A causal role for uric acid in fructose-induced metabolic syndrome.

The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.

[1]  N. Kamatani,et al.  Troglitazone decreases serum uric acid concentrations in Type II diabetic patients and non-diabetics , 2000, Diabetologia.

[2]  M. Matsuda,et al.  Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. , 1999, Diabetes care.

[3]  Richard J. Johnson,et al.  Uric acid, evolution and primitive cultures. , 2005, Seminars in nephrology.

[4]  D. Berkowitz Gout, hyperlipidemia, and diabetes interrelationships. , 1966, JAMA.

[5]  K. Suzuki,et al.  Serum uric acid and risk for development of hypertension and impaired fasting glucose or Type II diabetes in Japanese male office workers , 2002, European Journal of Epidemiology.

[6]  S. L. Baker,et al.  Excess fruit juice consumption by preschool-aged children is associated with short stature and obesity. , 1997, Pediatrics.

[7]  B. Wexler,et al.  Effect of increased serum urate levels on virgin rats with no arteriosclerosis versus breeder rats with preexistent arteriosclerosis. , 1977, Metabolism: clinical and experimental.

[8]  G. Bray,et al.  Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. , 2004, The American journal of clinical nutrition.

[9]  Ali H Mokdad,et al.  Increasing prevalence of the metabolic syndrome among u.s. Adults. , 2004, Diabetes care.

[10]  E. Block,et al.  Hyperuricemia induces endothelial dysfunction. , 2005, Kidney international.

[11]  O. E. Michaelis,et al.  Plasma fructose, uric acid, and inorganic phosphorus responses of hyperinsulinemic men fed fructose. , 1986, Journal of the American College of Nutrition.

[12]  K. Raivio,et al.  Fructose-induced hyperuricaemia. , 1967, Lancet.

[13]  T. Vasankari Metabolic effects of dietary fructose. , 2003, The American journal of clinical nutrition.

[14]  E. H. Ahrens,et al.  CARBOHYDRATE METABOLISM IN TWO FORMS OF HYPERGLYCERIDEMIA. , 1964, The Journal of clinical investigation.

[15]  K. Raivio,et al.  Fructose-induced adenine nucleotide catabolism in isolated rat hepatocytes. , 1977, Canadian journal of biochemistry.

[16]  M. Leschke,et al.  Reduced peripheral and coronary vasomotion in systemic hypertension. , 1992, European heart journal.

[17]  A. Saeki,et al.  [Hyperuricemia and insulin resistance]. , 1996, Nihon rinsho. Japanese journal of clinical medicine.

[18]  Y. Kawano,et al.  Decreases in serum uric acid by amelioration of insulin resistance in overweight hypertensive patients: effect of a low-energy diet and an insulin-sensitizing agent. , 2002, American journal of hypertension.

[19]  H. Milionis,et al.  Effects of statin treatment on uric acid homeostasis in patients with primary hyperlipidemia. , 2004, American heart journal.

[20]  U. Gresser,et al.  Benzbromarone and fenofibrate are lipid lowering and uricosuric: a possible key to metabolic syndrome? , 1994, Advances in experimental medicine and biology.

[21]  M. Brownlee Biochemistry and molecular cell biology of diabetic complications , 2001, Nature.

[22]  S. Yamashita,et al.  Effect of visceral fat accumulation on uric acid metabolism in male obese subjects: visceral fat obesity is linked more closely to overproduction of uric acid than subcutaneous fat obesity. , 1998, Metabolism: clinical and experimental.

[23]  G. Reaven,et al.  Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. , 1991, JAMA.

[24]  A. Kashiwagi,et al.  Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2- imbalance in insulin-resistant rat aorta. , 1999, Diabetes.

[25]  Walter C Willett,et al.  Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. , 2004, JAMA.

[26]  A. Marette,et al.  Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent. , 1998, American journal of physiology. Endocrinology and metabolism.

[27]  M. Elisaf,et al.  Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. , 2004, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[28]  L. Lindholm,et al.  Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study) , 2003, Journal of hypertension.

[29]  E. Parks,et al.  Carbohydrate-induced hypertriacylglycerolemia: historical perspective and review of biological mechanisms. , 2000, The American journal of clinical nutrition.

[30]  P. Vollenweider,et al.  Clustering of cardiovascular risk factors mimicking the human metabolic syndrome X in eNOS null mice. , 2003, Swiss medical weekly.

[31]  F. Messerli,et al.  Serum uric acid in essential hypertension: an indicator of renal vascular involvement. , 1980, Annals of internal medicine.

[32]  F Vinicor,et al.  The continuing epidemics of obesity and diabetes in the United States. , 2001, JAMA.

[33]  B N Prichard,et al.  Adverse reactions to diuretics. , 1992, European heart journal.

[34]  T. Nakagawa,et al.  Mild hyperuricemia induces glomerular hypertension in normal rats. , 2002, American journal of physiology. Renal physiology.

[35]  P. Gorden,et al.  Effect of angiotensin and norepinephrine upon urate clearance in man. , 1968, The American journal of medicine.

[36]  P. Deedwania Mechanisms of endothelial dysfunction in the metabolic syndrome , 2003, Current diabetes reports.

[37]  G. Reaven Role of Insulin Resistance in Human Disease , 1988, Diabetes.

[38]  Steven L Gortmaker,et al.  Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis , 2001, The Lancet.

[39]  篠崎 一哉 Abnormal Biopterin Metabolism Is a Major Cause of Impaired Endothelium-Dependent Relaxation Through Nitric Oxide/O2[-] Imbalance in Insulin-Resistant Rat Aorta , 2000 .

[40]  T. Ogihara,et al.  Serum Uric Acid and Plasma Norepinephrine Concentrations Predict Subsequent Weight Gain and Blood Pressure Elevation , 2003, Hypertension.

[41]  A. Aljada,et al.  Contemporary Reviews in Cardiovascular Medicine Metabolic Syndrome A Comprehensive Perspective Based on Interactions Between Obesity, Diabetes, and Inflammation , 2022 .

[42]  K. Raivio,et al.  FRUCTOSE-INDUCED HYPERURICÆMIA , 1967 .

[43]  M. Wolf,et al.  Insulin Resistance and Alterations in Angiogenesis: Additive Insults That May Lead to Preeclampsia , 2004, Hypertension.

[44]  Jukka T Salonen,et al.  The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. , 2002, JAMA.

[45]  G. Reaven,et al.  Fructose-induced insulin resistance and hypertension in rats. , 1987, Hypertension.