Sugar, uric acid, and the etiology of diabetes and obesity - PubMed (original) (raw)
Review
Sugar, uric acid, and the etiology of diabetes and obesity
Richard J Johnson et al. Diabetes. 2013 Oct.
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.
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.
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.
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.
Similar articles
- Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes?
Johnson RJ, Perez-Pozo SE, Sautin YY, Manitius J, Sanchez-Lozada LG, Feig DI, Shafiu M, Segal M, Glassock RJ, Shimada M, Roncal C, Nakagawa T. Johnson RJ, et al. Endocr Rev. 2009 Feb;30(1):96-116. doi: 10.1210/er.2008-0033. Epub 2009 Jan 16. Endocr Rev. 2009. PMID: 19151107 Free PMC article. Review. - Energy and fructose from beverages sweetened with sugar or high-fructose corn syrup pose a health risk for some people.
Bray GA. Bray GA. Adv Nutr. 2013 Mar 1;4(2):220-5. doi: 10.3945/an.112.002816. Adv Nutr. 2013. PMID: 23493538 Free PMC article. Review. - Sugary drinks in the pathogenesis of obesity and cardiovascular diseases.
Brown CM, Dulloo AG, Montani JP. Brown CM, et al. Int J Obes (Lond). 2008 Dec;32 Suppl 6:S28-34. doi: 10.1038/ijo.2008.204. Int J Obes (Lond). 2008. PMID: 19079277 Review. - Sugar consumption, metabolic disease and obesity: The state of the controversy.
Stanhope KL. Stanhope KL. Crit Rev Clin Lab Sci. 2016;53(1):52-67. doi: 10.3109/10408363.2015.1084990. Epub 2015 Sep 17. Crit Rev Clin Lab Sci. 2016. PMID: 26376619 Free PMC article. Review. - Fructose and uric acid: is there a role in endothelial function?
Jia G, Aroor AR, Whaley-Connell AT, Sowers JR. Jia G, et al. Curr Hypertens Rep. 2014 Jun;16(6):434. doi: 10.1007/s11906-014-0434-z. Curr Hypertens Rep. 2014. PMID: 24760443 Free PMC article. Review.
Cited by
- The Impact of Fructose Consumption on Human Health: Effects on Obesity, Hyperglycemia, Diabetes, Uric Acid, and Oxidative Stress With a Focus on the Liver.
Baharuddin B. Baharuddin B. Cureus. 2024 Sep 24;16(9):e70095. doi: 10.7759/cureus.70095. eCollection 2024 Sep. Cureus. 2024. PMID: 39355469 Free PMC article. Review. - Relationship between serum uric acid levels and periodontitis-A cross-sectional study.
Bai J, Zhou C, Liu Y, Ding M, Zhang Z, Chen Z, Feng P, Song J. Bai J, et al. PLoS One. 2024 Sep 27;19(9):e0310243. doi: 10.1371/journal.pone.0310243. eCollection 2024. PLoS One. 2024. PMID: 39331593 Free PMC article. - Association Between Serum Uric Acid Levels and Metabolic-Associated Fatty Liver Disease in Southeast China: A Cross-Sectional Study.
Ren S, Chen S, Huang J, Yu R, Wu Y, Peng XE. Ren S, et al. Diabetes Metab Syndr Obes. 2024 Sep 7;17:3343-3354. doi: 10.2147/DMSO.S476045. eCollection 2024. Diabetes Metab Syndr Obes. 2024. PMID: 39268333 Free PMC article. - Prevalence of Hyperuricemia and Associated Factors Among Patients With Type 2 Diabetes Mellitus in Northwestern Tanzania: A Cross-Sectional Study.
Abdel KA, Kalluvya SE, Sadiq AM, Ashir A, Masikini PI. Abdel KA, et al. Clin Med Insights Endocrinol Diabetes. 2024 Aug 30;17:11795514241274694. doi: 10.1177/11795514241274694. eCollection 2024. Clin Med Insights Endocrinol Diabetes. 2024. PMID: 39220387 Free PMC article. - Effects of long-term dehydration and quick rehydration on the camel kidney: pathological changes and modulation of the expression of solute carrier proteins and aquaporins.
Damir HA, Ali MA, Adem MA, Amir N, Ali OM, Tariq S, Adeghate E, Greenwood MP, Lin P, Alvira-Iraizoz F, Gillard B, Murphy D, Adem A. Damir HA, et al. BMC Vet Res. 2024 Aug 16;20(1):367. doi: 10.1186/s12917-024-04215-4. BMC Vet Res. 2024. PMID: 39148099 Free PMC article.
References
- Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 2006;290:F625–F631 - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical