Uric acid, meat and fructose || The cause of diabetes?

Uric acid is under fire lately, with lots of respected PhDs and MDs saying that uric acid is the cause of diabetes, cardiovascular disease, metabolic syndrome, chronic kidney disease, hypertension, gout, etc, etc (R).

It’s bad.

And the reason why they focus on uric acid, is because they want to demonize sugar and meat.

In this article, I want to go over uric acid, what increases it, and what’s really the culprit behind metabolic syndrome.

Purine (uric acid precursor) benefits

Uric acid is created from purines, which have many important functions in the body.

Notable purines are adenine, guanine, hypoxanthine, xanthine, theophylline, theobromine, caffeine, uric acid and isoguanine.

Aside from the crucial roles of purines (adenine and guanine) in DNA and RNA, purines are also significant components in a number of other important biomolecules, such as ATP, GTP, cyclic AMP, NADH, and coenzyme A.

They may also function directly as neurotransmitters, acting upon purinergic receptors. E.g. adenosine activates adenosine receptors.

Uric acid benefits

Uric acid accounts for 50-75% of the total antioxidant capacity in the blood (R).

In fact, it has been argued that human evolution has led to favouring urate over ascorbate as a major serum antioxidant, as evidenced by the loss of the gene for uricase, the enzyme that metabolizes urate, and the concurrent loss of L-glucuronate oxidase, the enzyme that synthesizes vitamin C.” (R)

Uric acid:

  • Has a protective action in vitamins C and E with the stabilizing activities in these vitamins and the presence of ascorbic acid in plasma is required for the antioxidant effect of uric acid.
  • Has a direct effect on the inhibition of free radicals such as peroxyl radical and peroxynitrite, and indirectly via chelating transition metal ions to make stable complexes, thus protecting the cell membrane and DNA (R, R).
  • Has antioxidant activity in the brain, where it’s being a protector for several diseases such as multiple sclerosis and neurodegenerative disease. Higher concentration of uric acid is associated with a lower risk of developing Parkinson’s and Alzheimer’s disease (R).
  • Is a very potent inhibitor of AChE (the enzyme that breaks down acetylcholine), thus helping against dementia and cognitive impairment (R). Patients with gout have a lower risk of developing dementia. This phenomenon exists for both non-vascular and vascular types of dementia. (R)

How uric acid is created

The balance between the production of urate (in the liver) or urate excretion (in the intestine (25-35%) and kidney (65-75%)) pathways determines an individual’s serum urate levels. Familial and twin studies estimating the heritability of serum urate suggest genetic factors explain 25% to 60% of the variability in serum urate levels (R).

#1 Exogenous sources of uric acid.

Uric acid is created from purines. Purines are created in the body and can also be obtained from the diet.

Beer, meat, organ meat and seafood are the richest dietary sources of purines.

So in theory, the more purines you consume, the more uric acid you produce and the higher your risk of metabolic syndrome.

Since seafood and organ meat are very high in purines, have you ever seen someone who eats a lot of seafood and organ meat get metabolic syndrome?

Nope.

The production of uric acid depends on purine ingestion, however, a purine-rich diet would be responsible for an increase in only 1 to 2 mg/dL of uric acid (R). A level of 7mg/dl is considered undesirable.

Seven foods were associated with raised serum urate levels (beer, liquor, wine, potato, poultry, soft drinks, and meat (beef, pork, or lamb)) and eight foods were associated with reduced serum urate levels (eggs, peanuts, cold cereal, skim milk, cheese, brown bread, margarine, and non-citrus fruits) in the male, female, or full cohorts. Three diet scores, constructed on the basis of healthy diet guidelines, were inversely associated with serum urate levels and a fourth, data driven diet pattern positively associated with raised serum urate levels, but each explained ≤0.3% of variance in serum urate. In comparison, 23.9% of variance in serum urate levels was explained by common, genome wide single nucleotide variation. Similarly, the diet scores explained very little variance in serum urate levels (0.28% for the DASH diet, 0.15% for the Healthy Eating diet, 0.06% for the Mediterranean diet, and 0.16% for the data driven diet patterntable 2).” (R)

So clearly, dietary purines almost don’t matter in the big picture of total uric acid levels.

Worst and best foods for uric acid:

Beer, both due to its alcoholic content and high-quality purine. Beer intake has a stronger power to increase uric than liqueur, but moderate wine intake does not increase uric acid. Alcohol intake in general increases uric acid concentrations by reducing excretion and increasing urate production (R).

Dairy product intake has an inverse relation with uric acid. Probably, the mechanism for such association is due to milk-forming proteins (lactalbumin and casein), which have a uricosuric effect (R).

There is an inverse relation between coffee intake and uric acid concentrations [48], despite coffee being high in purines. Decreased uric acid concentrations are likely due to improved insulin resistance observed with increased coffee intake, which occurs mainly due to chlorogenic acid, an antioxidant found in coffee.

#2 Endogenous produced uric acid

Fructose has been deemed evil, since it can “deplete” ATP and increase AMP. AMP is converted to inosine, which is a purine, which is then converted to uric acid. Uric acid in turn supposedly contributes to insulin resistance.

Briefly, during fructose metabolism, fructose is converted into fructose 1-phosphate by fructokinase primarily in the liver. This enzyme uses phosphate and ATP, thus lowering ATP and increasing AMP. Next, the enzyme fructose-1-p aldolase (also known as aldolase B) breaks fructose 1-phosphate into dihydroxyacetone phosphate (DHAP) and d-glyceraldehyde.

When there is a high intake of fructose, conversion into fructose 1-phosphate is fast, but the reaction with aldolase is slow. Hence, fructose 1-phosphate accumulates, and intracellular phosphate decreases. This decrease stimulates AMP deaminase (AMPD), which converts AMP to uric acid through a few steps.

But as you can see, ADP is re-converted to ATP by triose kinase (later down the channel, thus rescuing low ATP).

Firstly, evidence suggests that a large amount of fructose can be converted to glucose in the intestine before it even reaches the liver. Secondly, eating fruit or having sugar with a meal slows down the absorption of fructose, thus reducing the influx of fructose in the liver. Thirdly, consuming moderate amounts of fructose even on its own will only acutely increase uric acid, which will be back to normal after roughly 2 hours. Fourthly, it’s not necessarily the increase in uric acid that is bad. In itself, uric acid accumulation does not cause obesity (R). More on that in a bit.

Yes, isolated fructose and pure sugar can increase uric acid acutely, due to enhanced production. But this increase in uric acid has lots of protective properties.

On the other hand, fructose consumption from honey (when consumed on its own) or apple increases uric acid much less compared to sugar. However, is this increase bad?

No, because:

  • Fruit doesn’t cause insulin resistance, diabetes or metabolic syndrome.
  • The increase in uric acid from sugar increases the total antioxidant capacity in the blood (R).

The increase in uric acid from the diet usually decreases back to baseline in 2 hours (R).

What’s the actual cause of excess uric acid (and gout) then?

  • Insulin resistance
  • Excess fat tissue
  • Inflammation
  • Hypothyroidism
  • Excess oxalates (produce endogenously or consumed exogenously) – it competes with uric acid for excretion (R).
  • Lactic acid – it competes with uric acid for excretion (R).
  • Ketone bodies – it competes with uric acid for excretion (R).
  • Elevated triglycerides – The synthesis of fatty acids (triglycerides) in the liver is associated with the de novo synthesis of purine, accelerating uric acid production.
  • Low testosterone
  • Being overall acidic. Sodium bicarbonate helps to enhance uric acid excretion (R).
  • Glyphosate (R)
  • Nutritional deficiencies

Insulin resistance

Insulin resistance usually causes hyperinsulinemia and hyperinsulinemia 1) inhibits uric acid excretion in the kidney and 2) enhances uric acid production by upregulating xanthine oxidoreductase (R).

Serum uric acid levels linearly increased with increasing serum insulin levels (R) and administration of metformin or troglitazone, each of which improves insulin resistance in liver and muscle tissues, was previously found to decrease serum uric acid levels in a manner unrelated to renal uric acid excretion (R).

So the big thing here is to test your fasting insulin and then make sure it’s around and below 5mIU/L.

If it’s higher, then you likely have some work to do to improve insulin sensitivity.

You can also look at your HOMA-IR score, which should be below 1.7. You can calculate it by multiplying insulin (uIU/mL) with glucose (mg/dL)).

Excess fat tissue

Everyone has a limit on how much fat they can gain before it starts to become inflammatory and release too much fat into the circulation. Excess fat in the blood will contribute to insulin resistance and hyperinsulinemia.

Hypoxanthine (a purine), which is produced by the adipose tissue, is increased in individuals with obesity. This hypoxanthine is taken up by the liver and converted to uric acid, resulting in increased uric acid production.

In addition, a recent study found a positive association between body mass index (BMI) and plasma xanthine oxidoreductase (XOR) activity, the rate-limiting enzyme that converts hypoxanthine to xanthine and xanthine to uric acid (R).

In short, excess fat produces and released hypoxanthine and enhance its conversion to uric acid.

Thyroid

The thyroid gland produces mostly T4 and some T3, which is the active thyroid hormone. Most T3 is created from T4.

Low T3 causes hypothyroidism.

T3 optimizes kidney function and enhances uric acid excretion. On the other hand, T3 also enhances uric acid production.

Hypothyroid individuals excrete less uric acid and form more urate crystal deposits in connective tissue (creating gout), whereas in hyperthyroidism, uric acid excretion usually exceeds uric acid production (R, R, R).

The results demonstrated that serum levels of uric acid in patients with subclinical hypothyroidism were significantly higher than those of controls and patients with subclinical hyperthyroidism.” (R)

Keep in mind that, “while gout is associated with high serum urate, the association is not as strong as would be expected. Many people with elevated serum urate never experience gout, and many gout sufferers have normal levels of serum urate.” (R)

Testosterone

Most people with gout are overweight, have insulin resistance, have elevated inflammation and low testosterone.

Serum uric acid levels are negatively associated with serum testosterone (R) and low testosterone level (<400 ng/dL) are significantly associated with a serum urate level ≥ 7 mg/dL (R).

Studies have found long-term testosterone replacement therapy can produce significant decrease in body mass index (BMI), improvement in insulin resistance and glycemic control and lower uric acid.

The interesting thing is that, giving men high doses of testosterone resulted in an increase in muscle mass as well as uric acid. “Since the level of serum creatinine represents an individual’s muscle volume and the muscle is a major source of purine, which induces UA upregulation, the serum UA elevation observed during TRT is at least partially attributed to an increase in muscle mass.” (R)

So, by increasing muscle mass, TRT can also increase uric acid (which is one of the main anti-oxidants in muscle). But because it lowers fat mass, improves insulin sensitivity and lowers inflammation, the increase in uric acid doesn’t lead to gout.

Nutritional deficiencies

Here are a few examples of deficiencies that lead to high uric acid:

  • Vitamin D (R).
  • Magnesium (R, R, R).
  • Vitamin C. High vitamin-C intake shows an inverse relation with uric acid (R).
  • Zinc (R, R). Increases it when it’s low and lower’s it when it’s high.
  • Selenium (R).
  • Calcium lowers uric acid, especially when consumed via milk (R).
  • Salt. A low salt diet (3g for 7 days) increased uric acid, whereas a high salt diet (18g) significantly lowers uric acid, by enhancing excretion (R).
  • Excess (free) iron increases uric acid, by stimulating xanthine oxidase.

Point being, eat a nutrient-dense diet, as shown on the testosterone food pyramid.

Other things that influence risk of getting gout

  • Blood pH (too acidic promote crystal formation)
  • Fungal infection and mold. Colchicine, one of the most common drugs used to treat gout, is an antitubulin drug, and its mode of action is the same as that of the antibiotic drug Griseofulvin, which is used to treat yeast infections. Patients with gout experienced dramatic improvements in acute gout following administration of griseofulvin specifically to treat a superficial fungal infection
  • Leaky gut
  • Gut dysbiosis – due to excess alcohol, undigested meat, glyphosate, etc.

Learn how you can double, triple and in some cases even quadruple your testosterone!

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