#87 - Rick Johnson, M.D.: Fructose—The common link in high blood pressure, insulin resistance, T2D, & obesity?
Dr. Rick Johnson, Professor of Nephrology, explains how fructose metabolism drives metabolic diseases like obesity, diabetes, and hypertension, highlighting the role of uric acid. He also discusses salt intake, artificial sweeteners, and potential therapies.
Deep Dive Analysis
17 Topic Outline
Rick Johnson's Journey to Fructose Research
Revisiting Salt and Blood Pressure Conventional Wisdom
Defining Glucose, Fructose, and Common Sugars
Evolutionary Mutation and Human Fructose Sensitivity
Uric Acid: Beyond Gout to Metabolic Health
Fructose Metabolism: ATP Depletion and Fat Storage
Why Drinking Sugar is Worse Than Eating It
Fructose's Role in Metabolic Syndrome and Diabetes
Fructose and Cancer Cell Metabolism
Fructokinase Inhibitors as Potential Therapies
Clinical Approach to High Uric Acid Levels
Salt Intake, Hydration, and Fructose Production
High Glycemic Carbs and Endogenous Fructose Production
Artificial Sweeteners vs. Real Sugar
Umami, Purines, and Metabolic Illness
Practical Advice on Fructose and Fruit Consumption
Managing Children's Sugar Intake
6 Key Concepts
Osmolality
Osmolality refers to the number of molecules in a set volume of fluid, such as blood. An increase in serum osmolality (or serum sodium) is what acutely triggers a rise in blood pressure, rather than just the total amount of salt consumed.
Uricase Mutation
This is an ancient genetic mutation in apes, inherited by humans, that led to a much stronger uric acid response to fructose. While it was a survival mechanism allowing for more efficient fat storage during scarcity, it makes humans uniquely sensitive to sugar's metabolic harms today.
ATP Depletion by Fructose
Unlike glucose metabolism, fructose metabolism by the enzyme fructokinase consumes ATP in an unregulated manner. This causes cellular energy (ATP) levels to plummet significantly, signaling the body to enter an energy preservation and fat storage mode.
AMP Deaminase (AMPD) Pathway
This metabolic pathway is triggered by the fall in intracellular phosphate and ATP depletion during fructose metabolism. It converts AMP (adenosine monophosphate) to uric acid and drives processes leading to fat storage, insulin resistance, and eventually diabetes, acting opposite to the fat-burning AMPK pathway.
Aldose Reductase
Aldose reductase is an enzyme that can convert glucose into fructose within the body. It can be induced by factors like high salt diets, dehydration, high uric acid levels, or high glucose intake, leading to the internal production of fructose even when dietary fructose is absent.
Pair Feeding
A research technique where animals are given the exact same amount of food (calories) to control for total energy intake. Studies using pair feeding demonstrate that even without weight gain, fructose can still cause fatty liver, insulin resistance, and metabolic syndrome, illustrating that not all calories have the same metabolic effect.
9 Questions Answered
It's not merely the amount of salt, but the salt concentration (serum osmolality) in the blood that acutely raises blood pressure. If salt is consumed with sufficient water to prevent a rise in serum sodium, the blood pressure increase can be blocked.
Humans inherited a uricase mutation from ancient apes, which leads to a much stronger uric acid response when fructose is metabolized. This evolutionary adaptation, originally beneficial for fat storage during scarcity, now makes humans more susceptible to sugar's negative metabolic impacts.
Glucose metabolism is regulated to prevent significant ATP depletion, but fructose metabolism by fructokinase is unregulated, causing a rapid and substantial drop in cellular ATP and phosphate. This drop acts as a 'May Day' signal, switching the body into an energy preservation and fat storage mode.
When sugar-containing liquids are consumed quickly, a high concentration of fructose rapidly reaches the liver, leading to a more pronounced ATP depletion and metabolic cascade compared to eating the same amount of fructose with fiber or other foods that slow absorption.
Yes, high glycemic diets (e.g., from starches like potatoes or rice) can lead to elevated glucose levels. This can induce the enzyme aldose reductase in the liver, which converts glucose into fructose endogenously, thereby driving fatty liver, insulin resistance, and obesity even without dietary fructose.
Artificial sweeteners are generally considered a lesser evil than real sugar, as they don't cause weight gain in the same way and primarily activate sweet taste buds rather than triggering metabolic pathways. However, their long-term safety is not fully understood, and water remains the best choice.
Purines are components of DNA and RNA. When broken down, they form uric acid. Consuming foods high in purines, such as certain meats (e.g., anchovies) or brewer's yeast in beer, can increase uric acid levels and potentially contribute to metabolic issues.
Avoid all liquid forms of fructose (e.g., fruit juice, soda). Whole fruits offer beneficial nutrients, but large quantities of high-fructose fruits should be consumed in moderation. Berries are generally a good choice, while dried fruit is best avoided due to its concentrated fructose and loss of beneficial components.
The risk for pre-diabetes, insulin resistance, hypertension, and kidney disease begins to increase when serum uric acid levels are above 5.5 mg/dL, although standard lab ranges for gout may flag higher thresholds.
16 Actionable Insights
1. Eliminate Fructose-Containing Liquids
Strictly avoid all liquids containing fructose, such as fruit juice, sodas, and sports drinks, because their rapid absorption and high concentration dramatically increase metabolic harm and the risk of obesity and related diseases.
2. Reduce High Glycemic Carbohydrates
Limit intake of high glycemic carbohydrates like bread, potatoes, chips, and rice, as they can induce an enzyme (aldose reductase) in the liver to convert glucose into fructose, driving metabolic disease even without direct fructose consumption.
3. Increase Water Intake Daily
Drink plenty of water, such as six glasses a day, to help suppress some of the negative metabolic effects of fructose and potentially aid in weight management and kidney health.
4. Pair Salt with Water
Consume water with or before salty foods to prevent a rapid rise in serum sodium and osmolality, which can trigger blood pressure increases and the body’s internal production of fructose.
5. Test Serum Uric Acid Levels
Get your serum uric acid levels measured, as risks for pre-diabetes, insulin resistance, hypertension, and kidney disease begin to increase when levels are consistently above 5.5 mg/dL.
6. Consider Allopurinol for High Uric Acid
Discuss with your doctor the option of taking allopurinol if your uric acid levels are 8 mg/dL or higher, or even 5.5-8 mg/dL, especially with kidney disease, to lower uric acid and mitigate metabolic risks.
7. Limit Whole Fruit Consumption
While whole fruit offers benefits, limit intake, especially of large or very sweet fruits, to avoid consuming excessive fructose; for those with conditions like NAFLD, aim for around 10 grams of fructose per day from whole fruit.
8. Avoid Dried Fruit
Steer clear of dried fruit because it is a concentrated source of fructose, often lacking many of the beneficial components found in fresh, whole fruit.
9. Prioritize Low-Fructose Fruits
Choose fruits with lower fructose content, such as kiwi, lime, lemon, and all types of berries (blueberries, raspberries, strawberries), as they are generally considered safe and beneficial.
10. Be Wary of Umami-Rich Foods
Exercise caution with high umami foods, especially those containing MSG or high purine content (like shrimp or beer), as they may contribute to obesity and raise uric acid levels through pathways distinct from sugar.
11. Limit Beer Consumption
Be aware that beer is particularly effective at inducing metabolic syndrome, including abdominal obesity, fatty liver, and high blood pressure, due to its umami-activating brewer’s yeast and alcohol content.
12. Choose Diet Soda Over Regular
If a sweetened beverage is desired, opt for diet soda over regular soda, as regular soda’s sugar content makes it metabolically more dangerous than artificial sweeteners.
13. Educate Children on Sugar Harms
Teach children about the negative health impacts of sugar, encourage them to read food labels, and avoid giving them regular soft drinks and fruit juice, while allowing occasional treats with artificial sweeteners.
14. Maintain Optimal Blood Pressure
Aim for an optimal blood pressure of 120/80 mmHg, as even slightly elevated pressures (e.g., 140/90 mmHg) confer an increased risk for heart failure, stroke, and other cardiovascular diseases.
15. Continue Regular Exercise
Maintain a regular exercise routine, as its broad benefits for mitochondrial function, vascular health, and kidney function far outweigh any theoretical concerns about heat shock protein induction related to hypertension.
16. Stay Informed on Fructokinase Inhibitors
Keep an eye on the development of fructokinase inhibitors, as these drugs are showing promise in clinical trials for treating conditions like fatty liver and could become a significant future therapeutic option.
7 Key Quotes
What's happened in the last couple decades has been the increasing knowledge that it isn't really the salt amount that makes a difference, but the salt concentration.
Rick Johnson
But when fructose is metabolized, the energy in the cell falls before it goes up. It's the only nutrient that lowers energy in the cell.
Rick Johnson
Fructose turns out to be used by animals as a mechanism to store fat.
Rick Johnson
Sugar is much more likely to cause obesity if you drink it rather than if you eat it.
Rick Johnson
If we could reduce our fructose intake, I think it would have a huge, huge effect.
Rick Johnson
I mean, personally, I would not drink any liquids that have sugar in it or a fructose or high fructose corn syrup. That's fine. So we're going to draw a hard line there. Hard line.
Rick Johnson
You know, it was so disappointing when I realized that dried fruit was the fructose of fruits without the good things in it.
Rick Johnson
2 Protocols
Rick Johnson's Clinical Approach to High Uric Acid
Rick Johnson- Measure serum uric acid levels in patients.
- If serum uric acid is 8 mg/dL or higher (or certainly 9 mg/dL+), initiate allopurinol treatment.
- If serum uric acid is between 5.5 and 8 mg/dL, discuss the pros and cons of treatment with the patient, especially considering treatment for chronic kidney disease (e.g., at 6.5 mg/dL with CKD).
- Inform patients about the risk of rash (including Stevens-Johnson syndrome) and instruct them to discontinue the drug and contact the clinic if a rash develops.
- Prefer xanthine oxidase inhibitors (like allopurinol or fibroxastat) to reduce intracellular uric acid, considering allopurinol's potentially better cardiovascular safety profile based on current data.
General Dietary Advice for Metabolic Health
Rick Johnson- Avoid drinking any liquids that contain sugar, fructose, or high fructose corn syrup.
- Reduce intake of high glycemic carbohydrates, specifically 'the big four': bread, potatoes, chips (potato/corn), and rice.
- When consuming salty foods, ensure adequate water intake to prevent a rise in serum sodium and subsequent endogenous fructose production.
- Be mindful of umami-rich foods, particularly those high in purines (e.g., shrimp, beer), as they may raise uric acid and contribute to metabolic issues.
- Consume whole fruits in moderation, prioritizing berries and avoiding large quantities of high-fructose or very large fruits. Avoid dried fruit due to its concentrated fructose content.