Sugar, uric acid, and the etiology of diabetes and obesity

Richard J Johnson, Takahiko Nakagawa, L Gabriela Sanchez-Lozada, Mohamed Shafiu, Shikha Sundaram, Myphuong Le, Takuji Ishimoto, Yuri Y Sautin, Miguel A Lanaspa, Richard J Johnson, Takahiko Nakagawa, L Gabriela Sanchez-Lozada, Mohamed Shafiu, Shikha Sundaram, Myphuong Le, Takuji Ishimoto, Yuri Y Sautin, Miguel A Lanaspa

Abstract

The intake of added sugars, such as from table sugar (sucrose) and high-fructose corn syrup has increased dramatically in the last hundred years and correlates closely with the rise in obesity, metabolic syndrome, and diabetes. Fructose is a major component of added sugars and is distinct from other sugars in its ability to cause intracellular ATP depletion, nucleotide turnover, and the generation of uric acid. In this article, we revisit the hypothesis that it is this unique aspect of fructose metabolism that accounts for why fructose intake increases the risk for metabolic syndrome. Recent studies show that fructose-induced uric acid generation causes mitochondrial oxidative stress that stimulates fat accumulation independent of excessive caloric intake. These studies challenge the long-standing dogma that "a calorie is just a calorie" and suggest that the metabolic effects of food may matter as much as its energy content. The discovery that fructose-mediated generation of uric acid may have a causal role in diabetes and obesity provides new insights into pathogenesis and therapies for this important disease.

Figures

FIG. 1.
FIG. 1.
Fructose-induced nucleotide turnover. Fructose is rapidly phosphorylated in the hepatocyte by KHK to fructose-1-phosphate (F-1-P), which uses ATP as a phosphate donor. Intracellular phosphate (PO4) levels decrease, stimulating the activity of AMP deaminase 2 (AMPD2). AMPD2 converts AMP to inosine monophosphate (IMP). IMP is metabolized to inosine by 5′ nucleotidase (5′NT), which is further degraded to xanthine and hypoxanthine by xanthine oxidase (XO), ultimately generating uric acid.
FIG. 2.
FIG. 2.
Classic and alternative lipogenic pathways of fructose. In the classical pathway, triglycerides (TG) are a direct product of fructose metabolism by the action of multiple enzymes including aldolase B (Aldo B) and fatty acid synthase (FAS). An alternative mechanism was recently shown (30). Uric acid produced from the nucleotide turnover that occurs during the phosphorylation of fructose to fructose-1-phosphate (F-1-P) results in the generation of mitochondrial oxidative stress (mtROS), which causes a decrease in the activity of aconitase (ACO2) in the Krebs cycle. As a consequence, the ACO2 substrate, citrate, accumulates and is released to the cytosol where it acts as substrate for TG synthesis through the activation of ATP citrate lyase (ACL) and fatty acid synthase. AMPD2, AMP deaminase 2; IMP, inosine monophosphate; PO4, phosphate.
FIG. 3.
FIG. 3.
Uric acid: potential mechanisms for insulin resistance and diabetes. Uric acid may contribute to insulin resistance in the liver by inducing mitochondrial oxidative stress and steatosis (28). Uric acid also blocks the ability of insulin to stimulate vasodilation of blood vessels, which is important for the delivery of glucose to the skeletal muscle (4,32). Uric acid also induces local inflammation in the adipose tissue with a reduction in the production of adiponectin (44). Finally, uric acid may also have direct effects on the islet cells leading to local oxidative stress and islet dysfunction (5). Mt, mitochondria; PO4, phosphate.

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