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Takahiko Nakagawa,1 Hanbo Hu,1 Sergey Zharikov,1 Katherine R. Tuttle,2 Robert A. Short,2,3 Olena Glushakova,1 Xiaosen Ouyang,1 Daniel I. Feig,4 Edward R. Block,1 Jaime Herrera-Acosta,5, Jawaharlal M. Patel,1 and Richard J. Johnson1
To be able to determine the effects of fructose in developing hypermetabolic syndrome. y To be able to determine the treatments on how to reduce uric acid in fructose induced hypermetabolism and its effects.
The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake. Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake.
METABOLIC SYNDROME CONSISTS of a cluster of cardiovascular disease risk factors that include obesity, glucose intolerance, hyperinsulinemia, dyslipidemia, and hypertension. The epidemic correlates with pronounced changes in the environment, behavior, and lifestyle and is considered one of the main threats to human health worldwide. Metabolic syndrome confers a greater than threefold increased risk for cardiovascular mortality
Definition of Terms: Dyslipidemia: it is the elevation of plasma cholesterol. or a low high density lipoprotein level that contributes to the development of atherosclerosis. and individual lipoproteins. or both. TGs. Dyslipidemias were traditionally classified by patterns of elevation in lipids and lipoproteins. . that is associated with insulin resistance and increased risk of cardiovascular pathology. triglycerides (TGs). Glucose Intolerance: is a pre-diabetic state of dysglycemia. Diagnosis is by measuring plasma levels of total cholesterol.
. to its active metabolite oxypurinol. Hypertension: is a chronic medical condition in which the systemic arterial blood pressure is elevated. Allopurinol: is a drug used primarily to treat hyperuricemia (excess uric acid in blood plasma) and its complications. Allopurinol is rapidly metabolized by its target. which is also an inhibitor of xanthine oxidase. xanthine oxidase. It is the opposite of hypotension.Hyperinsulinemia: is a condition in which there are excess levels of circulating insulin in the blood.
Benzobromarone: is a uricosuric agent used in the treatment of gout. Hyperuricemia: is a level of uric acid in the blood that is abnormally high. the upper end of the normal range is 360 µmol/L (6 mg/dL) for women and 400 µmol/L (6.8 mg/dL) for men. It is structurally related to the antiarrhythmic amiodarone. a firstline treatment. In humans. especially when allopurinol. fails or produces intolerable adverse effects. .
called glucose.Oral Glucose Tolerance Test: The oral glucose tolerance test (OGTT) measures the body's ability to use a type of sugar. An OGTT can be used to diagnose prediabetes and diabetes. . An OGTT is most commonly done to check for diabetes that occurs with pregnancy (gestational diabetes). that is the body's main source of energy.
or fruit sugar. Fructose is a component of sucrose. It is one of the three important dietary monosaccharides along with glucose and galactose. Glucose is derived from hexanal.Dextrose: The term dextrose is derived from dextrorotatory glucose. Fructose: Fructose. Glucose is called an aldohexose. is a simple monosaccharide found in many foods. a chain of six carbon atoms terminating with an aldehyde group. . The other five carbon atoms each bear alcohol groups.
and hyperuricemia) of metabolic syndrome. Second. 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 . pair-feeding studies showed that fructose.Four sets of experiments were performed. hypertriglyceridemia. induced features (hyperinsulinemia. in rats receiving a high-fructose diet. and not dextrose. First.
These data provide the first evidence that uric acid may be a cause of metabolic syndrome.Uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. 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. .
In the current study. y . This raised the possibility that uric acid may have a pathogenetic role in metabolic syndrome. we show that fructose-induced metabolic syndrome is partially prevented by lowering serum uric acid in the rat.One distinction between fructose and glucose is that fructose raises serum uric acid (38). Elevated serum uric acid predicts the development of obes One distinction between fructose and glucose is that fructose raises serum uric acid. Elevated serum uric acid predicts the development of obesity and hypertension. The reduction of endothelial nitric oxide (NO) bioavailability by uric acid may be a mechanism for insulin resistance and hypertension.
. WI. which is mainly composed of starch. Male Sprague-Dawley rats (150 200 g) were housed in standard conditions and fed a control (n = 7) or 60% fructose diet (Harlan. The control diet contained 46% carbohydrate. Louis. One-half of the fructose-fed rats were administered allopurinol (150 mg/l in the drinking water. MO) for an additional 6 wk to lower serum uric acid. The caloric content of these diets are 3.Methods: Experiment I: treatment of fructose-induced hyperuricemia with allopurinol. respectively. Sigma. At 4 wk. Madison. St. whereas the fructose diet contained 60% fructose as the carbohydrate.6 kcal/g. blood samples were obtained at 11 AM after 4 h of fasting. Fresh drinking water containing allopurinol was replaced every 2 days.1 and 3. n = 14) for 10 wk.
in which rats were fasted overnight (16 h) and then administered 1.5 g/kg of a 50% glucose solution by gavage. and fructose+allopurinol. an oral glucose tolerance test (OGTT) was performed. fructose. and 120 min for blood glucose and serum insulin measurement. The rats were then killed. Blood was sampled at 0. 60.Rats were divided into three groups: control. . 30. At 10 wk.
. fructose. allopurinol was initiated on the day when the fructose diet was given (from week 0 to week 8). Three groups (control. Body weight was measured every 2 wk. Food consumption was measured for 3 days at 8 wk. n = 8 each) were designed for this prevention study. To assess the effect of preventing hyperuricemia during the period of the study. and fructose+allopurinol.Experiment II: prevention of fructose-induced hyperuricemia with allopurinol.
Body weight and the consumptionof food were measured weekly for 8 wk. All groups were fed with the control diet for 8 wk. the effect of benzbromarone. allopurinol. In this experiment. Sigma). n = 8 each) were studied. . Three groups (control. a uricosuricagent (150 mg/l in the drinking water.Experiment III: effect of lowering of uric acid by either allopurinol or benzbromarone on body weight and food consumption. was also examined to confirm the effect of lowering of uric acid on body weight and food intake. Fresh drinking water containing benzbromaronewas replaced every 2 days. and benzbromarone.
IL). Systolic blood pressure was assessed as the mean value of three consecutive measurements obtained in the morning using a tail-cuff sphygmomanometer (Visitech BP2000. NC). Serum uric acid was measured by the uricase method. CA). Rat insulin was measured by ELISA (Crystal Chem.y Measurements. . Chicago. Apex. Visitech Systems. All animals were preconditioned for blood pressure measurements 1 wk before each experiment. Blood glucose was measured with the ONE TOUCH system (Johnson&Johnson. Milpitas.
NJ) or a Triglyceride-SL assay kit (Diagnostic Chemicals. Serum lipids were measured with an autoanalyzer (VETAce.The insulin sensitivity index was calculated using the formula of Matsuda and DeFronzo [10. Charlottetown. Canada).73. . P < 0. PE.0001) with the rate of whole body glucose disposal during the euglycemic insulin clamp. Alfa Wassermann. which is highly correlated (r = 0.000/square root of (fasting glucose x fasting insulin) x (mean glucose x mean insulin during OGTT)]. West Caldwell.
total food intake per animal was calculated from the food left over. and uric acid were measured. Because experiment II showed that each rat normally eats 25 30 g/day. Rats were pair-fed with a 60% dextrose diet or a 60% fructose diet for 4 wk. we administered 25 g of the diet to each rat every day.425 g·rat 1·28 days 1). . after 5 h of fasting. a third group of fructose-fed rats was administered benzbromarone. both of which are isocaloric. insulin. At 4 wk.Experiment IV: comparison between 60% dextrose and 60% fructose in development of metabolic syndrome and effect of lowering uric acid with benzbromarone. Total food intake is the subtraction of the leftover food from the total food administered (1. At 4 wk. Their body weight was measured weekly. triglyceride. In addition to the above two groups.
fructose-fed rats had a lower urinary excretion of uric acid. 1B. allopurinol prevented the reduced excretion of uric acid in fructose-fed rats. To examine the role of uric acid in this model. we examined the urinary excretion of uric acid in these animals to clarify the mechanisms of hyperuricemia in fructose-fed rats. one-half of the fructose-fed rats were treated with allopurinol (a xanthine oxidase inhibitor) for 6 additional wk. . the body weight of fructose-fed rats tended to increase compared with rats fed a normal diet (Table 1). As shown in Fig. whereas the fructose-fed rats that did not receive treatment continued to be hyperuricemic (Fig. These data demonstrate that fructose feeding induces early features of metabolic syndrome in rats.Result: Serum uric acid levels. systolic blood pressure. In addition. and fasting insulin levels were elevated in fructose-fed rats compared with rats fed a control diet at 4 wk (Table 1). Interestingly. This treatment was effective at lowering uric acid. 1A). In addition.
Table 1. pmol/l 190±12 188±0. not significant. . Experiment I: general characteristics of control and fructose groups at 4 wk Control (n = 7) Fructose (n = 14) y y y y y Initial body weight. mg/dl Insulin at 4 wk.3 121±64 176±51 NS P=0. NS. g Body weight at 4 wk. of rats.1 357±15 375±22 127±3 148±15 1. n.05 P<0. g Systolic BP at 4 wk.3±0.05 Values are means ± SD.05 P<0.01 P<0.3 2. mmHg Uric acid at 4 wk. BP. blood pressure. No.4±0.
01 vs.01 vs.*P < 0. A: Fr rats are hyperuricemic at 9 wk. *P < 0. control. UA. #P < 0. C: hypertension develops in Fr rats. Effects of allopurinol (AP) treatment for hyperuricemia on metabolic parameters in fructose-fed (Fr) rats. #P < 0. uric acid.05 vs. which is significantly reduced by AP.05 vs. Fr. Fr. B: Fr reduced urinary excretion of UA at 9 wk. . and this is completely prevented by AP. blood pressure. #P < 0. 1. and this is prevented by AP. BP. #P < 0. Fr. Values are means ± SD. E: serum triglyceride level correlates directly with the serum UA.01 vs. control and Fr+AP. D: serum triglycerides (TG) are increased in Fr rats. control.01 vs. control.Fig.05 vs. and this is prevented by AP (150 mg/l). *P < 0.
.y Fructose Fed Rats (after 4 weeks) y Elevated serum uric acid levels y Elevated systolic blood pressure y Elevated fasting insulin y Increased body weight Generalization: fructose feeding induces early features of metabolic syndrome in rats.
and this was partially but significantly lower in allopurinol-treated rats (Fig. Allopurinol prevented the increase in body weight. Postprandial hyperinsulinemia also occurred in fructose-fed rats administered an OGTT. 1D). 2A).Fructose-fed rats treated with allopurinol showed an improvement in metabolic syndrome. Allopurinol significantly reduced systolic blood pressure in fructose-fed rats (Fig. 470 ± 28 g in control and 474 ± 37 g in fructose+allopurinol. although this did not reach significance (522 ± 57 g in fructose vs. 2B). 1C). While no groups developed fasting or postprandial hyperglycemia (Fig. resulting in improved insulin sensitivity (Fig. although pressures remained higher than that observed in control rats. fructose-fed rats developed fasting hyperinsulinemia that was reversed with allopurinol (Fig. 1E). P = not significant). Fructose-fed rats also showed an increase in body weight compared with controls. 2C). 2B). Fructose-fed rats also developed marked hypertriglyceridemia that was abolished by allopurinol treatment (Fig. . The reduction in serum uric acid correlated directly with the decrease in triglyceride levels (Fig.
y fructose fed rats fructose fed rats with alopurinol insulin levels insulin levels decreased prevented weight gain Hypertriglyceridemia control ------------------ .
P < 0. the elevation of uric acid with the fructose diet was prevented over the 6-wk period in fructose-fed rats.01). control. P < 0. At 8 wk. As shown in Fig. 3B).We also examined the effectiveness of allopurinol in preventing the development of metabolic syndrome. final weights in fructose vs. although this did not reach statistical significance . while fructosefed rats gained weight compared with control rats (456 ± 24 vs. and the development of hypertriglyceridemia was completely prevented (Fig. allopurinol-treated rats had lower weight gain (final weight 426 ± 26 g. 3D). Allopurinol-treated rats had significantly lower fasting insulin levels compared with fructosefed rats (Fig. Allopurinol was given simultaneously with the fructose diet from the starting point to avoid fructose-induced hyperuricemia. as opposed to treating rats to inhibit its progression. the total food intake over 3 days in fructose-fed rats was slightly higher (92 ± 2 g) compared with that of the fructose+allopurinol group (88 ± 4 g). In addition. fructose-fed rats). 3A.05 vs. 414 ± 24 g.
.Fructose Fed Rat with Allopurinol Treatment: y Fructose increases BP y Allopurinol treatment decrease BP y Fructose increases triglyceride level y Allopurinol treatment decreases triglyceride level in the blood y Fructose increases body weight y Allopurinol treatment prevents increase in weight but not significant y Allopurinol treatment decreases uric acid level in the blood same with triglyceride level y Allopurinol traetment improves insulin sensitivity.
C: AP also prevented the increase in body weight induced with fructose. A: AP (150 mg/l) prevented the rise in UA in Fr rats.Fig. Blocking of hyperuricemia in Fr rats with AP prevents features of metabolic syndrome. 3.05 vs. P < 0. control and Fr+AP. B: AP treatment was associated with significantly lower fasting insulin levels compared with Fr rats at 8 wk. Statistical analysis among 3 groups was by ANOVA with Bonferroni correction .
and hyperinsulinemia (Table 3). only the fructose-fed rats developed hyperuricemia. hypertriglyceridemia. Nevertheless. Finally. allopurinol or benzbromarone (a uricosuric agent) was administered to rats on control diets for 8 wk. these effects observed in fructose-fed rats were significantly improved by lowering uric acid levels with benzbromarone. A third group received the control diet alone. Total food consumption at 8 wk and final body weight were not different among the three groups (Table 2). the 3). Importantly. To address this possibility. In this experiment. we compared the effects of the 60% dextrose and 60% fructose diets on the development of metabolic syndrome. food intake was controlled so that each group received the same intake of calories and had the same weight gain.The observation that administration of allopurinol to fructose-fed rats prevented obesity led to additional studies to ensure that allopurinol did not have specific effects on food intake or body weight. uricosuric agent (Table .
mg/dl 162±7 469±69 1452±68 1.5 164±3 504±37 1562±118 0. of rats. Experiment III: effect of lowering uric acid on body weight and food consumption for 8 wk Control (n = 8) Allopurinol (n=8) Benzbromarone (n=8) Initial body weight.3 Values are means ± SD.5±0.5±0.4 160±8 468±43 1494±90 1. g Total food intake for 8 wk.Table 2. No. g Final body weight at 8 wk.1±0. . n. g Uric acid at 8 wk.
uric acid dose dependently blocked the vasorelaxation of AA rings in response to acetylcholine. we examined the acute effect of uric acid on acetylcholine-induced vasodilation of rat AA rings. . To further examine this relationship. 4. It is known that impaired NO response to insulin may be a mechanism for the development of insulin resistance (36). uric acid has been shown to potently reduce NO levels in cultured bovine endothelial cells (18). As shown in Fig. Previously.In Vitro Studies Endothelial dysfunction is common in metabolic syndrome.
. the segments were incubated with various concentrations of uric acid (0 15 mg/dl) in an organ bath chamber for 30 min.5 µM U-46619 (a thromboxae A2 mimetic. Stable construction was induced by 0. oxygenated with 95% O2-5% CO2 at 37°C. Holliston. Sigma)-mediated AA contraction or acetylcholine (5 µM)-mediated vasodilation.Vasorelaxation in Rat Aortic Artery Segment Rat aortic artery (AA) segments (1. After 1-h equilibration of resting force of 1.5 µM U-46619 for 10 min before acetylcholine-induced vasorelaxation. respectively. The vascular tensions were continuously monitored with an isometric force transducer (Harvard Apparatus. the vascular smooth muscle cell or endothelium integrity of this AA segment was confirmed by monitoring 0. To standardize the data. After being washed several times.5 g. MA).to 0. the U-46619-induced stable increase in vascular tone was set as 100%.to 3-mo-old rats and suspended in individual organ chambers (Radnoti Four-Unit Tissue Bath System) with 5 ml in Earl's solution.5-mm diameter x 3to 4-mm length) were isolated from 2.
y * P < 0. No. Experiment IV: effect of pair-feeding with 60% dextrose and 60% fructose diets at 4 wk on development of metabolic syndrome and of lowering uric acid with benzbromarone Dext 60% Fruc 60% Fruc 60% + Benzbromarone y y y y y y Initial body weight.1±0. n.3 Triglyceride at 4 wk.4±0.01 vs. of rats. g 700±10 Uric acid at 4 wk.y Values are means ± SD.01 vs. mg/dl 1.9* 419±6 204±62 144±7 360±20 698±15 1. dextrose. No. fructose. dextrose.1±0. y Table 3. fructose.4 293±86 147±42 Values are means ± SD. . mg/dl 112±28 Insulin at 4 wk. y P < 0. n. g 144±7 Final body weight at 4 wk. pmol/l 112±43 144±5 364±17 709±6 2.05 vs.05 vs. of rats. g 353±14 Total food intake for 4 wk. y P < 0. y P < 0.
control.5 µM). ACh (5 µM)-induced vasorelaxation was assessed in the presence of various concentrations of UA for 10 min after stable construction by U-46619 (0.7 mg/dl UA. 4. ##P < 0. 0.01 vs. #P < 0. n = 4.05 vs. UA inhibits AChmediated vasodilation in rat aortic artery segments.7 mg/dl UA.01 vs. *P < 0. 0. .Fig.
Hyperinsulinemia can also increase uric acid reabsorption. Fructose relatively increase uric acid levels in the blood. Dyslipidemia can increase systolic blood pressure by increasing blood viscosity. Hyperuricemia. . thereby increasing PVR resulting in increase in BP. It is because into the cell therefore it will develop hyperinsulinemia and hyperglycemia.In this study. Glucose intolerance can develop dyslipidemia by increasing lipid level by the flux of free fatty acid from adipocyte. And furtherby can develop complication in the heart or heart disease. can inhibit Nitric Oxide production that can developed hyperinsulinemia and glucose intolerance. metabolic syndrome is usually developed by the increase uric acid levels in the blood.
Both of this drug can lower serum uric acid thereby can also prevent hyperglycemia. Therefore correcting the disease of hypermetabolic syndrome.There are medications that lowers uric acid levels in the blood such as allopurinol or benzbromarone. hyperinsulinemia. . dyslipidemia. hypertension and obesity.
FRUCTOSE Increases URIC ACID Inhibits NO2 Hyperglycemia Glucose intolerance Hyperinsulinemia .
FFA flux from adipocyte Increase lipid in blood Acute (increases blood viscosity) Obesity Chronic (atherosclerosis) .
Increase PVR Increases BP Hypertension Cardiac Complications .
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