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Uric Acid and Its Metabolic Effects, Part 2


NOTE: This is the second part in the series. In PART ONE, I discussed what uric acid is, how it’s formed, its involvement in gout, and a bit more. We’ll start here with the issues associated with elevated uric acid levels.

Uric Acid and Hypertension:

Many authors in many studies correlated elevated UA with elevated blood pressure. Dr. Rick Johnson of the Univ of Florida College of Medicine worked with rats. He determined that UA elevates blood pressure in two ways: through oxidative stress, resulting in constriction of blood vessels, and direct effects on the kidneys and how they excrete sodium (Johnson et al. Scientific America. 2015).

What about bigger rats? Yep, Dr. Johnson studied humans, too (Johnson et al. JAMA. 2008). 90% of studied individuals with hypertension had elevated UA. Treating them with the UA-lowering medication allopurinol brought 85% of the patient's blood pressure to the normal range simply by lowering their UA.

As for empiricism…in my clinical experience, hypertension is much harder to control in the setting of elevated UA, commonly requiring three or more medications. Lowering UA by some means commonly results in considerable blood pressure improvements on less medication.

Uric Acid and Inflammation:

As I tell patients, inflammation is ideally turned on when we are sick and injured, and then it should be turned off. As Spiga et al. report (Arter, Throb, and Vas Bio. June 2017), inflammation and elevated UA go hand in hand.

Inflammation is a core etiological driver of heart disease, dementia, cancers, diabetes, and basically every chronic illness. We are so accustomed to looking at individual chronic diseases as if they have their own unique causation drivers. Slowly, the concept of metabolic dysfunction and inflammation as the principal drivers of disease is taking hold.

“It’s also astonishing to think that the same inflammatory strategies our bodies heavily use for millennia to ward off microbial invaders and help heal open wounds could slip beyond our control and leave us chronically inflamed: it’s as if, from an evolutionary perspective, we’ve become victims of our own success” Dr. Perlmutter.

In Laboratory Testing, I wrote about CRP (C Reactive Protein). It is a normal constituent of our immune system. It increases in response to any inflammatory stimuli, and in medicine, is used to look for inflammatory disease but also in asymptomatic patients to assess the risk of heart disease. Arterial disease in the heart or elsewhere is driven by inflammation. Many studies have demonstrated the predictive value of CRP for having cardiovascular events.

Ruggiero et al. (Am J of Card. July 2007) showed that increases in UA directly predict increases in CRP. Rothenbacher et al. (PLOS ONE. 2012) took it a step further and found that elevated UA was actually a better predictor of cardiovascular events than CRP. Furthermore, they suggested that elevated UA independently could be causing these disease processes.

Metabolic Syndrome:

Many of you have this condition and do not know. Sugar-fueling, carb-loading, beer-drinking competitive endurance athletes have it and do not know it or do not care because they feel fit.

It is a constellation of conditions comprising five key features:

  1. High blood pressure
  2. Elevated blood sugar
  3. Increased waist circumference (over 40 inches in men or 35 inches in women)
  4. Elevated triglycerides
  5. Low HDL (good cholesterol)

Having this condition implies a sick metabolism and increases the risk of heart disease, type 2 diabetes, numerous cancers, dementia, stroke, and other conditions. The risk of dying from COVID-19 is also considerably higher in those with Metabolic Syndrome.

UA is so implicated in metabolic dysfunction and driving this condition that it is now considered “a new marker for metabolic syndrome” (Billiet et al. Rheumatology 2014).

Biochemical Geek-out:

-Nitric Oxide (NO):

It seems to me, as a humble, cognitive colossus and endurance hack, that human performance doing sphincter tone-threatening activities might be more efficiently achieved with increased blood flow to muscles. I went to skool a long time fer that. Perhaps you’ve read about NO and its ability to “vasodilate” (dilate blood vessels).

NO’s role in insulin function is more recently understood. Wang et al. (Diabetes Dec 2013) describes how NO helps insulin function optimally in muscle cells, thus allowing the entry of glucose and the formation of glycogen.

Here’s a news flash: UA compromises NO in major ways, resulting in less being formed and also damaging NO functionality. This collectively increases the risk of heart disease, diabetes, and even difficulty with erections (which affect baby-makin and our very survival!). Suddenly, those with a Y chromosome are listening. And probably those without a Y.

Let me rephrase this because athletic performance (on the road and in the sack) is at stake. Insulin, when functioning properly, stimulates the uptake of glucose into muscle, and this action is dependent on NO. UA hampers NO. UA formation is driven by fructose. Sugar is half fructose. Why in the hell would you want to consume sugar with any regularity or EVER fuel with it?

-Piss Off:

Proper fluid regulation by the kidneys is paramount to health and, certainly, athletic performance. Fructose and its metabolism drive the formation of vasopressin, AKA Antidiuretic Hormone (don’t piss, hang-onto-water hormone).

Excess body fluid is not healthy. It interferes with your power-to-weight ratio, puts a strain on the heart, and affects metabolism. Let’s fuel with sugar! Idiots.


Adenosine triphosphate, ATP, is the energy currency of our body. It is generated by the mitochondria within our cells. For you athletes, lots of ATP generation is critical to performance. With training, we develop enhanced mitochondrial ability to make ATP.

When we consume sugar, the enzyme fructokinase metabolizes the fructose piece. This process uses ATP. Douard et al. (J of Phys. Jan 2013) showed that a cellular fructose load, as provided by sugar-sweetened beverages, causes ATP to reduce by 40-50%. Sugar impairs performance by depleting our primary energy currency. The notion that sugar is a good fuel source for endurance pursuits is deeply physiologically and biochemically flawed, and in essence, science shows the opposite is true.

When ATP is used, AMP is created. This goes on to create UA.

-AMPK and AMPD2:

AMPK is adenosine monophosphate-activated protein kinase. It is extremely favorable for a healthy human metabolism. This enzyme, when activated, shifts our metabolism to the burning of fat. It also directs cellular cleaning called autophagy (discussed later with intermittent fasting). Activation of AMPK occurs by a healthful diet, some supplements, intermittent fasting, and the medication metformin.

AMPD2 is the opposing enzyme. It is adenosine monophosphate deaminase 2. It increases fat storage.

Studies on hibernating animals (Lanaspa et al. PLOS ONE. April 2015) showed that they increase fat storage, particularly in their livers, by activating AMPD2. When hibernating, they toggle to activation of AMPK to then burn this stored fat. Fascinating right? Uric acid drives this activation of AMPD2, as it does in us, and fatty livers, abdominal obesity, and metabolic syndrome are the result. Most humans are biochemically always preparing for hibernation.

When we consume sugar, fructose levels spike. Fructose, along with excessive dietary purines, undergo metabolism that yields AMP (adenosine monophosphate), the precursor to both AMPK and AMPD2. AMP also triggers the formation of UA, which then signals the AMP to be converted to AMPD2

Sugar > Fructose > Elevated AMP > Elevated UA > AMPD2 formation > Slow metabolism/fat formation > metabolic disease > poor baby makin


Lanaspa et al. (Natl Acad of Sci. Mar 2018) showed how rats fed high amounts of salt converted glucose into fructose. High salt triggered a “sugar swap.” This resulted in the rats becoming obese. In humans, Lanaspa et al. showed that this sugar swap occurs through the actions of the enzyme aldose reductase. Excessive salt activates this enzyme. It is highly plausible that excessive salt consumption could drive the formation of a host of maladies, as sugar does. Not just elevated blood pressure but Fatty Liver Disease, insulin resistance, Type 2 diabetes, and unwanted weight gain.

Salt, although by itself has no calories, stimulates appetite through fructose formation and thirst via vasopressin formation (see Piss Off above).

Effect of Sleep on Uric Acid:

The effects of sleep, both healthy and detrimental, are all about biology, including neurologic and hormonal changes. Metabolism is greatly affected.

Sleep also has potent epigenetic effects on our genome. Moller-Levet et al. (Proc of the Nat Acad of Sci. Mar 2013) showed that a week of sleep deprivation altered the function of over 700 genes involved in immune function, metabolism, and inflammation. Mullington et al. (Best Pra & Res Clin Endo & Metab. Oct 2010) further elucidated the specific immune and inflammatory chemicals triggered by sleep deprivation. These include CRP, Tumor Necrosis Factor, interleukins, and other inflammatory cytokines. I have no idea what Tumor Necrosis Factor is, but it sure sounds scary, and I don’t want it in me or even near me.

A 2004 study showed that participants who slept 4 hours a night for only two consecutive nights had a 28% increase in the hunger hormone ghrelin. I’ve written about ghrelin before, and if I ever get a dog, I’ll name it Ghrelin. Or Bart. Consequently, the study subjects craved salt, sweets, and starchy food (Univ of Chicago Med Center. ScienceDaily. Dec 2004).

In 2017, 18,000 pre-diabetic adults were studied. Those who slept less than 6 hours had a 44% increased risk of developing full-blown type 2 diabetes. Those who slept less than 5 hours had a dramatic 68% increased risk of developing type 2 diabetes (Borght et al. Regulatory Peptides Feb 2011). I consider pre-diabetes a pandemic. Individual and global health and our global economy hinges on the prevention of type 2 diabetes and its massive related burden of disease, including cardiovascular, neurologic, and malignant.

Poor sleep drives UA formation. Several authors have shown sleep and UA have an inverse relationship…less sleep, more UA. In addition, there is a direct relationship between elevated UA and sleep apnea. The higher the blood UA is, the more people stop breathing at night. Not good for baby-makin. Alright, I’ll stop.

Effect of Intermittent Fasting on Uric Acid:

The advice to eat frequently is hilarious. Here’s a good one…doctors and nutritionists still tell people that they need to eat in order to maintain a healthy metabolism. Knee slapper. Or this one…you need to eat, or you’ll digest your muscle. That one really cracks me up! How about this: you gotta eat so your brain is sharp. Or…breakfast is the most important meal of the day. There is nothing funnier than idiots acting as authorities.

I do agree that breakfast is pretty darn important if you’re carb-adapted. Because if you don’t eat, not only will you suffer, but everyone around you will. Just make sure it’s cereal, Pop-Tarts, a bagel, and a Frappe Fruppy Froo-Froo Swirly Coolatta Mocha Shmoka. With vanilla.

Not only are we humans perfectly suited for going without eating, but there is overwhelming evidence that it represents a powerful strategy to prevent disease, treat disease, slow aging, and lose weight. I have written a two-part article on Intermittent Fasting (EN 123 and 124). I’m told it’s up for a Pulitzer.

Explained therein is that there are numerous ways to implement fasting, also known as time-restricted feeding. A work day might look different than a day off. If you normally eat at 8, just move it back to 9. At 12-14 hours without food, benefits are occurring.

So often, patients tell me they’re not even particularly hungry in the morning; they just eat because they think they should. I’m a big advocate of skipping breakfast, and I do it 96.6% of the time. Once a month, I’ll have breakfast with my 9-year-old at the Pin & Cue. My God, I love that place. It has retained its local flavor in this Whitefish madhouse.

Anyway, three days a week I eat once, at dinner. The only exception is if I have a killer workout. I’ll have some protein within an hour after completion. A bit more on muscle…with fasting, Growth Hormone and ketones are increased. Both preserve muscle.

Autophagy is the degrading and recycling of cellular components. This process has been known about for over 50 years. Dr. Ohsumi is responsible for elucidating the mechanisms and genes responsible, for which he won a Nobel Peace Prize in 2016. He just beat me out with my work on how running from bears evokes a stress response. To understand the importance of autophagy, it is interesting to see what happens when the process is inhibited due to mutations in the genes responsible for it. Cancer, neurological disease, and other disease processes are the result.

Numerous studies show that autophagy is amplified during fasting and is triggered by AMPK (discussed above). But why am I talking about all of this? This is an article on uric acid! Because fasting increases UA. What!?

Yes, fasting can temporarily increase uric acid. With fasting, ketones are released. They compete with UA for excretion from the kidneys. With elevated ketones, less UA is removed from the body. In my experience, this does not always occur; it is usually a small increase, and I have never seen gout triggered by fasting. Not even in my patients that eat a ketogenic diet continually, which is the vast minority of people that enjoy the benefits of periodic fasting. Ultimately, physiology improves in so many ways that baseline UA commonly goes down several points.

Here is a key point: Weight loss is the best way to lower UA. Fasting is a key component of sustainable weight loss through the burning of fat.


Most disseminated advice is not actually adhered to by the pontificator. I’m ok with that. I gain perspective and motivation even from charlatans and hypocrites.

This perspective has formed in me the concept of not waiting and advocating for yourself. Don’t wait for your medical provider to guide you in a healthful way. It’s the rare provider that’s equipped to do so. It’s not their fault; it’s the system they operate in. And it’s their fault.

Here’s a summary of action items that can be implemented now:

  1. Check your uric acid levels. Preferably in a fasting state and without vigorous exercise in the few days preceding the blood draw.
  2. Eat sugar on rare occasions, in small amounts, and with mindfulness, next to never drink sugar or fructose.
  3. Reduce all sources of carbohydrates and reserve them for the evening meal.
  4. Be mindful of salt.
  5. Prioritize restorative sleep. The sweet spot for most people is 7-8 hours.
  6. Know your medication. Aspirin, testosterone, topiramate, sildenafil, PPI’s (acid medication), diuretics, beta-blockers, and others can result in elevated UA.
  7. Supplements. There are a few supplements that have shown efficacy in lowering uric acid. One of the more effective and least expensive is vitamin C at 500-1000 mg daily.
  8. Intermittently fast.

Embark on the change you wish to take place. Your individual health is of paramount importance. Not just to you but to those that rely on you. Not to put undue pressure on you, but our country, all of society, and the global future of humanity depends on you being metabolically well. Future babies are counting on you.

Chen et al. Arthritis & Rheumatology. Feb 2009
Ayoub-Charette et al. BMJ Open. May 2019
Jensen et al. J Hepatol. May 2018
Basaranoglu et al. Hepatol Surg, Nutr. April 2015
Zgaga et al. PLOS ONE. 2012
Yu et al. Asia Pac J of Clin Nut. 2018
Johnson et al. Scientific America. 2015
Johnson et al. JAMA. 2008
Spiga et al. Arter, Throb, and Vas Bio. June 2017
Ruggiero et al. Am J of Card. July 2007
Rothenbacher et al. PLOS ONE. 2012
Billiet et al. Rheumatology. 2014
Wang et al. Diabetes. Dec 2013
Douard et al. J of Phys. Jan 2013
Lanaspa et al. PLOS ONE. April 2015
Lanaspa et al. Natl Acad of Sci. Mar 2018
Moller-Levet et al. Proc of the Nat Acad of Sci. Mar 2013
Mullington et al. Best Pra & Res Clin Endo & Metab. Oct 2010
Univ of Chicago Med Center. ScienceDaily. Dec 2004
Borght et al. Regulatory Peptides. Feb 2011


I am a nutritionist and we did learn that consuming three balanced meals plus two snacks a day was considered healthy! (Ugh, can’t believe I told sedentary people to do so). While I agree most people do not need to eat this many times per day, not everyone can jump into IF. Education and creating new, healthier eating habits is key before adding in IF. Otherwise, they just end up still eating all the wrong foods, just in a shorter timeframe. But more than likely, the readers of Hammer Nutrition are nutritionally knowledgeable.
Hammer Nutrition replied:
Hello Karen, thank you for your comments, full agreement! It is my sincere hope that our efforts to inform our clients help them understand these issues personal on a personal level and make thoughtful, sustainable changes to their diets. To me, the priority is 1) quality of calories, 2)volume of calories consumed each day and 3) timeframe in which these calories are consumed – compressed or not. However, neither compressed eating nor any amount of exercise can overcome the first two – which is why we spend so much time talking about these topics. BDF


Thank you for putting this information out. We are at a critical point of needing to assume responsibility for our own health. I have learned much reading your articles.
Hammer Nutrition replied:
Hello Mary, it’s our pleasure to share this information with you and others. You’ve hit the nail on the head with your comment! Thank you so much for articulating this important truth. BDF

Mary, DDS

Very encouraging for intermittent dieting.

Bud Phelan

Thanks for sharing your insights and experience. I am currently battling UA along with being diagnosed with CKD stage 3b.


Funny how Dr French dislikes authorities. He is certainly not one of them.
Hammer Nutrition replied:
Alfred, There’s not much constructive about your comment, and what triggered your ire does not matter to me. But you’re right. I have little respect for dogmatic, emotional, and stagnant authority figures who have traded their empiric and practical sense for the illusion of knowledge. And I’ve never professed to be an authority. I’m learning like everyone else. Bayne

Alfred Hauslden

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