Causal or Noncausal Relationship of Uric Acid With Diabetes.

Abstract

Humans and great apes have higher serum uric acid due to mutations that reduced activity and then silenced the uricase gene about 15 million years ago (1). Uricase degrades intracellular urate in the liver, resulting in low serum uric acid. Parallel silencing of uricase occurred in lesser apes, suggesting natural selection for higher serum uric acid. Uric acid is an antioxidant in the extracellular environment, reacting with superoxide (to make allantoin) and with peroxynitrite (to make triuret). These antioxidant properties of uric acid were proposed to be beneficial by protecting against aging and cancer-associated oxidative stress (2). A different hypothesis has also been proposed (3). The uricase mutation occurred during a period of global cooling that caused seasonal famines for ancestral apes living in Europe due to loss of fruit availability during winter months. The primary food for these ancestral apes was fruit rich in fructose, a nutrient that predisposes to increased hepatic and visceral fat stores and insulin resistance due to its unique metabolism in which transient ATP depletion occurs (4). The nucleotide turnover generates urate intracellularly with a rise in serum uric acid. The intracellular urate causes mitochondrial oxidative stress and inhibits AMPK, resulting in liver fat accumulation, gluconeogenesis, and metabolic syndrome (5,6). Inhibition of uricase amplifies the effects of fructose to induce metabolic syndrome, whereas expressing the ancestral uricase in human liver …