Sunday, February 28, 2016

Does Fructose Increase Uric Acid?

Sugar sweetened beverages (SSBs) are consistently associated with gout in observational studies.  The fructose component of sucrose/HFCS is thought to be responsible for this by directly increasing uric acid production.  The proposed mechanism is as follows:

In the first few steps of glycolysis glucose is converted to fructose-1,6-bisphosphate and then gets split to DHAP and GA3P.  Fructose-1,6-bisphosphate has 2 phosphate groups that have been taken from ATP.  So the cell actually loses 2 ATP in the first few steps of glycolysis (the preparatory phase), but gets this back and a 2 more in the later steps (the pay-off phase).  Fructolysis is very similar, it also gets 2 phosphate groups from ATP and also ends up getting split to DHAP and GA3P [1].

Fructolysis is similar to glycolysis (and extremely different to alcohol metabolism), but there’s a major difference – the enzymes catalysing the early steps of glycolysis where ATP is used (glucokinase and phosphofructokinase) are tightly regulated whereas the similar steps in fructolysis lack such regulation [1].  People claiming fructose increases uric acid argue that this is the critical difference between glucose and fructose, and that high intake of fructose can deplete intracellular ATP from the early stages of fructose metabolism, turning it into AMP, which then gets broken down to uric acid [2] (also see Robert Lustig’s video).

There’s the mechanism, but what actually happens to uric acid levels or gout when you manipulate sugar/fructose or SSB intake?  So I searched on PubMed for relevant clinical trials:

  • In healthy adults, supplementing 200g of fructose increased many aspects of the metabolic syndrome including uric acid levels [3]
  • In healthy adults, supplementing 150g of fructose or 150g of glucose increased glucose and insulin levels but neither affected uric acid levels.  Triglycerides increased in the fructose group but not the glucose group [4]
  • In overweight men, an isocaloric high fructose diet (25% TE) and isocaloric high glucose diet (25% TE) both increased weight, liver triglycerides, plasma triglycerides to a similar extent, but the high fructose diet increased uric acid and insulin resistance whereas the high glucose diet didn’t.  Hepatic ATP and Pi didn’t change in either group [5]
  • In overweight adults, a calorie restricted diet with moderate fructose diet outperformed a calorie restricted diet lower fructose diet for weight loss but both significantly improved insulin sensitivity and reduced uric acid levels (largely a fruit vs. grains study) [6]
  • In mostly healthy adults, different doses of sucrose or HFCS didn’t affect the AUC for insulin, glucose, triglyceride and uric acid levels throughout the day [7] (potential conflict of interest)
  • In mostly healthy adults, different doses of sucrose or HFCS for 10 weeks didn’t affect glucose or uric acid levels, but a higher intake of sugar was related to greater weight gain [8] (potential conflict of interest)
  • In mostly healthy adults, diets of 9% fructose, 9% glucose, 18% sucrose and 18% HFCS didn’t increase uric acid levels or blood pressure and there were no significant differences between the groups [9] (potential conflict of interest)
  • In mostly healthy young adults, after 2 weeks of complex carbohydrate or 10%, 17.5% or 25% of energy from SSBs, the SSBs produced dose dependent increases in body weight, plasma triglycerides and uric acid [10]
  • In healthy adults, 2 weeks of substituting sucrose for fructose (between 63-99g per day) reduced HDL-C and total-C, but didn’t affect glucose tolerance, insulin resistance, uric acid or triglycerides [11]
  • In obese adults with type 2 diabetes, 60g of fructose supplementation for 12 weeks reduced fasting glucose and HbA1c, and didn’t affect total-C, LDL-C, HDL-C, triglycerides and  uric acid [12]
  • In people with and without hyperinsulinemia, 5 weeks of 20% fructose resulted in higher triglycerides and total cholesterol than 20% corn starch, particularly in the people with hyperinsulinemia.  Uric acid was also higher in the fructose group and was mostly unchanged in the postprandial state for both groups [13]
  • In people with poorly controlled type 2 diabetes, supplementing 60g of fructose per day for 12 months reduced fasting glucose and HbA1c, and body weight, blood lipids, lipoproteins and uric acid wasn’t affected [14]
  • In people with well controlled type 2 diabetes, replacing 30g of starch with fructose per day for 2 months as part of a calorie restricted diet (1400-1600 calories) resulted in no significant difference in body weight, HbA1c, fasting glucose and insulin, uric acid, total-C, HDL-C and triglycerides between the two groups, although triglycerides increased in the fructose group [15]
  • In adults with obesity, consuming either 30% of calories from fructose or glucose for 1 day resulted in lower leptin (particularly pronounced among those with insulin resistance) and higher triglycerides in the fructose group over the 24 hour period, but uric acid was not different between the groups (24 hour glucose and insulin were obviously lower in the fructose group too) [16]
  • In healthy young adults, ingesting a 100g mix of glucose and fructose resulted in significantly higher postprandial uric acid and triglycerides than ingesting 100g of glucose.  Although the total AUC for uric acid only increased by about 6-7% (postprandial glucose and insulin were obviously lower the glucose+fructose group) [17]
  • A fructose tolerance test (75g fructose) increases the 2 hour AUC for uric acid by 28.3%, 17.0% and 12.5% for healthy controls, people with obesity and people with kidney disease respectively [18]
  • Healthy young men were given different combinations of fructose and glucose in a 300 calorie drink.  The higher the proportion of fructose, the greater the increase in postprandial uric acid.  The was no relationship between the ratio of glucose to fructose with postprandial ghrelin or appetite (which is interesting considering fructose doesn’t increase insulin very much) (potential conflict of interest) [19]
  • In healthy adults, consumption of a fruit and vegetable puree didn’t affect uric acid (and increased plasma antioxidant capacity) [20]

There were a few postprandial studies and most found that fructose modestly increased postprandial uric acid.  Whether this is due to ATP depletion is uncertain as no studies looked how fructose effects postprandial uric acid and ATP simultaneously.  Human research looking at this mechanism directly is quite limited [21], but fructose infusions (250 mg/kg over 30-60 minutes) have been used to increase ATP depletion in people with non-alcoholic steatohepatitis and healthy controls [22].  I think the mechanism of ATP depletion is likely, but looking at the magnitude and time course of the effect, it doesn’t seem sufficient to result in pathologically high uric acid levels in healthy people and doesn’t affect fasting uric acid levels (or for most of the day) [5].

Fasting uric acid levels on the other hand seem to be related to insulin resistance in these trials, as uric acid consistently increased when insulin resistance was developing, and vice versa.  The mechanism here is that insulin reduces uric acid clearance and insulin resistance will result higher insulin levels [11].  I think it’s more likely that the relationship in observational studies between SSBs and uric acid levels/incidence of gout is mediated by insulin resistance and that there isn’t much of a relationship between fruit or total fructose also for this reason as fruit doesn’t cause insulin resistance

It’s important to note that the fructose intake in these trials was often abnormally large and the trials were quite short (usually only a few to several weeks long).  It’s difficult to know whether the same effect would be seen with smaller changes over many decades.  This field also has an issue with conflicts of interest (particularly in HFCS vs. sucrose studies).  I don’t think it’s a coincidence that the studies with a potential conflict of interest showed less adverse outcomes with sugar/fructose consumption

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