In humans, there is a two- to threefold increased risk for hyperuricemia and gout in men and women who consume two or more beverages sweetened by high-fructose corn syrup per day.7,8 Fructose, unlike other sugars, produces uric acid when it is broken down inside cells, leading to elevated serum levels. Modern dietary habits, therefore, likely explain the surge in gout cases and possibly uric acid-related metabolic syndrome.
Uricase (urate oxidase) is an enzyme that catalyzes the oxidation of uric acid to 5-hydroxyisourate, which is then further metabolized and excreted as waste, mostly by the kidneys. Uricase is produced by virtually all organisms from bacteria to mammals. For reasons that until recently remained unknown, humans and modern great apes (i.e., gorillas, orangutans, chimpanzees and bonobos) are the only mammals that do not make uricase. In these species, the uricase gene is present, but inactive. As a result, humans and higher primates have higher serum urate levels than other mammals.
In 2010, Richard Johnson and Peter Andrews proposed a hypothesis that the uricase gene mutation was an evolutionary product of a need for northern migrating apes of 15 million years ago to survive harsh winters.9,10 With fructose-laden fruit as a major dietary component, the primates could benefit from increased available blood sugar and fat from increased insulin resistance. This “thrift gene” would give the brain access to glucose, enabling proper function during times when foraging for food would be most essential. The mutation would survive through the evolution of humans.
The Research
With modern dietary habits and the abundance of available food, the “thrift gene” would lead to pathologic consequences. When uricase is inhibited, rats respond to a fructose challenge by increasing blood pressure and liver fat.11
In 2006, an elegant study showed that lowering serum uric acid with allopurinol was able to prevent metabolic syndrome in rats fed a fructose-rich diet.12
Hyperuricemia itself may cause metabolic syndrome. A 2012 study followed young adults 18–30 years old for 15 years.13 They showed that hyperuricemia was an independent risk factor for diabetes and pre-diabetes. Several other studies have shown a relationship between hyperuricemia, type II diabetes and insulin resistance.14,15 The mechanism of this relationship is still not clear. Elevated serum insulin levels, as in type II diabetes, cause a decrease in renal uric acid excretion. Insulin requires nitric oxide for glucose uptake in cells. Elevated uric acid levels can then lead to further insulin resistance by directly blocking nitric oxide bioavailability.