BASIC RESEARCH

Thiazide Diuretics Exacerbate Fructose-Induced Metabolic Syndrome

Sirirat Reungjui, Carlos A. Roncal, Wei Mu, Titte R. Srinivas, Dhavee Sirivongs, Richard J. Johnson and Takahiko Nakagawa
JASN October 2007, 18 (10) 2724-2731; DOI: https://doi.org/10.1681/ASN.2007040416

Abstract

Fructose is a commonly used sweetener associated with diets that increase the prevalence of metabolic syndrome. Thiazide diuretics are frequently used in these patients for treatment of hypertension, but they also exacerbate metabolic syndrome. Rats on high-fructose diets that are given thiazides exhibit potassium depletion and hyperuricemia. Potassium supplementation improves their insulin resistance and hypertension, whereas allopurinol reduces serum levels of uric acid and ameliorates hypertension, hypertriglyceridemia, hyperglycemia, and insulin resistance. Both potassium supplementation and treatment with allopurinol also increase urinary nitric oxide excretion. We suggest that potassium depletion and hyperuricemia in rats exacerbates endothelial dysfunction and lowers the bioavailability of nitric oxide, which blocks insulin activity and causes insulin resistance during thiazide usage. Addition of potassium supplements and allopurinol with thiazides might be helpful in the management of metabolic syndrome.

The metabolic syndrome (MS) is a constellation of risk factors for cardiovascular disease and type 2 diabetes and consists of abdominal obesity, hypertriglyceridemia, low HDL cholesterol, high BP, insulin resistance, and hyperglycemia.1,2 Endothelial dysfunction and hyperuricemia also are closely associated with MS.3,4

Hydrochlorothiazide (HCTZ) is beneficial in patients with hypertension because it reduces morbidity and mortality, especially the frequency of stroke and congestive heart failure.5,6 As a result, thiazides are recommended as the first-line therapy for hypertension.6 However, many patients with hypertension have MS. In turn, HCTZ usage, although critical in the management of hypertension, can have several adverse effects, such as electrolyte disorders (hypokalemia, hyponatremia, and hypomagnesemia), hyperuricemia, hyperlipidemia, and impairment of glucose metabolism in addition to volume depletion.7–10 These adverse effects result in the development or exacerbation of MS. Although low-dosage thiazides have led to a reduction of these adverse effects, they increase the incidence of new onset of diabetes9 and can be associated with hypokalemia, hyperuricemia, and hyperlipidemia.11

Understanding the precise mechanisms by which HCTZ exacerbates MS is important. Some evidence suggests that thiazide-induced hypokalemia may mediate insulin resistance.12,13 In addition, experimental hyperuricemia can cause endothelial dysfunction,3,14 hypertension,15 and hyperinsulinemia.3,16 Furthermore, we recently reported that hyperuricemia causes the development of MS, and allopurinol, which lowers uric acid levels, improves these features of MS in fructose (F)-fed rats.3 We therefore hypothesized that hypokalemia and hyperuricemia may be primary mechanisms by which the thiazides facilitate the MS and that acceleration of MS by thiazides may be prevented by potassium (K) supplementation and allopurinol.

In this study, we administered thiazides to rats with MS, because this syndrome is common in patients with hypertension and it is important to determine whether thiazides can exacerbate its features. Although there are various models of MS in animals, we selected the F-induced model of MS. Indeed, the increasing incidence of MS in humans in the past two decades coincides with a marked increase in F intake.17,18 Importantly, that high F consumption causes features of the MS has been documented in clinical studies.19–21 Similarly, high-F diets cause MS in rodents, including hypertension, insulin resistance, and hypertriglyceridemia.3,22,23 In this study, we hypothesized that HCTZ use exacerbates F-induced MS and examined the role of hypokalemia and hyperuricemia in this process.

RESULTS

Body Weights

All rats were pair fed to eliminate effects of food intake on the results, which can influence glucose, insulin, and triglyceride levels. Although this will not allow us to determine whether thiazides can cause weight gain because access was not ad libitum, it did allow us to determine whether thiazides alter triglyceride and glucose levels independent of effects on food intake. As such, the average body weights were similar in all groups at week 20, as shown in Table 1.

View this table:
Table 1.

Renal function, serum K, serum Mg2+, and urinary uric acid excretion evaluated at week 20 of the study

F-Induced Features of MS in Rats

At week 4, the F-fed rats developed early features of MS, including hypertension (Figure 1), hypertriglyceridemia (normal diet 125 ± 55 versus F 325 ± 104 mg/dl; P < 0.001) and hyperuricemia (normal diet 1.7 ± 0.3 versus F 2.2 ± 0.4 mg/dl; P = 0.01). Serum cholesterol was significantly higher at week 14 (Figure 2). No significant difference in serum glucose was observed between the F group and the normal diet group (Figure 2).

Figure 1.
Figure 1.

SBP at weeks 4 and 16. The rats receiving F develop hypertension. HCTZ reduces the SBP. KCL further reduces BP at week 16. Similarly, allopurinol reduces BP reduction at both weeks 4 and 16. Data are means ± SD. P at least <0.05 *versus normal diet, &versus F, $versus F+HCTZ, and #versus F+HCTZ+KCL.

Figure 2.
Figure 2.

Time courses of serum uric acid (A), serum glucose (B), serum cholesterol (C), and serum triglycerides (D). The rats receiving F developed hyperuricemia and hypertriglyceridemia throughout the study. Hypercholesterolemia was detected at week 14. The combination of HCTZ with F causes more hyperuricemia and hyperglycemia as shown at weeks 14 and 20. Serum cholesterol and triglyceride are numerically higher with HCTZ use but did not reach statistical significance. KCL tends to reduce serum glucose at week 20 (P = 0.06). Allopurinol treatment significantly reduces serum uric acid and triglycerides at all time points and serum glucose at week 20. Data are means ± SD. P at least <0.05 *versus normal diet, &versus F, $versus F+HCTZ, and #versus F+HCTZ+KCL.

HCTZ Reduced Systolic BP but Aggravated F-Induced MS

HCTZ use reduced systolic BP (SBP) in the F+HCTZ group compared with the F group at weeks 4 and 16 (Figure 1). The level of serum K was significantly lower in the F+HCTZ and F+HCTZ+allopurinol groups at week 20, whereas all HCTZ-treated rats also developed hypomagnesemia (Table 1). An increase of serum HCO3− was also observed (F 23.0 ± 0.9; F+HCTZ 24.7 ± 1.1; F+HCTZ+KCL 25.6 ± 1.8; F+HCTZ+allopurinol 25.7 ± 1.5 mEq/L; all P <0.05 versus the F group).

HCTZ use did not exacerbate MS early at week 4; the metabolic profile of the F group and the F+HCTZ group was similar at this time. However, HCTZ aggravated insulin resistance (Figure 3) and hyperuricemia at week 14 (F 2.2 ± 0.5 versus F+HCTZ 2.7 ± 0.5 mg/dl; P = 0.04) and at week 20 (F 2.2 ± 0.6 versus F+HCTZ 2.8 ± 0.6 mg/dl; P = 0.02). Serum glucose was also increased by HCTZ at week 14 (F 150 ± 10 versus F+HCTZ 176 ± 13 mg/dl; P = 0.006) and at week 20 (F 160 ± 26 versus F+HCTZ 186 ± 22 mg/dl; P = 0.02). Although serum triglycerides were higher in the F+HCTZ group, they did not reach statistical significance (Figure 2).

Figure 3.
Figure 3.

QUICKI at week 14. The combination of F+HCTZ significantly lowers insulin sensitivity than the normal diet or the F. Treatment with allopurinol improves insulin sensitivity. KCL tends to improve insulin sensitivity, but this was NS. Data are means ± SD. P < 0.05 *versus normal diet, &versus F, and $versus F+HCTZ.

K Supplementation Reduced SBP and Improved Insulin Resistance

K supplementation significantly reduced SBP in F+HCTZ+KCL rats at week 16 (F+HCTZ 136 ± 4 versus F+HCTZ+KCL 131 ± 5 mmHg; P = 0.04), whereas no effect was observed at week 4 (F+HCTZ 129 ± 5 versus F+HCTZ+KCL 127 ± 3 mmHg; P > 0.05). By insulin tolerance test, serum glucose was not decreased despite insulin administration in the F+HCTZ group, whereas insulin-induced reduction of serum glucose was observed in the F+HCTZ+KCL group (Figure 4). These data suggest that K supplementation improves insulin sensitivity, which was deteriorated by fructose with HCTZ. Compatibly, K supplementation tended to lower serum glucose at week 20 (F+HCTZ 186 ± 22 versus F+HCTZ+KCL 166 ± 20 mmHg; P = 0.06). No significant change of serum uric acid and serum triglycerides was observed in the F+HCTZ+KCL group compared with the F+HCTZ group.

Figure 4.
Figure 4.

The insulin tolerance test at week 18. Blood glucose levels were not lowered by insulin in rats receiving F with or without HCTZ, consistent with insulin resistance. In contrast, KCL and allopurinol treatment improve the insulin response similar to that observed with the normal diet group. Data are means ± SD. P at least <0.05 *versus normal diet, &versus fructose diet, and $versus F+HCTZ.

Lowering Uric Acid with Allopurinol Improved Hypertension, Hypertriglyceridemia, Hyperglycemia, and Insulin Resistance

Allopurinol treatment significantly reduced the level of serum uric acid in the F+HCTZ group. In addition, allopurinol significantly reduced SBP (Figure 1), and serum triglycerides were also significantly lower than the F+HCTZ group at weeks 4, 14, and 20 (Figure 2).

Insulin resistance was improved by allopurinol (Figures 3 and 4). In addition, serum glucose was significantly lower at week 20 (F+HCTZ 186 ± 22 versus F+HCTZ+allopurinol 166 ± 14 mg/dl; P = 0.04).

To investigate further the role of uric acid, we examined the correlation between uric acid and other factors. When individual data on rats were examined at week 20, serum uric acid positively correlated with serum triglycerides, serum cholesterol, and serum glucose (Figure 5). Furthermore, there was a significant correlation between serum uric acid and SBP at week 4 (r = 0.53, P = 0.003) and serum insulin at week 14 (r = 0.42, P = 0.009).

Figure 5.
Figure 5.

Correlations of various metabolic factors in fructose/HCTZ-induced MS in the rat.

Insulin and Other Factors

At week 14, serum insulin concentrations in normal, F, F+HCTZ, F+HCTZ+KCL, and F+HCTZ+allopurinol groups were 1846 ± 452, 2561 ± 1286, 3449 ± 1200, 3058 ± 1514, and 2319 ± 971 pg/ml, respectively. Significant differences of serum insulin were detected between F+HCTZ and normal (P = 0.002) and borderline significance between F+HCTZ and F+HCTZ+allopurinol (P = 0.05). Serum insulin levels positively correlated not only with serum glucose but also with serum triglycerides and serum cholesterol (Figure 5), suggesting an association between insulin resistance and dyslipidemia.24,25

Renal Function and Urinary Excretion of Sodium, K, and Uric Acid

Although there was no significant difference in serum creatinine between groups, an increased urinary protein excretion by F suggests renal dysfunction. However, an elevation of blood urea nitrogen (BUN) in all HCTZ-treated groups (groups 3, 4, and 5) could be attributed to volume depletion induced by HCTZ, because F did not raise BUN.

With respect to urinary electrolytes, HCTZ significantly increased daily urinary sodium excretion at week 1 (normal 0.4 ± 0.2; F 0.5 ± 0.1; F+HCTZ 0.8 ± 0.4; F+HCTZ+KCL 0.8 ± 0.2; and F+HCTZ+allopurinol 0.9 ± 0.3 mEq/d; all P < 0.05 versus normal or F). Urinary K excretion was also significantly higher in the F+HCTZ group (1.5 ± 0.4 mEq/d) and the F+HCTZ+allopurinol group (1.4 ± 0.3 mEq/d) as compared with the F group (1.2 ± 0.1 mEq/d). Because of K supplementation, the F+HCTZ+KCL group had normal serum K level with high urine K (3.1 ± 1.1).

The F group developed hyperuricemia (Figure 2) with higher urinary uric acid excretion per day and uric acid clearance compared with the normal group (Table 1), which suggested an increase of uric acid production. Similar to that observed in humans, HCTZ enhanced hyperuricemia (Figure 2), which could be attributed to a reduction of urinary uric acid excretion (Table 1). Allopurinol acutely reduced 32.3% of urinary uric acid excretion compared with the F+HCTZ group during the first week (P < 0.05), which could be due to a reduced production of uric acid by allopurinol. However, it is of note that urinary uric acid excretion and uric acid clearance increased during the chronic phase despite allopurinol use (Table 1).

K Supplementation or Allopurinol Increase Urinary Nitric Oxide Excretion

Urine nitrate/nitrite excretion is a marker of nitric oxide (NO) bioavailability as well as endothelial function.26,27 F decreased urine nitrate/nitrites, which were further lowered by HCTZ. However, K supplementation or allopurinol treatment increased urinary nitrate/nitrite excretion (Figure 6).

Figure 6.
Figure 6.

Urine nitrate/nitrite level. The levels of urinary nitrate and nitrite in rats receiving F are lower than that observed in the normal diet group. HCTZ induces a further reduction of urinary nitrate and nitrite. KCL and allopurinol treatment increases the level of urinary nitrate and nitrite compared with the F+HCTZ. Data are means ± SD. P at least <0.05 *versus normal diet, &versus F, and $versus F+HCTZ.

DISCUSSION

The principal new finding in this study is that we can show experimentally that correcting the serum K and uric acid abnormalities in F-induced MS in rats can largely prevent the metabolic abnormalities that are associated with thiazides. The beneficial effects of these treatments were associated with an increase in urine nitrite/nitrates, suggesting the involvement of endothelial dysfunction on the development of MS with thiazide usage.

Hypokalemia occurs in 6.5 to 50% of patients receiving diuretics,28–30 with the average reduction of serum K from thiazides reported at approximately 0.3 to 1.1 mEq/L.6,31,32 Previous studies suggested that hypokalemia may be a factor causing hyperglycemia, hyperinsulinemia, and insulin resistance in patients receiving thiazides, because these features can be improved with K supplements.13,33 It also has been shown that K depletion, even without frank hypokalemia, can cause insulin resistance.34 In our experiments, HCTZ produced a significant reduction in serum K (0.3 mEq/L), although this did not reach the criteria of hypokalemia (serum K <3.5 mEq/L). Our important finding is that this mild K depletion was significantly associated with exacerbation of hyperglycemia, insulin resistance, and a reduction of urine NO excretion, all of which were corrected by K supplementation. The observation that K supplements prevented the reduction of urine NO in F-fed rats receiving HCTZ is consistent with an improvement in endothelial function. K supplementation has been shown to act as an endothelium-derived hyperpolarizing factor35 and release NO to preserve endothelial function,36 whereas K depletion was found to attenuate endothelial-dependent vasorelaxation.37 In turn, an inhibition of endothelial NO is known to cause insulin resistance.38

Unlike glucose, F is the only sugar that rapidly increases serum uric acid in humans as well as rodents.3 Recently, we found that F-induced hyperuricemia has a causal role in the pathogenesis of MS.3 This study demonstrated that HCTZ enhanced hyperuricemia in rats receiving a high-F diet by reducing urinary uric acid excretion, although F likely increases the production of uric acid. Decreased urinary uric acid excretion could be due to an increase in uric acid reabsorption in proximal tubule, which may be mediated by thiazide-induced volume contraction.39

Another important finding is that the lowering of serum uric acid by allopurinol was associated with an improvement of the features of MS. We also found that a lowering of uric acid by allopurinol was associated with an increase in urinary NO excretion. Given that uric acid inhibits endothelial NO bioavailability as well as endothelial function,3,14,40 a lowering of uric acid could improve endothelial function in this model. Collectively, these findings suggest that hyperuricemia, by virtue of reducing NO, plays a role in the pathogenesis of the MS aggravated with HCTZ.

The inhibition of uric acid production by allopurinol likely accounts for the reduction of urinary uric acid excretion during the first week. However, with long-term allopurinol treatment, the reduction in uric acid excretion was not observed. Although the precise mechanism remains unknown, hyperuricemic rats are known to develop renal vasoconstriction with a reduction of renal blood flow, and this is reversed by allopurinol.41 In turn, an increase in renal blood flow will result in increased uric acid excretion.42 In this scenario, by improving endothelial dysfunction and renal blood flow, the lowering of uric acid could paradoxically enhance excretion.

The effect of high F intake on insulin sensitivity is still debated. As recently reviewed,43 some groups have observed that healthy individuals develop insulin resistance after high F consumption, whereas others have reported no effect on glucose metabolism as well as insulin sensitivity. One reason for this discrepancy is dosage. For example, when 1000 kcal is given, insulin resistance develops in 1 wk19; when 864 kcal/d is consumed, insulin resistance is observed only in organs with high fructokinase activity (liver, fat cells) and takes 4 wk20; and when lower dosages are given, no insulin resistance is observed, even after 1 mo.21 Similar situations occur in the rat. With high dosages (60% F), insulin resistance occurs within 4 to 8 wk3; with dosages similar to that in the current American diet (15% total energy intake), it takes slightly more than 1 yr.44 However, the rat is more resistant because it has low uric acid levels; indeed, if uricase is inhibited, then 20% F will induce hyperinsulinemia rapidly.45 Furthermore, F, by virtue of increasing the circulation of fatty acids, may lead to the ectopic deposition of fat in liver and skeletal muscle that will cause insulin resistance indirectly.46 This indirect induction of insulin resistance by F could also account for the discrepancy in some of these studies. Because F and its metabolites fructose-3-phosphate and 3-deoxyglucosone cause oxidative stress and nonenzymatic glycation,47 the polyol pathway could also be involved in development of MS.

This study demonstrates that HCTZ aggravates the MS in F-fed rats and that K supplementation and reducing uric acid levels may provide some protection. Nevertheless, it will be important to determine whether similar protection can be provided by these maneuvers in humans. In this regard, we are involved in a randomized, controlled trial to determine whether lowering of uric acid will improve features of MS associated with thiazide use in black individuals with stage 1 hypertension.

CONCISE METHODS

All animal studies were approved by the University of Florida Institutional Animal Use and Care Committee.

Pilot Studies

Because variable dosages of HCTZ have been commonly used in other studies (e.g., 3 to 80 mg/kg per d48,49), we performed pilot studies to determine the minimum adequate dosage of HCTZ for this study. Because the aim of study was to examine the role of hypokalemia on adverse effects of HCTZ, we identified the lowest dosage that can reduce BP along with a mild reduction of serum K. We therefore gave three different dosages of HCTZ (Sigma-Aldrich, St. Louis, MO) to normal rats. As a result, we found that 10 mg/kg per d HCTZ is the lowest dosage that reduced BP and induced mild hypokalemia.

Experimental Protocol

Male Sprague-Dawley rats (150 to 200 g; Charles River, Wilmington, MA) were placed on a standard diet (Harlan, Madison, WI) for a 5-d run-in period, then the rats were divided into five groups (n = 8) with similar body weight and baseline blood chemistry: Group 1: Normal standard diet (Harlan); group 2 (F): 60% fructose diet (Harlan); group 3 (F+HCTZ): In addition to 60% fructose diet, HCTZ 10 mg/kg per d was supplied in drinking water; group 4 (F+HCTZ+KCL): 60% F diet with HCTZ and 1% K chloride (KCL) in drinking water; the concentration of KCL in drinking water was increased at weeks 5 (1.5% KCL), 15 (1.75% KCL), and 17 (2% KCL) to maintain normal serum K+ level through the whole study; and group 5 (F+HCTZ+allopurinol): 60% F diet plus HCTZ and allopurinol 150 mg/L (Sigma-Aldrich) in drinking water.

We pair-fed rats to ensure equivalent caloric intake, thereby avoiding the influence of different food intake on the metabolic abnormalities. Body weight was measured weekly. At weeks 1, 4, 14, and 20, metabolic cages were used for urine collection overnight, where water but no food was freely accessed. After 4 h of fasting, serum was also collected from the tail vein at weeks 4, 14, and 20. At the end of week 20, rats were killed.

Tail-Cuff BP Measurement

SBP was measured in conscious rats with tail-cuff sphygmomanometer (Visitech BP2000, Apex, NC) at weeks 4 and 16 as described previously.3

Biochemical Measurements

Serum and urine K concentrations were determined with the atomic absorption spectrophotometer (Perkin-Elmer 306, Downers Grove, IL). By use of an autoanalyzer (VetAce; Alfa Wassermann, West Caldwell, NJ), the routine chemistries including glucose, cholesterol, triglycerides, uric acid, BUN, and creatinine were measured in serum. In addition, urine protein concentration and urine creatinine were determined.

Serum Insulin and the Quantitative Insulin Sensitivity Check Index

Fasting serum glucose and insulin were obtained at week 14. Serum insulin was determined with the rat insulin ELISA kit (Crystal Chem, Chicago, IL). Quantitative Insulin Sensitivity Check Index (QUICKI) is a mathematical model based on log-transformed fasting plasma glucose and insulin values by equal 1/(log [glucose] + log [insulin]). QUICKI predicts insulin sensitivity, with lower values representing more insulin resistance. QUICKI shows a good correlation with the hyperinsulinemic-euglycemic clamp method, especially in individuals with impaired glucose tolerance.50

Insulin Tolerance Test

At week 18, 0.75 U/kg recombinant human insulin (Novolin; Novo Nordisk, Princeton, NJ) was administered intraperitoneally after rats had been fasted for 16 h. Blood glucose was determined on tail blood via hand-held blood glucose monitor (OneTouch; Johnson & Johnson, Milpitas, CA) at five points: 0, 15, 30, 45, and 60 min after insulin injection.

Measurement of Urinary NO

Urine was determined for NO by using the nitrate/nitrite colorimetric assay kit (Cayman Chemical Co., Ann Arbor, MI).

Statistical Analyses

All data are shown as means ± SD. One-way ANOVA (SPSS 14.0; SPSS, Chicago, IL) and post hoc multiple comparisons were used to determine the significance between the mean of multiple groups with the least-significant difference test for equal and Dunnett test for unequal variances. The homogeneity of variance was clarified by Levene test. The paired and unpaired t tests were used to compare the continuous variables of the specific two groups. Pearson correlation was used to address potential associations between groups. Statistical significance was defined as P < 0.05.

DISCLOSURES

T.N., S.R., and R.J.J. are listed as inventors on several patent applications related to uric acid and cardiovascular disease from the University of Florida or University of Washington. R.J.J. is also on the Scientific Board of Nephromics, Inc.

Acknowledgments

The work was supported by funding from the National Institutes of Health grants DK-52121, HL-68607, and HL-79352 and funds from Gatorade. S.R. is supported by a fellowship from the Anandamahidol Foundation of Thailand.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • See related editorial, “The Fructose Nation,” on pages 2619–2621.

REFERENCES

  1. ↵
    Hall WD, Watkins LO, Wright JT Jr, Wenger NK, Kumanyika SK, Gavin JR 3rd, Ferdinand KC, Watson K, Clark LT, Flack JM, Reed JW, Horton EW, Saunders E; African-American Lipid and Cardiovascular Council: The metabolic syndrome: Recognition and management. Dis Manag 9 : 16 –33, 2006
    OpenUrlCrossRefPubMed
  2. ↵
    Liberopoulos EN, Mikhailidis DP, Elisaf MS: Diagnosis and management of the metabolic syndrome in obesity. Obes Rev 6 : 283 –296, 2005
    OpenUrlCrossRefPubMed
  3. ↵
    Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ: A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 290 : F625 –F631, 2006
    OpenUrlCrossRefPubMed
  4. ↵
    Deedwania PC: Mechanisms of endothelial dysfunction in the metabolic syndrome. Curr Diab Rep 3 : 289 –292, 2003
    OpenUrlCrossRefPubMed
  5. ↵
    Turnbull F: Effects of different blood-pressure-lowering regimens on major cardiovascular events: Results of prospectively-designed overviews of randomized trials. Lancet 362 : 1527 –1535, 2003
    OpenUrlCrossRefPubMed
  6. ↵
    The ALLHAT Study Group: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium-channel blocker vs. diuretic. JAMA 288 : 2981 –2997, 2002
    OpenUrlCrossRefPubMed
  7. ↵
    Plavinik FL, Rodrigues CI, Zanella MT, Ribeiro AB: Hypokalemia, glucose intolerance, and hyperinsulinemia during diuretic therapy. Hypertension 19[Suppl 2] : 1126 –1129, 1992
    OpenUrl
  8. Punzi HA, Punzi CF; Antihypertensive and Lipid-Lowering Heart Attack Trial Study; Trinity Hypertension Research Institute: Metabolic issues in the Antihypertensive and Lipid-Lowering Heart Attack Trial Study. Curr Hypertens Rep 6 : 106 –110, 2004
    OpenUrlCrossRefPubMed
  9. ↵
    Verdecchia P, Reboldi G, Angeli F, Borgioni C, Gattobigio R, Filippucci L, Norgiolini S, Bracco C, Porcellati C: Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension 43 : 963 –969, 2004
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW, Applegate WB: Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program. J Hypertens 18 : 1149 –1154, 2000
    OpenUrlCrossRefPubMed
  11. ↵
    Lindholm LH, Persson M, Alaupovic P, Carlberg B, Svensson A, Samuelsson O: 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). J Hypertens 21 : 1563 –1574, 2003
    OpenUrlCrossRefPubMed
  12. ↵
    Amery A, Birkenhager W, Brixko P, Bulpitt C, Clement D, Deruyttere M, De Schaepdryver A, Fagard R, Forette F, Forte J: Glucose intolerance during diuretic therapy in elderly hypertensive patients. A second report from the European Working Party on high blood pressure in the elderly (EWPHE). Postgrad Med J 62 : 919 –924, 1986
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Andersson OK, Gudbrandsson T, Jamerson K: Metabolic adverse effects of thiazide diuretics: The importance of normokalaemia. J Intern Med Suppl 735 : 89 –96, 1991
    OpenUrlPubMed
  14. ↵
    Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ: Hyperuricemia induces endothelial dysfunction. Kidney Int 67 : 1739 –1742, 2005
    OpenUrlCrossRefPubMed
  15. ↵
    Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, Lan HY, Kivlighn S, Johnson RJ: Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 38 : 1101 –1106, 2001
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Nakagawa T, Tuttle KR, Short RA, Johnson RJ: Hypothesis: Fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome. Nat Clin Pract Nephrol 1 : 80 –86, 2005
    OpenUrlCrossRefPubMed
  17. ↵
    Bray GA, Nielsen SJ, Popkin BM: Consumption of high-fructose corn syrup in beverages may play a role in the epidermic of obesity. Am J Clin Nutr 79 : 537 –543, 2004
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Schulze MB, Manson JE, Ludwig DS, Colditz GA, Stampfer MJ, Willett WC, Hu FB: Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. JAMA 292 : 927 –934, 2004
    OpenUrlCrossRefPubMed
  19. ↵
    Beck-Nielsen H, Pedersen O, Lindskov HO: Impaired cellular insulin binding and insulin sensitivity induced by high-fructose feeding in normal subjects. Am J Clin Nutr 33 : 273 –278, 1980
    OpenUrlAbstract/FREE Full Text
  20. ↵
    Faeh D, Minehira K, Schwarz JM, Periasamy R, Park S, Tappy L: Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men. Diabetes 54 : 1907 –1913, 2005
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Le KA, Faeh D, Stettler R, Ith M, Kreis R, Vermathen P, Boesch C, Ravussin E, Tappy L: A 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humans. Am J Clin Nutr 84 : 1374 –1379, 2006
    OpenUrlAbstract/FREE Full Text
  22. ↵
    Sharabi Y, Oron-Herman M, Kamari Y, Avni I, Peleg E, Shabtay Z, Grossman E, Shamiss A: Effect of PPAR-gamma agonist on adiponectin levels in the metabolic syndrome: Lessons from the high fructose fed rat model. Am J Hypertens 20 : 206 –210, 2007
    OpenUrlCrossRefPubMed
  23. ↵
    Delbosc S, Paizanis E, Magous R, Araiz C, Dimo T, Cristol JP, Cros G, Azay J: Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat. Atherosclerosis 179 : 43 –49, 2005
    OpenUrlCrossRefPubMed
  24. ↵
    Grundy SM: Atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance. Clin Cornerstone 8[Suppl 1] : S21 –S27, 2006
    OpenUrl
  25. ↵
    Avramoglu RK, Basciano H, Adeli K: Lipid and lipoprotein dysregulation in insulin resistant states. Clin Chim Acta 368 : 1 –19, 2006
    OpenUrlCrossRefPubMed
  26. ↵
    Puddu P, Puddu GM, Zaca F, Muscari A: Endothelial dysfunction in hypertension. Acta Cardiol 55 : 221 –232, 2000
    OpenUrlCrossRefPubMed
  27. ↵
    Sousa T, Fernandes E, Nunes C, Laranjinha J, Carvalho F, Pinho D, Morato M, Albino-Teixeira A: Scavenging of nitric oxide by an antagonist of adenosine receptors. J Pharm Pharmacol 57 : 399 –404, 2005
    OpenUrlCrossRefPubMed
  28. ↵
    Frishman WH, Burris JF, Mroczek WJ, Weir MR, Alemayehu D, Simon JS, Chen SY, Bryzinski BS: First-line therapy option with low-dose bisoprolol fumarate and low-dose hydrochlorothiazide in patients with stage I and stage II systemic hypertension. J Clin Pharmacol 35 : 182 –188, 1995
    OpenUrlPubMed
  29. Widimsky J, Cifkova R: The heart in hypertension and arrhythmias. Herz 15 : 49 –53, 1990
    OpenUrlPubMed
  30. ↵
    Bloomfield RL, Wilson DJ, Buckalew VM Jr: The incidence of diuretic-induced hypokalemia in two distinct settings. J Clin Hypertens 2 : 331 –338, 1986
    OpenUrlPubMed
  31. ↵
    Hollifield JW, Slaton PE: Thiazide diuretics, hypokalemia and cardiac arrhythmias. Acta Med Scand Suppl 647 : 67 –73, 1981
    OpenUrlPubMed
  32. ↵
    Moser M: Low-dose diuretic therapy for hypertension: Clin Ther 8 : 554 –562, 1986
    OpenUrlPubMed
  33. ↵
    Helderman JH, Elahi D, Andersen DK, Raizes GS, Tobin JD, Shocken D, Andres R: Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium. Diabetes 32 : 106 –111, 1983
    OpenUrlAbstract/FREE Full Text
  34. ↵
    Norbiato G, Bevilacqua M, Meroni R, Raggi U, Dagani R, Scorza D, Frigeni G, Vago T: Effects of potassium supplementation on insulin binding and insulin action in human obesity: Protein-modified fast and refeeding. Eur J Clin Invest 14 : 414 –419, 1984
    OpenUrlCrossRefPubMed
  35. ↵
    Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH: K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 396 : 269 –272, 1998
    OpenUrlCrossRefPubMed
  36. ↵
    Sudhir K, Kurtz TW, Yock PG, Connolly AJ, Morris RC: Potassium preserves endothelial function and enhances aortic compliance in Dahl rats. Hypertension 22 : 315 –322, 1993
    OpenUrlAbstract/FREE Full Text
  37. ↵
    Yang BC, Li DY, Weng Y, Lynch J, Wingo CS, Mehta JL: Increased superoxide anion generation and altered vasoreactivity in rabbits on low-potassium diet. Am J Physiol 274 : 1955 –1961, 1998
    OpenUrl
  38. ↵
    Nakagawa T, Sato W, Glushakova O, Heinig M, Clarke T, Campbell-Thompson M, Yuzawa Y, Atkinson MA, Johnson RJ, Croker B: Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. J Am Soc Nephrol 18 : 539 –550, 2007
    OpenUrlAbstract/FREE Full Text
  39. ↵
    Iwaki K, Yonetani Y: Decreased renal excretion of uric acid following diuretic administration in rats. Jpn J Pharmacol 34 : 389 –396, 1984
    OpenUrlPubMed
  40. ↵
    Zoccali C, Maio R, Mallamaci F, Sesti G, Perticone F: Uric acid and endothelial dysfunction in essential hypertension. J Am Soc Nephrol 17 : 1466 –1471, 2006
    OpenUrlAbstract/FREE Full Text
  41. ↵
    Sanchez-Lozada LG, Tapia E, Avila-Casado C, Soto V, Franco M, Santamaria J, Nakagawa T, Rodriguez-Iturbe B, Johnson RJ, Herrera-Acosta J: Mild hyperuricemia induces glomerular hypertension in normal rats. Am J Physiol Renal Physiol 283 : F1105 –F1110, 2002
    OpenUrlCrossRefPubMed
  42. ↵
    Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, Rodriguez-Iturbe B, Herrera-Acosta J, Mazzali M: Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 41 : 1183 –1190, 2003
    OpenUrlAbstract/FREE Full Text
  43. ↵
    Havel PJ: Dietary fructose: Implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism. Nutr Rev 63 : 133 –157, 2005
    OpenUrlCrossRefPubMed
  44. ↵
    Blakely SR, Hallfrisch J, Reiser S, Prather ES: Long-term effects of moderate fructose feeding on glucose tolerance parameters in rats. J Nutr 111 : 307 –314, 1981
    OpenUrlAbstract/FREE Full Text
  45. ↵
    Sanchez-Lozada LG, Lopez-Molina R, Soto V, Tapia E, Avila-Casado C, Bautista R, Nakagawa T, Franco M, Johnson RJ: Low fructose caloric intake concomitant to hyperuricemia induces hyperinsulinemia and renal structural damage in rats [Abstract]. J Am Soc Nephrol 2007 . The authors will present this study as poster in the ASN meeting 2007 and they are doing more experiments to complete the study.
  46. ↵
    Kelley DE, Goodpaster BH, Storlien L: Muscle triglyceride and insulin resistance. Annu Rev Nutr 22 : 325 –346, 2002
    OpenUrlCrossRefPubMed
  47. ↵
    Chung SS, Ho EC, Lam KS, Chung SK: Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol 14[Suppl] : S233 –S236, 2003
    OpenUrlAbstract/FREE Full Text
  48. ↵
    Webb RL, Navarrete AE, Davis S: Effects of valsartan and hydrochlorothiazide alone and in combination on blood pressure and heart rate in conscious-telemetered spontaneously hypertensive rats (SHR). Am J Hypertens 11 : 59 –65, 1998
    OpenUrlCrossRefPubMed
  49. ↵
    Kobayashi H, Sano T, Tarazi RC, Fouad-Tarazi FM: Effects of antihypertensive drugs on heart and resistance vessels. Cardiovasc Res 24 : 137 –143, 1990
    OpenUrlCrossRefPubMed
  50. ↵
    Straczkowski M, Stepien A, Kowalska I, Kinalska I: Comparison of simple indices of insulin sensitivity using the euglycemic hyperinsulinemic clamp technique. Med Sci Monit 10 : CR480 –CR484, 2004
    OpenUrlPubMed
Back to top

In this issue

View Selected Citations (0)
Print
Download PDF
Email Article
Citation Tools
Request Permissions
Thiazide Diuretics Exacerbate Fructose-Induced Metabolic Syndrome
Sirirat Reungjui, Carlos A. Roncal, Wei Mu, Titte R. Srinivas, Dhavee Sirivongs, Richard J. Johnson, Takahiko Nakagawa
JASN Oct 2007, 18 (10) 2724-2731; DOI: 10.1681/ASN.2007040416
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section