When we think about diabetes and metabolic health, our minds immediately jump to blood sugar, insulin, and carbohydrates. But what if I told you there's another player in this complex metabolic story that's been hiding in plain sight? In a fascinating conversation between Dr. Casey Means and neurologist Dr. David Perlmutter, author of "Drop Acid," a compelling case emerges for uric acid as a central driver of metabolic dysfunction—including diabetes, obesity, and cardiovascular disease.
For decades, uric acid has been relegated to discussions about gout, that painful joint condition affecting the big toe. However, emerging research suggests that uric acid may be orchestrating a much broader metabolic symphony, and understanding it could revolutionize how we approach diabetes prevention and management.
What Is Uric Acid and Why Should People with Diabetes Care?
Uric acid is a waste product created when our bodies break down purines—compounds found in certain foods and our own cells. Traditionally, doctors have only worried about uric acid when it reaches levels high enough to cause gout, typically around 7 mg/dL or higher. But here's the problem: optimal levels for metabolic health appear to be much lower—below 5.5 mg/dL.
The statistics are sobering. When uric acid levels exceed 7 mg/dL, research shows:
- 16% increased risk of death from any cause
- 38% increased risk of cardiovascular death
- 32% increased risk of stroke
- 155% increased risk of dementia
- 55% increased risk of Alzheimer's disease
With 88% of American adults having at least one component of metabolic syndrome, understanding uric acid's role has never been more critical. For people with diabetes or prediabetes, elevated uric acid may be both a consequence of and contributor to their metabolic struggles.
The Evolutionary Twist: When Survival Mechanisms Backfire
To understand why uric acid matters so much today, we need to travel back 15 million years. Our ancestors underwent a genetic mutation that eliminated the enzyme uricase, which breaks down uric acid. As a result, humans have 4-5 times higher uric acid levels than other mammals.
Why would evolution favor this change? The answer lies in survival. Elevated uric acid triggers a cascade of metabolic changes:
- Signals the body to store fat
- Raises blood sugar levels
- Promotes insulin resistance
- Increases blood pressure
- Stimulates excessive eating behavior
These changes were advantageous when our ancestors faced long winters and unpredictable food supplies. The ability to store fat efficiently and increase appetite meant better survival odds during famine. However, in our modern environment of 24/7 food availability—especially sugar-rich processed foods—these same mechanisms have become liabilities, driving the diabetes and obesity epidemics we face today.
Fructose: The Primary Villain in the Uric Acid Story
While uric acid comes from multiple sources, fructose stands out as the primary driver of elevated levels. When we consume fructose, it's directly metabolized into uric acid, essentially telling our bodies that "winter is coming" and it's time to store fat.
The numbers are staggering. A century ago, Americans consumed about 15 grams of fructose daily. Today, that number has quadrupled. High fructose corn syrup appears in approximately 60% of packaged grocery foods, from bread to salad dressing to pasta sauce.
But before you swear off all fruit, here's an important distinction: whole fruit contains fiber, vitamin C, and bioflavonoids that help mitigate uric acid production. The real culprits are:
- Refined sugar (table sugar is 50% fructose)
- High fructose corn syrup
- Fruit juice (fructose without protective fiber)
- Agave nectar (ironically marketed as healthy, but extremely high in fructose)
Other contributors include alcohol—particularly beer due to its high purine content from brewer's yeast—and purine-rich foods like organ meats, though these are less significant than fructose.
The Shocking Connection: Your Body Can Make Fructose from Glucose
Here's where the story takes a surprising turn that's especially relevant for people with diabetes. Your body doesn't just get fructose from food—it can manufacture it internally through something called the polyol pathway.
The polyol pathway converts glucose into fructose inside your cells, and it's activated by three main triggers:
- Dehydration and high sodium levels: When you're dehydrated or consume excess salt, your body interprets this as a drought signal and activates the pathway to create fructose. This fructose then generates uric acid, triggering all those fat-storage and insulin-resistance mechanisms.
- Elevated blood glucose: High blood sugar levels directly activate this pathway. This means that poorly controlled diabetes creates a vicious cycle—high glucose converts to fructose, which raises uric acid, which causes more insulin resistance, which raises glucose further.
- Alcohol consumption: Alcohol activates the polyol pathway, creating fructose even without any sugar consumption.
This discovery is profound. It means that even someone avoiding all dietary fructose can still produce it internally if they're dehydrated, consuming too much salt, have elevated blood sugar, or drink alcohol regularly.
Research shows that high-salt diets can induce insulin resistance in just five days through this mechanism. This helps explain why salt consumption correlates with obesity, diabetes, and hypertension—effects that go beyond simple fluid retention.
How Uric Acid Sabotages Your Metabolism at the Cellular Level
Understanding the cellular mechanisms helps explain why uric acid is so problematic for people with diabetes:
Mitochondrial dysfunction: Uric acid inhibits AMP kinase, an enzyme that promotes fat burning and healthy metabolism, while activating AMP deaminase, which does the opposite. It downregulates mitochondrial function, reducing your cells' ability to produce energy efficiently.
Nitric oxide suppression: Uric acid inhibits nitric oxide, a crucial molecule that keeps blood vessels dilated and responsive. Without adequate nitric oxide, blood vessels constrict, blood pressure rises, and insulin has difficulty doing its job. This vascular dysfunction also explains why elevated uric acid increases erectile dysfunction risk by 38%—a canary in the coal mine for broader vascular problems.
The feed-forward loop: Perhaps most insidiously, uric acid stimulates fructokinase, the enzyme that metabolizes fructose. This creates a self-perpetuating cycle where uric acid makes your body more efficient at producing even more uric acid from fructose.
Brain and behavior changes: Uric acid causes inflammation that disrupts communication between the prefrontal cortex (your rational decision-maker) and the amygdala (your emotional center). This neurological change blunts satiety signals, increases appetite, and promotes risk-taking behavior—all designed to motivate food-seeking when survival is threatened, but disastrous for dietary adherence in modern life.
Practical Steps to Lower Uric Acid and Improve Metabolic Health
The good news is that uric acid is modifiable. Here are evidence-based strategies to optimize your levels:
-
Eliminate added sugars: This is the single most important step. Read labels carefully and avoid products with added sugar, high fructose corn syrup, or agave nectar. Aim for zero added sugar in your diet.
-
Stay well hydrated: Adequate hydration dilutes sodium levels and prevents activation of the polyol pathway. Make water your primary beverage throughout the day.
-
Moderate salt intake: While some salt is necessary, excess sodium triggers fructose production internally. Be especially mindful of pairing salty foods with carbohydrates (like chips or pretzels), as this combination is particularly problematic.
-
Optimize blood sugar control: Since elevated glucose activates the polyol pathway, good diabetes management becomes even more important. Every improvement in blood sugar control helps break the vicious cycle.
-
Limit alcohol: If you drink, avoid beer due to its high purine content, and minimize alcohol overall since it activates the polyol pathway.
-
Exercise regularly: Physical activity stimulates AMP kinase, counteracting one of uric acid's negative effects on metabolism.
-
Consider targeted supplements: Research shows that quercetin (500mg daily) can reduce uric acid levels by 8%, while vitamin C (500mg daily) aids in uric acid excretion through the kidneys.
-
Test your levels: You can check uric acid through your doctor or with at-home finger-stick tests. Target a level below 5.5 mg/dL. Avoid testing while fasting or immediately after vigorous exercise, as both can temporarily elevate results.
The Bottom Line: An Evolutionary Mismatch We Can Address
The uric acid story reveals a fascinating evolutionary mismatch. Our bodies carry ancient programming designed for feast-famine cycles, but we're living in an era of constant food abundance—particularly fructose-rich processed foods. These survival mechanisms, once beneficial, now contribute to epidemic levels of diabetes, obesity, and cardiovascular disease.
For people with diabetes or those at risk, understanding uric acid opens new avenues for intervention. It explains why sugar is problematic beyond just raising blood glucose. It reveals how dehydration and excess salt can worsen insulin resistance. It shows how alcohol affects metabolism independent of its calorie content. And it provides actionable targets for improvement.
The research on uric acid and metabolic health is still evolving, with pharmaceutical companies now studying fructokinase inhibitors and scientists exploring ways to measure aldose reductase (the enzyme that converts glucose to fructose) clinically. But you don't need to wait for new medications to benefit from this knowledge.
By minimizing added fructose, staying hydrated, managing salt intake, optimizing blood sugar control, and monitoring your uric acid levels, you can work with your evolutionary biology rather than against it. In doing so, you may find that managing diabetes becomes easier, weight loss more achievable, and overall metabolic health significantly improved.
The key insight is this: metabolic dysfunction isn't just about willpower or simple calorie math. It's about understanding and addressing the deeper biological signals—like uric acid—that drive hunger, fat storage, and insulin resistance. Armed with this knowledge, you can make informed choices that support rather than sabotage your metabolic health.
References
-
Perlmutter, D. (2022). Drop Acid: The Surprising New Science of Uric Acid—The Key to Losing Weight, Controlling Blood Sugar, and Achieving Extraordinary Health. Little, Brown Spark.
-
Johnson, R. J., Lanaspa, M. A., & Gaucher, E. A. (2011). Uric acid: a danger signal from the RNA world that may have a role in the epidemic of obesity, metabolic syndrome, and cardiorenal disease: evolutionary considerations. Seminars in Nephrology, 31(5), 394-399.
