Chicken or the Egg? Hyperuricemia, Insulin Resistance, and Hypertension
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See related article, pp 703–711
Apparently, the egg came first. I recall considerable time spent discussing this causality dilemma during school days. These discussions were of little practical importance, but here, we are many years later considering a similar quandary, which might influence treatment of cardiometabolic diseases. What comes first, hyperuricemia or the diseases themselves? They are linked, but we don’t know whether the relationship is causal. We must solve this puzzle. Hyperuricemia is common, it is increasing in prevalence,1 and we have widely available cheap drugs to address it.
Uric acid is a breakdown product of purine metabolism, regulated by the enzyme xanthine oxidase. Humans have higher levels of uric acid than most mammals because of a loss-of-function mutation in the gene encoding the uricase enzyme. We rely on renal and intestinal secretion of uric acid to maintain homeostasis. Hyperuricemia can arise because of reduced renal or extrarenal excretion or overproduction of uric acid. Genes account for ≈7% of its variance. Diuretics and β-blockers and high intake of meat, seafood, fructose, alcohol, and sodium also raise uric acid levels.2 The relationship with fructose intake is particularly interesting.3 Fructose metabolism by fructokinase causes a fall in intracellular ATP concentrations and generates intracellular uric acid.4 This intracellular uric acid causes a mitochondrial oxidative stress, leads to more generation of fructose via stimulation of aldose reductase, and upregulates fructokinase activity. Experimental studies …