that difference is huge.

Even “Ketosis” Is Not a Binary State

The well-known threshold of 0.5 mmol/L beta-hydroxybutyrate used to define “nutritional ketosis” is convenient for research and monitoring.

But biologically, there is no wall at 0.5 mmol/L.

A person can go from 0.1 to 0.4 mmol/L and have already significantly increased fat utilization.

Conversely, measurable ketones can persist after a meal while substrate partitioning has profoundly shifted.

Metabolism doesn’t abruptly switch from “glucose ON” to “ketones ON.”

It oscillates.

That’s why the relevant question isn’t checking every two hours whether your ketone meter still shows the desired number.

**The question is whether the body retains the ability to make these transitions.**

Mattson Asks Exactly This Question

In 2025, Mark Mattson dedicated an entire perspective in *Nature Metabolism* to **cyclic metabolic switching**.

His hypothesis is particularly interesting: some benefits of intermittent fasting may precisely come from alternating between a ketogenic state during fasting and a non-ketogenic state during refeeding.

During fasting, lipid mobilization, ketones, adaptive stress responses, mitochondrial changes, and autophagy-related mechanisms are stimulated.

With nutrient return, the context changes: activation of growth and plasticity pathways including mTOR, protein synthesis, and rebuilding.

Mattson explicitly highlights the difference with continuous ketogenic diets: these do not necessarily produce this alternation between ketogenic and non-ketogenic states.

This is not yet proof that permanent ketosis causes disease.

But it destroys a simplistic idea:

**staying in ketosis is not the same as knowing how to enter and exit ketosis efficiently.**

We Already Know the Problem at the Other Extreme

Metabolic inflexibility is extensively studied in obesity, insulin resistance, and type 2 diabetes.

In a metabolically healthy person, food intake normally triggers a significant shift in fuel utilization.

In some insulin-resistant states, this response becomes much less dynamic: the body adapts less efficiently its lipid and carbohydrate oxidation to the context.

This is precisely one of the core phenomena behind the scientific concept of metabolic flexibility.

This does not mean “burning glucose causes diabetes.”

The problem is far more complex: chronic energy excess, ectopic fat storage, hyperinsulinemia in some individuals, insulin resistance, physical activity, muscle mass, genetics, sleep, and other factors all play roles.

But the result relevant here is clear:

**a body unable to properly switch energy strategies becomes metabolically less flexible.**

What if we applied exactly the same logic in the other direction?

What If You Stayed in Ketosis for 20, 30, or 50 Years?

This is the question almost never asked.

We have decades of research on the consequences of chronic glucose metabolism disturbances.

But what happens in a healthy person deliberately maintaining nutritional ketosis almost permanently for 20, 30, or 50 years?

The current scientific answer is far less spectacular than some influencers claim:

**we don’t know.**

We lack controlled human trials following healthy adults in permanent nutritional ketosis for 30 or 50 years.

Claiming this situation is necessarily dangerous would be scientifically dishonest.

But claiming it is proven optimal for a lifetime is equally so.

And some data are beginning to raise particularly interesting questions.

Metabolism Specializes in What It Is Asked to Do

Take healthy people and abruptly reduce their carbohydrate availability.

In just six days with 75% of energy from fats, researchers observed decreased carbohydrate oxidation and about a twofold increase in muscle expression of PDK4.

PDK4 inhibits pyruvate dehydrogenase complex activity, a key step allowing pyruvate from glucose to enter mitochondrial oxidative pathways.

In other words, muscle rapidly adapts to low glucose availability by reducing its propensity to oxidize it.

Researchers noted this adaptation did not correspond to pathological global insulin resistance: non-oxidized glucose could be redirected more toward glycogen storage.

This is a crucial distinction.

**It is not necessarily disease. It is specialization.**

But specialization is still not the same as flexibility.

Older studies had already shown that after only six days of extremely low-carb feeding, muscle pyruvate dehydrogenase kinase activity increased three to fivefold while active PDH activity dropped sharply.

The body does exactly what is expected.

It adapts.

The question then becomes: **what happens when this adaptive pressure is maintained for years or decades?**

We don’t know yet.

When Glucose Is Reintroduced, the Difference Becomes Visible

In nine young healthy men, only three days of low-carb, high-fat feeding was enough to cause higher blood glucose during an oral glucose tolerance test.

Again, this does not mean a low-carb diet causes diabetes in three days.

It means the body adapted to the previous context.

More interestingly, trained cyclists habituated for over six months to a low-carb/high-fat diet showed lower glucose tolerance than comparable cyclists on mixed diets. Their muscles also contained less GLUT4 and IRS1, key components of muscle glucose and insulin response.

The authors themselves emphasize this may represent a physiological adaptation to chronically low carbohydrate availability rather than pathological insulin resistance.

But precisely.

This observation forces the question keto marketing avoids:

**If your metabolism performs worse when suddenly presented with a fuel it barely uses, should we really call that superior flexibility?**

Probably not.

It looks more like excellent specialized adaptation to the dominant fuel.

And What About Really Long-Term Data?

The longest human data mainly come from therapeutic ketogenic diets used for certain epilepsies.

At Johns Hopkins, 28 patients on ketogenic diets for 6 to 12 years were retrospectively studied.

Therapeutic benefit on seizures was significant for many.

But seven developed kidney stones, six had fractures, and the number of children below the 10th percentile for height increased markedly during follow-up.

This study obviously does not prove that a healthy adult following a carnivore diet develops the same issues.

These are children with epilepsy, often medically treated, using specific therapeutic diets.

But it teaches us something essential:

**Therapeutic ketosis maintained for years produces adaptations and effects that must be monitored. It is not physiologically invisible.**

A meta-analysis pooling 36 studies and 2,795 people on ketogenic diets estimated the overall incidence of kidney stones at about 5.9% over an average 3.7-year follow-up. In adults analyzed separately, the estimate was 7.9%, with a wide uncertainty margin.

This does not make kidney stones an inevitable keto consequence.

But it makes it difficult to claim that voluntarily maintaining ketosis for several decades is a metabolically harmless intervention with already proven safety.

It is not.

The Thyroid Also Shows the Signal Is Systemic

In a randomized crossover trial with eleven young healthy adults, three weeks of nutritional ketosis significantly reduced T3 concentration and increased T4, without significant changes in TSH or resting metabolism.

Is this change bad?

We cannot say.

It may be a perfectly physiological energy adaptation.

But do we know what maintaining this adaptation for thirty years means?

No.

And that is precisely the difference between hypothesis and certainty.

Same with Blood Lipids

Keto can improve several markers.

Triglycerides often decrease and HDL often rises.

But responses don’t all move in the same direction.

A recent meta-analysis of randomized adult trials found improved triglycerides and HDL alongside an average LDL cholesterol increase. The authors explicitly highlight the lack of very long-term cardiovascular data to understand all consequences.

In young healthy normal-weight women, four weeks of a controlled ketogenic diet with 77% fat increased LDL and ApoB in all participants.

We cannot turn these results into a simplistic statement like:

“keto = cardiovascular disease.”

That would be scientifically false.

But we also cannot claim:

“I’m in ketosis, so all my markers automatically become irrelevant.”

That would be the exact same intellectual error.

Athletes May Provide the Most Striking Example

Keto works.

It works extremely well for what it is specifically asked to do: **massively increase fat oxidation capacity.**

In endurance athletes, a few weeks of keto adaptation can nearly double certain fat oxidation rates.

But the price of this specialization appears when demand changes.

In elite walkers, keto adaptation greatly increased fat oxidation but decreased exercise economy: more oxygen was needed to maintain the same speed. Groups with high or periodized carbohydrate availability improved performance, whereas this improvement was not similarly found in the keto group.

A physiological review summarizes the phenomenon well: keto adaptation powerfully increases fat use but comes with a reciprocal reduction in carbohydrate use and may limit effective glycogen use at high intensities.

Here again, the same story.

**Remarkable adaptation.**

But not necessarily maximal flexibility.

Keto-Carnivore Confuses Two Concepts

Eating carnivore absolutely does not require artificially staying in deep ketosis all day.

Meat provides protein and amino acids.

A meal triggers hormonal responses.

mTOR responds to nutrients.

Insulin does not vanish just because you eat almost no carbs.

Then, as you move away from the meal, the hormonal environment changes again.

A properly constructed carnivore approach can perfectly fit this physiological alternation.

What becomes much more questionable is the **keto-carnivore designed around permanent ketone maintenance**, where butter, fat, MCT oil, or sometimes exogenous ketones are added with an obsession never to see BHB drop.

This is no longer about flexibility.

**It’s about maintaining a state.**

Calling this “metabolic flexibility” is a misunderstanding.

Low Carb Is Not Keto

This is also why we must stop confusing low carb and ketogenic.

A low-carb diet can perfectly allow significant metabolic variations throughout the day.

It can enable high fat use between meals, increased ketones during some periods, then ketone decreases in the presence of nutrients and according to energy needs.

Being low carb does not mean:

**“I must show 1.5 mmol/L ketones twenty-four hours a day.”**

It can mean exactly the opposite:

**“I don’t continuously overload my body with glucose, but I keep its ability to use multiple substrates when relevant.”**

This is a fundamental difference.

The Ketogenic Diet Has Its Indications. That’s Not the Question.

The ketogenic diet can be extremely relevant in certain therapeutic situations, notably refractory epilepsies.

It can also facilitate weight loss in some people, lower triglycerides, improve some glycemic parameters, and serve as an interesting temporary metabolic tool.

So the question is not:

“Does keto work?”

Of course, it causes measurable physiological adaptations.

The real question is:

**“Why would a healthy person want to turn a metabolic adaptation into a permanent state for life?”**

These are two totally different propositions.

True Metabolic Flexibility Has No Side

The problem of a modern person constantly fed, snacking from morning to night, unable to properly mobilize reserves and dependent on repeated energy intake is not intellectually solved by proposing the exact opposite:

staying voluntarily in the same ketogenic state every hour of every day.

You’ve just moved the cursor.

A flexible organism must manage the fed state.

Then the post-absorptive state.

Mobilize fats.

Increase ketones when the context justifies it.

Use glucose when it becomes available or necessary.

Replenish reserves.

Respond to glycolytic effort.

Then return to fat oxidation when demand changes.

That is flexibility.

It’s not a war of glucose versus fat.

It’s not a war of insulin versus ketones.

It’s not about chasing the highest BHB.

**It’s about maintaining a broad operating range.**

And maybe that’s where simplistic internet narratives make their biggest mistake.

They turn an extraordinarily adaptable organism into a single-fuel system.

Then they call this specialization “flexibility.”

At Athletic Carnivore, the question we ask is exactly the opposite:

**Is your body still capable of efficiently switching from one metabolic state to another?**

Because two people can eat exactly the same carnivore diet, have exactly the same ketone levels, yet respond completely differently to glucose, exercise, fasting, and refeeding.

The number on the ketone meter does not answer this question.

You have to look at the whole picture.

And at this stage, the question is no longer:

**“Am I in ketosis long enough?”**

It becomes:

**“If my body is truly flexible, why would I want to prevent it from leaving a metabolic state for the next fifty years?”**

**Understanding My Metabolic Terrain**

Main Scientific References

Goodpaster BH, Sparks LM. *Metabolic Flexibility in Health and Disease*. Cell Metabolism. 2017;25:1027–1036.

Anton SD et al. *Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting*. Obesity. 2018;26:254–268.

Mattson MP. *The cyclic metabolic switching theory of intermittent fasting*. Nature Metabolism. 2025;7:665–678.

Chokkalingam K et al. *High-fat/low-carbohydrate diet reduces insulin-stimulated carbohydrate oxidation but stimulates nonoxidative glucose disposal in humans: an important role for skeletal muscle pyruvate dehydrogenase kinase 4*. Journal of Clinical Endocrinology & Metabolism. 2007.

Webster CC et al. *Reduced Glucose Tolerance and Skeletal Muscle GLUT4 and IRS1 Content in Cyclists Habituated to a Long-Term Low-Carbohydrate, High-Fat Diet*. International Journal of Sport Nutrition and Exercise Metabolism. 2020.

Groesbeck DK, Bluml RM, Kossoff EH. *Long-term use of the ketogenic diet in the treatment of epilepsy*. Developmental Medicine & Child Neurology. 2006.

Acharya P et al. *Incidence and Characteristics of Kidney Stones in Patients on Ketogenic Diet: A Systematic Review and Meta-Analysis*. 2021.

Iacovides S et al. *Could the ketogenic diet induce a shift in thyroid function and support a metabolic advantage in healthy participants?* PLoS ONE. 2022.

Burke LM et al. *Crisis of confidence averted: Impairment of exercise economy and performance in elite race walkers by ketogenic low carbohydrate, high fat diet is reproducible*. PLoS ONE. 2020.

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