February 7, 2022

Nutritional Biochemistry

#194 – How fructose drives metabolic disease | Rick Johnson, M.D.

Fructose turns out to have been meant to be this wonderful system for survival, but in our culture with the amount of sugar in foods that we are eating (that either provide sugar or can be turned into fructose), this pathway has become hazardous.” —Rick Johnson

Read Time 54 minutes

Rick Johnson, Professor of Nephrology at the University of Colorado and a previous guest on The Drive, returns for a follow-up about unique features of fructose metabolism, and how this system that aided the survival of human ancestors has become potentially hazardous based on our culture’s dietary norms. In this episode, Rick explains how the body can generate fructose from glucose and how circulating glucose and salt levels can activate this conversion. He discusses the decline in metabolic flexibility associated with aging, as well as how factors such as sugar intake or menopause-associated hormone changes can alter responses to sugar across a lifetime. In addition, Rick lays out strategies for combating the development of metabolic illness using dietary changes and pharmaceutical therapies, and he discusses the impact of fructose metabolism and uric acid on kidney function and blood pressure. He concludes with a discussion of vasopressin, a hormone that facilitates fructose’s effects on weight gain and insulin resistance.


We discuss:

  • Unique features of fructose metabolism and why it matters [2:45];
  • A primer on fructose metabolism and uric acid [10:30];
  • Endogenous fructose production, the polyol pathway, and the effect of non-fructose sugars [22:00];
  • Findings from animal studies of glucose and fructose consumption [29:00]; 
  • What calorie-controlled studies say about the claim that a “calorie is a calorie” [42:15];
  • Implications for aging and disease [51:15];
  • Impact of endogenous fructose production on obesity and metabolic syndrome [1:01:30];
  • Why vulnerability to the negative effects of sugar increases with age and menopause [1:04:30];
  • Dietary strategies to reduce the negative impact of fructose [1:16:30];
  • The role of hypertension in chronic disease and tips for lowering blood pressure [1:30:45];
  • The impact of fructose and uric acid on kidney function and blood pressure [1:39:45];
  • The potential role of sodium in hypertension, obesity, and metabolic syndrome [1:49:00];
  • The role of vasopressin in metabolic disease [1:54:00];
  • More.


Unique features of fructose metabolism and why it matters [2:45]

  • We had a lot of follow up questions from our first podcast, which aired 2 years ago
  • The #1 question people ask is, “Hey, can you explain again, why is it that fructose metabolism is kind of unique from a nutrient standpoint in terms of creating this transient intracellular energy deficit.”
  • All nutrients, any kind of food is used to produce energy or ATP but there is a cost to producing energy
    • Some energy is used  to digest foods and some energy is used to metabolize foods
    • The idea follows the old adage, “you have to spend money to make money”; here we are thinking about ATP
  • Metabolism of fructose and alcohol can cause rapid ATP depletion
  • In terms of nutrient metabolism, fructose is pretty unique
  • The very first enzyme in fructose metabolism is called fructokinase (see the figure below)
    • Fructokinase is also known as ketohexokinase or KHK
    • This is a key enzyme in fructose metabolism
    • It phosphorylates fructose at the 1 position to generate fructose-1-phosphate
    • This enzymes in not controlled by negative feedback so it will phosphorylate fructose as soon as it sees it
      • It is not responsive to ATP levels; so if ATP levels start to drop, fructose metabolism continues
    • This first step in fructose metabolism requires ATP expenditure, so consuming large amounts of fructose causes severe ATP depletion
    • Similarly, if the fructose concentration is very low, there won’t be as much ATP depletion
    • So the degree of ATP depletion varies with the concentration of fructose

Figure 1. The first step of fructose metabolism leads to loss of ATP. Image Credit: Nature Reviews Nephrology 

  • As ADP is produced by fructokinase, it will be used to make ATP and AMP (shown in the figure below)
  • Under high energy conditions the cell has a ratio of ATP : ADP of 10:1 and a ratio of ATP : AMP of 100:1

Figure 2. As ADP  levels rise, ATP and AMP are produced.  Image Credit: Keeping the home fires burning: AMP-activated protein kinase

Why high fructose corn syrup is particularly bad

  • Fructose concentration relates to not just the amount of fructose, but how rapidly it’s absorbed
    • Liquid fructose (like a soft drink) consumed on an empty stomach, can get absorbed very quickly and even more quickly when it is high fructose corn syrup
    • There’s some debate on this, but in high fructose corn syrup, the fructose and glucose are already separated so that it may be absorbed differently than sucrose where it’s glucose and fructose bound together, but they are broken and they have to be degraded to the individual fructose and glucose in the gut before they’re absorbed
    • The figure below shows the relationship between structure of glucose, fructose, and sucrose

Figure 3. Sucrose is 1 glucose bound to 1 fructose.  Image credit: Wikimedia Commons

  • Drinking liquid fructose leads to very fast absorption; the concentration will be higher when it reaches the liver
  • The liver is one of the key sites of fructose metabolism that drives this whole process
  • When fructose gets to the liver, fructokinase phosphorylates it, and the ATP levels acutely fall

Cellular response to low ATP levels

  • The low ATP state is maintained primarily by a drop in intracellular phosphate that accompanies this and that activates this enzyme system that removes the breakdown of ATP products
    • These 2 reactions occur together (shown in the Figure 1)
      • ATP + H2O → ADP + Pi 
      • Fructose → Fructose-1-Phosphate
    • With ADP and Pi removed, ATP cannot be regenerated easily (see Figure 2)
    • Normally AMP and ADP get reformed to make more ATP
      • 2 ADP → ATP + AMP
      • They’re really important to make the ATP
    • The ATP levels fall
    • There’s the accumulation of ADP and AMP (adenosine monophosphate, AMP,  is one of the key ones) and then AMP is swept away
    • If the AMP is removed, then it’s hard to replenish the ATP because you’ve removed a key building block for ATP
      • AMP is removed by an enzyme called AMP deaminase, which turns out to be a very, very important enzyme in this pathway
  • AMP deaminase breaks down the AMP stepwise until it produces uric acid, which is the end product of purine metabolism
  • The adenine of ATP is a purine, and it eventually gets broken down to uric acid
  •  Uric acid inside the cell actually causes oxidative stress to the mitochondria
    • The mitochondria are also really important in ATP production
  • The oxidative stress affects the mitochondria in several ways
  • In all, fructose metabolism stimulates fat storage
  • Uric acid also inhibits AMP kinase (AMPK, AMP-activated protein kinase); this blocks energy production

It’s a brilliant system to set the energy levels down in a cell, and it mimics the condition of starvation.” – Rick Johnson

  • Reducing the energy in the cell triggers an alarm signal; it’s a survival pathway
    • This leads to a survival response, makes the animal get hungry, thirsty, forage for food, try to store fat, try to store glycogen

{end of show notes preview}

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Rick Johnson, M.D.

Richard Johnson is a professor of medicine in the Department of Nephrology at the University of Colorado since 2008 and he’s spent the last 19 years being a division chief across three very prestigious medical schools. An unbelievably prolific author, Rick has well over 700 publications in JAMA, New England Journal of Medicine, Science, et Cetera. He’s lectured across 40 countries, authored two books, including The Fat Switch, and has been funded extensively by the National Institute of Health (NIH). His primary focus in research has been on the mechanisms causing kidney disease, but it was in doing this that he became really interested in the connection between fructose (and fructose metabolism) and obesity, diabetes, heart disease, hypertension, and metabolic disease.

Disclaimer: This blog is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice, and no doctor/patient relationship is formed. The use of information on this blog or materials linked from this blog is at the user's own risk. The content of this blog is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard, or delay in obtaining, medical advice for any medical condition they may have, and should seek the assistance of their health care professionals for any such conditions.


  1. What about long-term fruitarians? They hardly age, it’s incredible, and they seem to be thriving, whilst eating ridiculous amounts of fruit everyday!

    • Yes! I was going to ask this too. I switched sweets with whole fruit and feel the difference. But even apples have high sugar. From what I’ve read, because whole fruits are filled with fiber, water, minerals and vitamins, it may slow down absorption and just pass through.

  2. I also would’ve like to see some commentary about how this pertains to non-concentrated sources of fructose. To me, anecdotally, it’s pretty clear that people who eat more fruit aren’t less healthy.

    So is fructose itself the concern? Or is it very clearly only concentrated and separated sources like HFCS?

  3. I’m curious about potassium’s role in endogenous fructose production. Would high potassium intake reduce endogenous fructose production, and would there still be a need to reduce exogenous sodium intake? Also, regarding uric acid, there is a study that concluded that “Dairy consumption was inversely associated with the serum uric acid level.” It made me wonder if excessive amounts of lactose could also turn on endogenous fructose production, like glucose. And what quantity would be that excessive amount.

  4. It is extremely concerning that Pfizer would suddenly stop the clinical trials on a drug that could have such a huge impact on society. But I think we all know why they would not want to move forward.

    Look how many Pfizer drugs are used to treat the symptoms of metabolic disease. Hypertension diabetes and everything in between.

  5. Great detailed interview, and thanks Peter for asking the right questions to clarify the confusing scientific concepts. From an evolutionary perspective this “seasonal adaptation” to get fat before winter makes perfect sense. Is fructose acting alone? Is the chow provided tested for glyphosate? Is there a source of high fructose corn syrup that isn’t adulterated by glyphosate? If you are not looking for, or measuring a chemical in food, are you sure its not affecting your science? Have you examined the studies on glyphosate and the kidney? Is fruit today the same as it was 15,000 years ago? Enzymes are made of amino acids, and glyphosate is an analogue of glycine, the smallest amino acid, how could that affect enzyme function? Are there “organic, non GMO ” mice, or rat chows? Its time to look a bit deeper into this concept, someone has to.

  6. The conversation over salt helping to create fructose was a little concerning. Do I need to stop drinking my LMNT electrolytes if I’m not on keto?

  7. So what do we do about metabolic resistance and pre diabetes? Stop eating sugar all together? What’s the solution?

  8. A bit confusing about salt/sodium. When eating low carb diet the experts (ex Virta group) are saying to increase salt. How does this relate to what is discussed above about salt increasing fructose levels. Salt or no salt for low carb?

  9. Great episode! I love Richard Johnson as a guest! Nerding out on endurance exercise and metabolism is my favorite topic so Johnson and San Milan are 2 of my favorites.

    Thank you both

  10. How does the drop in ATP after fructose ingestion impact athletic performance (mainly endurance), if at all? With the recommended 2:1 glucose:fructose energy drinks/gels/bars, we can go up to 30g fructose/hour. If ingested in 2 batches, that’s 15g in one bolus. Would that be sufficient to trigger the drop in ATP levels? Is it then better to spread the fructose ingestion more?

    Or are exercising athletes not sensitive to this ATP decreasing pathway due to totally different enzyme activity?

  11. A couple of perhaps nerdy questions:

    You say:
    The reaction catalyzed by fructokinase: fructose + ATP → fructose-1-phosphate + ADP + Pi

    If the phosphate from ATP was used to produce fructose-1-phosphate, leaving ADP, where did Pi come from?

    Also, why is AMP degraded instead of being regenerated to ATP.

  12. Yes, I was raised believing eating plenty of fruit and vegetables were the best way to stay healthy.
    Until my digestive system went haywire two years ago and it was discovered I was allergic to FRUCTOSE, and could no longer digest all the fruits and vegetables that I’d been eating for decades.
    During testing, it was discovered I had a condition called SIBO, Celiac disease.
    I began having hypertension a few years ago after living with low blood pressure all my life and now on BP medication(very small dose that seems to exasperate sugar issues!)
    Have been tested multiple times for diabetes according several tests which came back negative.

    After listening to Richard Johnson speak, I’m thinking deeply about Metobolic Syndrome.

    How serious can Fructose be?
    For some, dangerous.
    Imagine a stressful day, like so many of us have, and a minimal morning meal. Plus a commute ahead of us.
    On this particular day, I was blessed to have a packed lunch of hard boiled eggs, brown rice, hummus, water and a low calorie root beer sweetened with “Monkfruit”.
    It seemed convenient to drink the root beer while driving. Then have lunch at the destination.
    Fifteen minutes into the drive became shaky and very dizzy and found the closest place to pull off road. Thankful for the water and an egg prepacked had to rest for thirty minutes to partially recover. Without food or water, not sure I would made it even to ER!

    Recently, l have given up sugar and processed food, including restaurants and Starbucks.

    Way too many health problems come from added sugars.
    To all of you, who think you cannot do it. You can☺

    By removing sugar from your lifestyle within 7 days you won’t desire it. You will feel better, sleep better and your energy will improve.
    Since removing sugar, artificial sweeteners and fructose including caffeine to reduce (BS highs + lows + sugar cravings). You may feel calmer.
    In time, you may also notice
    Lower blood pressure
    Headaches have disappeared
    Improved vision
    Improved energy and circulation
    Reduced joint pain
    Improved sleep
    This is what I have experienced for myself.

    Excited to learn more from Peter Attia and Richard Johnson and their research.

    Thank you

  13. Dr. Peter, Great interview with Rick Johnson. Love the evolutionary angle of metabolic syndrome. I was trying to get my head around how/if metformin might play a role in muting the effect of fructokinase on the human body. Would like to hear your views on this, maybe in your next AMA? Regards, Rob (Vancouver)

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