Uric acid

[fred]

Fructose Intolerance triggers gout. Fructose Intolerance (FI) is a rare (one in 20,000) hereditary disease caused by body's lack of certain enzyme. When an FI patient consumes fructose and sucrose, they raise the blood uric acid level and cause gout. The treatment of FI is to avoid food and drinks that contain fructose, sucrose, and sorbitol. In certain cases, a patient can take uric acid lowering drugs to lower the uric acid level to prevent gout attacks."
If one is hereditary susceptible to gout, fruits may evoke it, as in that case fructose can raise the blood urate level.

[Kasper]

Here is more about the fructose uric acid link in type 2 diabetes:
"Obese patients with type 2 diabetes who consume higher amounts of fructose display reduced levels of liver adenosine triphosphate (ATP) -- a compound involved in the energy transfer between cells. The findings, published in the September issue of Hepatology, a journal of the American Association for the Study of Liver Diseases, indicate that elevated uric acid levels (hyperuricemia) are associated with more severe hepatic ATP depletion in response to fructose intake."
http://www.sciencedaily.com/releases/20 ... 104121.htm

Does that mean diabetes 2 patients shouldn't follow the wai diet ? (because of its high fructose content)
Or is this because of too much fructose consumption in a short time ?

I don't understand much of this article, so please enlighten me.

[RRM]

Uric acid is the main antioxidant in the human body, made from purines (in animal food, particlarly liver and sardines).
Elevated uric acid levels are associated with diabetes.
Specific proteins transport both fructose and uric acid.
So that if people with diabetes have elevated uric acid, and then consume much fructose,
insufficient fructose may be transported to the liver, causing an ATP insufficiency.

Does that mean diabetes 2 patients shouldn't follow the wai diet ? (because of its high fructose content)

It depends on whether their blood contains too much uric acid.
If the level of uric acid is elevated, consuming pure fructose may not be a good idea.
In the Wai diet, however, fructose comes with sufficient glucose, preventing a lack of ATP.

Or is this because of too much fructose consumption in a short time ?

Thats is not good for anyone, because our ability to process pure fructose is limited.
In the Wai diet fructose is not a problem, as fructose is accompanied with glucose and fructose uptake is more efficient in the presence of glucose.

[Kasper]

So that if people with diabetes have elevated uric acid, and then consume much fructose,
insufficient fructose may be transported to the liver, causing an ATP insufficiency.

I don't understand. Do you mean that if insufficient fructose is transported to the liver, this causes ATP insufficiency?
But if those diabetes people eat a diet low in fructose then they don't get ATP insufficiency.

If the level of uric acid is elevated, consuming pure fructose may not be a good idea.
In the Wai diet, however, fructose comes with sufficient glucose, preventing a lack of ATP.

How do you know that there is enough glucose in the wai diet to prevent a lack of ATP ?
They report already problems with 55%fructose 45%glucose sweeteners.
I'm not convinced that people with elevated uric acid will not have problems consuming lots of fruits.
I don't understand why you are so sure about this.

In the Wai diet fructose is not a problem, as fructose is accompanied with glucose and fructose uptake is more efficient in the presence of glucose.

But the problem is not the fructose uptake right ? The problem is that fructose causes ATP insuffiency in the liver.

[RRM]

I don't understand. Do you mean that if insufficient fructose is transported to the liver, this causes ATP insufficiency?

lower levels of ATP, which may be compensated by other sources of ATP.

How do you know that there is enough glucose in the wai diet to prevent a lack of ATP ?

All fruits come with substantial glucose. Glucose supplies ATP.
Fructose does not do so if not transported to the liver.

They report already problems with 55%fructose 45%glucose sweeteners.

What problems?
Lower ATP? I dont know whether that qualifies as a problem; it depends on the severity.

In the Wai diet fructose is not a problem, as fructose is accompanied with glucose and fructose uptake is more efficient in the presence of glucose.

But the problem is not the fructose uptake right ? The problem is that fructose causes ATP insuffiency in the liver.

Pure fructose, yes, will be a problem regarding both uptake and ATP, at least in people with elevated uric acid.
I think nobody consumes pure fructose though.

[Kasper]

What problems?
Lower ATP?

"Obese patients with type 2 diabetes who consume higher amounts of fructose display reduced levels of liver adenosine triphosphate (ATP) -- a compound involved in the energy transfer between cells. The findings, published in the September issue of Hepatology, a journal of the American Association for the Study of Liver Diseases, indicate that elevated uric acid levels (hyperuricemia) are associated with more severe hepatic ATP depletion in response to fructose intake."

It's about ATP depletion in the liver.

For the present study, 244 obese and diabetic adults from the Look AHEAD Study were evaluated, with dietary fructose consumption estimated by the food frequency questionnaire. Liver ATP and uric acid levels were measured in 105 patients who participated in the Look AHEAD Fatty Liver Ancillary Study. Researchers assessed the change in liver ATP content using an IV fructose challenge in 25 subjects, comparing patients with low fructose consumption (less than 15 grams per day) to those with high fructose consumption (greater than 15 grams per day).
The team found that participants with a high intake of dietary fructose had lower liver ATP levels at baseline and a greater change in ATP content following the fructose challenge than those who consumed a lower amount of fructose. Patients with high uric acid levels (5.5 mg/dL or more) displayed lower ATP stores in response to fructose.

Note that they didn't test pure fructose. It's about dietary fructose, and they already showed adverse effects of more then 15 gram dietary fructose a day (in people with high uric acid).

High and low uric acid levels are associated with diseases.
Here is an interesting article about the role of high uric acid in cancer:
http://www.clintransmed.com/content/1/1/16
"Although uric acid (UA) can function as a systemic antioxidant, its pro-inflammatory properties have been postulated to play an important role in the pathogenesis of cancer. Furthermore, obesity, Type 2 Diabetes Mellitus (T2DM), and the metabolic syndrome (MetS) are also associated with excess cancer, chronic inflammation, and with hyperuricemia, suggesting that UA may represent an important link between these disorders and the development of cancer."

[RRM]

It's about ATP depletion in the liver ... Obese patients with type 2 diabetes who consume higher amounts of fructose ...

Of course ATP will be lower when fructose intake is higher (in elevated serum uric acid).
But normally, this is reversed by glucose.
How is this not reversed by glucose?
Only if not reversed by sufficient glucose, it may present a problem.
In healthy people, consuming more fructose will result in relatively lower serum insulin,
so that more glucose remains available for ATP.

Maybe despite the lack of insulin stimulation, elevated free fructose somehow downregulates serum glucose
(stimulating glucose > glycerol and glycogen conversion), preventing sufficient liver-ATP repletion.
Or indirectly; Fructose does inhibit the conversion of glycogen to glucose (and glucose-6-phosphate) in the liver Bruynseels K et al,
which might prevent glucose induced hepatic ATP repletion.
But still, in healthy people the liver may still produce sufficient ATP from various sources...

Maybe ATP depletion in obese diabetics has a whole different cause, as "recovery from ATP depletion becomes progressively less efficient as body mass increases" Cortez-Pinto H,
which may involve numerous hormones. And the subjects in your study were obese.
But maybe the cause is even more specific:
"Patients with "primary" steatohepatitis ... have impaired ability to resynthesize ATP after a fructose challenge" Pessayre D et al
Steatohepatitis = fatty liver disease, inflammation of the liver; frequently found in people with diabetes and obesity,
involving lipid peroxidation of fat deposits in the liver.

[Kasper]

When I was studying uric acid a bit, I found something really intersting.
In short:
Uric acid is in humans much higher then in other organisms. There must be an evolutionary reason for this.
Uric acid has been linked to intelligence, and it may be that uric acid is a very good neuroprotector.
The sad thing is that uric acid is also something that triggers inflammation (gout), and it is unlikely that elevating uric acid (for better IQ) is a good idea health wise.
BUT, assuming this speculation is true, then CO2 may be even a better idea to boost intelligence. Look at this:

"The link between these different diseases could be the role played by oxidative stress in their aetiology and, in particular, the negative effects of peroxynitrite, a powerful oxidant formed by the reaction of the superoxide with nitric oxide, on the neurons.[51, 56] UA prevents peroxynitrite formation by neutralizing cellular superoxide and preventing its reaction with nitric oxide [56]. UA does not seem to be a direct scavenger of peroxynitrite in vivo, since the peroxynitrite binds to CO2 almost 1000 times faster than to UA.[57] However, UA is a scavenger of free radicals, such as CO3 and NO2, which are formed from the breakdown of peroxynitrite.[25, 26] Thus, a reduced concentration of UA could decrease the body's capacity to prevent the actions of peroxynitrite and other free radicals on the various neuronal components.[26] Besides its antioxidant effects, UA may also have neuroprotective effects through mechanisms mediated by astroglia, preventing the toxicity induced by glutamate.[25, 58] It does not seem likely that protection against these types of disease, with a higher prevalence at advanced ages, was the cause of the loss of uricase. However, it shows us that UA has an important role in neuronal activity, with increasing levels of UA favouring the development of more complex neuronal functions."

I can guarantee that reading this article is worth your time:
http://www.medscape.com/viewarticle/734579

[Kasper]

Uric acid is also interesting as it comes low dietary sodium.
"Fossil evidence suggests that hominids of the Miocene epoch (a period between 24 and 6 million years ago) inhabited sub-tropical forests and were woodland quadrupeds that had a diet based mainly on fruit.[37, 38] The salt content of the diet at the beginning of the Palaeolithic period, in the mid-Pleistocene (1–2 million years ago), was very low, ~690 mg/day (1.9 g NaCl) compared with a mean of 4000 mg/day (10 g NaCl) in the current American diet. Salt ingestion in hominids in the Miocene was probably even less, because they only ate fruit and leaves, estimating that with such a strict vegetarian diet salt ingestion could only be 225 mg (0.6 g NaCl). Watanabe et al. [17] demonstrated that the increase in UA can maintain blood pressure in conditions of low salt ingestion, both acutely (by stimulation of the renin–angiotensin system) as well as chronically (inducing sensitivity to salt by the development of microvascular and interstitial renal disease). The increase in blood UA could enable the hominids to maintain blood pressure in times of low salt ingestion and it has been suggested that this increase in blood pressure from the increase in UA could be essential for hominids to maintain their vertical position.[27]"

Serum uric acid increases in short-term dietary sodium restriction. http://www.ncbi.nlm.nih.gov/pubmed/1921253
If your body doesn't react with inflammation to uric acid, low dietary sodium may be able to improve neuroprotection.
But, I'm still not at all sure about if high uric acid could be desirable. It's quite complicated. A question that I can't answer:
Monosodium Urate (MSU) crystals cause inflammation in gout sufferers. Does MSU cause damage independent of the inflammation, or are MSU only bad if your body reacts with inflammation to it ?

[RRM]

Elevated uric acid by itself is not considered a medical condition.
Besides purines (sardine, brain, herring, mackerel), one may elevate uric acid levels by relative high sugar (fruits; fructose, sucrose) intake,
and also by fasting (increased uric acid recycling from old/damaged cells).
High uric acid may be relatively safe in combination with a low sodium diet.
Uric acid levels are also increased by high iron and molybdenum (beef, egg yolks), by stimulating xanthine oxidase,
and high zinc (beef, egg yolks), by inhibiting copper absorption,
in combination with low copper (no Brazil nuts, no avocado, no dried apricot), as copper may replace iron in xanthine oxidase.

Monosodium Urate (MSU) crystals cause inflammation in gout sufferers.
Does MSU cause damage independent of the inflammation, or are MSU only bad if your body reacts with inflammation to it ?

Uric acid stone formation (due to low water solubility of MSU) is inhibited by relative alkaline conditions (low protein intake),
and by preventing dehydration by consuming lots of water/juice and little salt.

Preventing excess MSU is all we need to do, as MSU actually has 2 biological purposes:
"evoking cell immunity and delivering several kinds of binding proteins into dendritic cells". Sakamaki I et al
All effects of excess MSU are (therefore) inflammational of nature (if not adequately counteracted),
including the formation of networks of extracellular fibers (if not adequately counteracted by antioxidants),
which includes autophagy Mitroulis I et al, which is also linked to fasting and longevity, btw.
This inflammatory response to MSU may be due to uric acid's role as "a local alarm signal that alerts the immune system to cell injury and helps to trigger immune responses" Rock KL et al.

Back to your question: All the direct effects of MSU i could find were all inflammatory responses:

"MSU stimulation induced robust (unconventional, vesicle mediated) protein secretion (including IL-18 and IL-1B) from human macrophages."
... "Also active forms of lysosomal proteases cathepsins (essential for the above)"
... "Additionally, proteins associated to phosphorylation events (modifying cytosolic, nuclear and membrane proteins by phosphorylation)" Valimaki E et al
"MSU crystals induce neutrophil extracellular traps formation", which is partially inhibited by various anti-oxidants. Schorn C
"MSU crystals trigger both inflammasome-dependent and independent pathways to generate the proinflammatory cytokine IL-1." Rock KL et al
"MSU crystals stimulate secretions of IL-1β (through serum amyloid A Migita K et al), TNF-α, IL-6, prostaglandin E(2) (PGE(2)) and nitric oxide (NO)" Yao X et al
"MSU is know to activate the NLRP3 inflammasome" Vyleta ML et al
"MSU may induce VCAM-1 expression" (in response to TNF-α or IL-1) Wang R et al
"MSU stimulate (in the skin, through P2Y(6) receptors) normal human keratinocytes to produce IL-1α, IL-8/CXCL8, and IL-6".Uratsuji H et al

[dime]

Wai dieters, do you know your uric acid levels from blood tests?

Strangely, when I had a blood test last year (6 months or so ago), I had a level of 5.4, and the reference range was 3.6 - 8.2. At that time I didn't do 100% wai.
In my recent test, the reference changed to 3.5 - 7.2, and my level is 7.1

[Oscar]

No idea, never had a blood test.

[RRM]

I dont know my uric acid level either.
7.1 is within normal.