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Editorial 2001-1091

Gout, Diet, and the Insulin Resistance Syndrome
ADEL G. FAM, MD, FRCPC,
Professor of Medicine,
Sunnybrook and Women's Health Sciences Centre,
University of Toronto,
2075 Bayview Avenue, M1-402,
Toronto, Ontario, Canada M4N 3M5
Address reprint requests to Dr. Fam.

Gout, one of the oldest known forms of arthritis, is characterized by chronic hyperuricemia (serum urate > 450 µmol/l or 7.0 mg/dl in men; and > 350 µmol/l or 6.0 mg/dl in women), recurrent attacks of acute arthritis provoked by the release of monosodium urate crystals into synovial spaces, and eventual development in some patients of urate tophi and chronic tophaceous gouty arthritis. Uric acid is the end product of purine metabolism1-3. About one-third of the human daily purine load is from diet, while two-thirds is generated endogenously. In the majority of patients with primary gout, hyperuricemia results from relative renal urate underexcretion ("relative urate underexcretors"), while in about 10% of subjects, hyperuricemia is due to endogenous overproduction of uric acid ("urate overproducers")2,3. Although gout is one of the better understood of the rheumatic diseases, and certainly one of the most gratifying to treat, a number of management issues, including the role of dietary measures, remain uncertain4.

DIETARY FACTORS IN THE PATHOGENESIS OF HYPERURICEMIA AND GOUT

Being a metabolic disorder, gout is significantly influenced by dietary factors that include overeating, obesity, alcohol abuse, dyslipidemia, and insulin resistance syndrome1,5-8. The connection of gout with gluttony, overindulgence in food and alcohol, and obesity dates from ancient times. In the 5th century BC, Hippocrates attributed gout to excessive intake of food and wine9. For treatment, he recommended dietary restriction and reduction of alcoholic beverages, and for acute attacks, the best medicine was large doses of white hellebore — a powerful purgative. The "status" of gout as a disease of the wealthy has survived over the centuries — if not in fact, in myth. Nearly all accounts of gout emphasize the role of overeating and of excessive consumption of alcohol in the causation of the disease; the "grog-blossom" nose is sometimes considered a marker of gout. In 1713, John Martin wrote in The Attila of the Gout: "as to the first and remote, or procatarctic causes of gout, there has been little wrangling among the physicians. The general opinion is that drunkenness & gluttony are the father & mother of this distemper, and that a moist air, too much sleep, want of exercise and sloth, are necessary causes. They likewise agree that excess of venery has no small hand in the production of it..."10. Several epidemiological studies have demonstrated a strong correlation between obesity and hyperuricemia1,5-7,10-12. Thus, 3.4% of subjects with a relative weight below the 20th percentile are hyperuricemic, compared with 11.4% of those above the 80th percentile6,11. Obesity is associated with both increased production and decreased renal excretion of urate13.

A diet rich in purines (Table 1) will produce only a small and transient rise of serum urate by about 60-120 µmol/l (1-2 mg/dl). Conversely, an isocaloric purine-free diet for 7-10 days will slightly lower serum urate by about 60-120 µmol/l (1-2 mg/dl)13,14. Habitual intake of a purine-rich diet may also uncover an underlying renal genetic defect that can lead to hyperuricemia. Mean serum urate levels are higher and the incidence of gout is greater among Filipinos living in the USA compared to individuals of identical racial background living in the Philippines. This is explained by the limited ability by some of these people to increase their renal excretion of urate when exposed to the high purine North American diet15.

Table 1. The purine content of certain foods and beverages.

Alcohol consumption has long been closely associated with hyperuricemia and gout1,5-7,9-12,16-19. In 1876, Alfred Garrod wrote: "the use of fermented liquors is the most powerful of all the predisposing causes of gout, nay so powerful that it may be a question whether gout would ever have been known to mankind had such beverage not be indulged in"16,17. The exact incidence of alcohol induced gouty arthritis is not known, but it is estimated that half the gout sufferers drink excessively17. In a case control study of drinking behavior of 24 patients with gout and 24 age, sex, and weight matched control subjects, the average weekly alcohol intake of gout sufferers was twice that of the control group (p < 0.02)17. A statistically significant relationship between alcohol abuse and acute gout (p < 0.05) was also described. Hyperuricemia was also found to be a significant correlate of alcohol abuse in an unselected group of male patients admitted to a general hospital18. A dietary study of 61 men with gout and 52 healthy men showed that although the average daily intake of most nutrients, including total purine nitrogen, was similar in both gout sufferers and control subjects, the group with gout drank significantly more alcohol than the controls19. The quantity of purine nitrogen derived from alcoholic drinks (mainly beer) was greater in gout sufferers. Alcohol intake, whether alone or with a purine-rich meal, produces greater effects on serum urate levels than a high purine diet. Many patients are aware that feasts containing purine-rich foods and liberal amounts of alcoholic drinks tend to provoke attacks of gout20. Such "aldermanic gout" is brought on by rapid changes in serum urate levels resulting from a combination of feasting and excessive alcohol consumption20. Similarly, 8 out of 9 patients with gout given whisky while fasting — a circumstance not uncommon in real life — experienced one or more episodes of acute gout21. Acetoacetic and beta-hydroxybutyric acidemia associated with fasting results in inhibition of renal urate excretion and a sharp rise of serum urate21. Although alcoholic and nonalcoholic patients with gout have comparable interval serum urate levels (9.7 ± 2.1 vs 9.5 ± 2.1 mg/dl, respectively), during acute attacks of gout, alcoholic patients tend to have significantly lower serum urate levels than nonalcoholics (7.7 ± 1.3 vs 10.1 ± 1.3 mg/dl, respectively)22. This is explained by the frequent coexistence in alcoholics of other provocative factors, such as concurrent trauma and hypothermia of the lower extremities22.

A number of mechanisms have been implicated in the pathogenesis of ethanol induced hyperuricemia17-30. These include: (1) Acute alcoholic excesses causing temporary lactic acidemia, reduced renal urate excretion, and exacerbation of hyperuricemia17,18,20-23. (2) Chronic alcohol ingestion stimulating purine production by accelerating the degradation of adenosine triphosphate to adenosine monophosphate via the conversion of acetate to acetyl CoA in the metabolism of ethanol24,25. (3) The purine content of beer, including the readily absorbed guanosine, producing a greater effect on uric acid production23,26. (4) Consumption of lead contaminated port wine, moonshine whisky, and other alcoholic beverages causing reduction in renal urate excretion and hyperuricemia ("saturnine gout")27-29. Also, persons who binge drink tend to forget to take their urate-lowering medications. A continued high alcohol intake may also impair the response to allopurinol therapy by inhibiting the conversion of the drug to its active metabolite, oxipurinol30. This results in reduced oxipurinol plasma levels, increased urinary excretion of unmetabolized allopurinol, and hence reduced urate-lowering effects30. It follows that urate-lowering drugs are often less effective in patients with gout who continue to drink31.

The presence in gout sufferers of an associated metabolic disorder, such as dyslipidemia and insulin resistance syndrome (IRS), may warrant treatment of its own accord, and often some modification of gout management. Nowhere has this been more true than in patients with both gout and IRS, since treatment of gout with a purine restricted diet that is usually rich in both carbohydrate and saturated fat may negatively influence the management of IRS.

Hyperlipidemia, usually hypertriglyceridemia (type IV hyperlipidemia), has been reported in 25-60% of gout sufferers6,7,32-34. The association has been attributed to both genetic and environmental factors (diet, obesity, alcohol consumption)34. Among genetic factors, 2 apolipoprotein genes are more common in patients with primary gout and hypertriglyceridemia: an uncommon allelic variant of the apoprotein CIII gene, the S2 allele (CIII is one of the 4 major apoproteins of low density lipoprotein)32, and an apolipoprotein E phenotype apo e4 allele33.

Recent data indicate that hypertriglyceridemia in patients with primary gout is often due to an underlying IRS, or metabolic syndrome X6-8,34-37. This is characterized by overall and abdominal obesity with visceral adiposity (a waist/hip ratio > 0.85, with a waist circumference > 100 cm)38; impaired glucose tolerance with resistance to the effects of insulin and compensatory hyperinsulinemia; and the dyslipidemic combination of hypertriglyceridemia, an increase in levels of apolipoprotein B, low density lipoprotein cholesterol (LDL-C), and atherogenic small dense LDL-C particles, and a decrease in high density lipoprotein cholesterol (HDL-C) levels.

IRS is often associated with hyperuricemia, hypertension, and coronary artery disease (CAD). The basic defect in this metabolic syndrome is insulin resistance, which can be detected years before the onset of type 2 diabetes mellitus. Although the exact pathogenesis of IRS is not fully understood, certain dietary factors, particularly fat and total calorie intake, in combination with decreased physical activity, lead to overall obesity with centripetal deposition of fat38. Centripetal obesity, in turn, is a powerful stimulus to increased insulin plasma levels38.

Euglycemic hyperinsulinemia, induced by exogenous insulin intravenous infusion, has been shown to reduce the renal excretion of urate and sodium in both healthy subjects and hypertensive patients39-42. This is mediated through stimulating renal tubular sodium-hydrogen exchanger, thereby facilitating reabsorption not only of sodium, chloride, and bicarbonate, but also of organic anions, such as urate40-42. This explains the frequent association of hyperinsulinemia and IRS with both hypertension and hyperuricemia. Dietary reduction of triglycerides with a low calorie, weight-reducing diet has been shown to increase renal excretion of urate in these patients39,43. Recently, 2 other cardiovascular risk factors, impaired endothelium dependent vasodilatation44 and reduced fibrinolytic activity with elevated plasminogen activator inhibitor-1 (PAI-1) plasma levels45, have been shown to be associated with IRS. Unexplained elevation of total plasma homocysteine levels is another CAD risk factor that has also been reported in gout sufferers46.

Since patients with IRS may initially present with hyperuricemia and/or gouty arthritis, it is important to screen these individuals for concomitant impaired glucose intolerance, dyslipidemia, hypertension, obesity, or other cardiovascular risk factors6-8,47,48. Hyperinsulinemia and IRS have been estimated to occur in 95% and 76% of gout sufferers, respectively39. Thus, even in the absence of clinical signs of gout, hyperuricemia may serve as a surrogate marker of IRS6-8,47,48. However, it is unlikely that hyperuricemia per se plays a causal role in the pathogenesis of CAD, and any apparent relationship is likely related to the frequent association of hyperuricemia with IRS, obesity, dyslipidemia, hypertension, and diabetes mellitus49. Early recognition of IRS will allow nonpharmacologic management by exercise50 and a diet that is high in unsaturated fats and dietary fiber51 and restricted in carbohydrates; and if there is significant impairment of glucose tolerance, management will include the use of drugs to increase insulin sensitivity, such as the thiazolidinediones (e.g., rosiglitazone)52.

DIETARY INTERVENTIONS IN THE TREATMENT OF HYPERURICEMIA AND GOUT

All too often patients enquire about dietary measures in the treatment of gout. There are 2 main approaches: the traditional low purine, low protein, alcohol restricted diet, and more recently, a weight-reducing, purine unlimited, calorie and carbohydrate restricted diet, with increased proportional intake of both protein and unsaturated fats (Table 2).

Table 2. Dietary interventions in the management of gout.

Traditional low purine, alcohol restricted diet. Dietary restriction of purine-rich foods (Table 1), once a mainstay in the management of gout, is of lesser importance now that potent, more effective urate-lowering drugs are available10,13,53. An isocaloric diet restricted in purines produces lowering of the urinary excretion of uric acid by about 200-400 (336 ± 39) mg/day/day (1.2-2.4 mmol/day), and a decrease of mean serum urate level by about 1-2 mg/dl (60-120 µmol/l)13,14. Patients are advised to avoid drinks or foods that they know might precipitate an acute gouty attack, such as large servings of meat and heavy beers. However, a rigid purine restricted diet is of dubious therapeutic value and can rarely be sustained for long.

Moderation in dietary purine consumption, rather than a strict low purine diet, may be helpful, particularly in patients with large tophi experiencing difficulty controlling the hyperuricemia, despite urate-lowering drug therapy13,53. Although high protein diets contain large quantities of purines and are associated with an increased rate of endogenous purine production, such diets often increase urinary urate excretion, and may even lower serum urate levels19,54. Tofu (soybean curd) is rich in protein, but most of the purines are lost during processing, and ingestion of tofu produces only a small rise of serum urate in both healthy individuals and gout sufferers55.

Many patients with gout are overweight, and weight reduction through gradual caloric restriction and exercise, in addition to its beneficial effects on any associated hypertension, dyslipidemia, or IRS, can enhance renal excretion of urate and lowering of serum urate39,43,56. "Crash" dieting and sustained fasting are best avoided, as they may induce lactic acidemia, worsening hyperuricemia, and precipitate attacks of gout. Limitation of alcoholic beverages produces a comparatively greater effect on serum urate levels than purine restriction, and may also reduce the requirements for urate-lowering drugs. Although correction of obesity and purine excess and alcohol avoidance will reduce serum urate, there are no longterm studies of the effectiveness of such an approach, and the benefits are often limited by the relatively small percentage reduction in serum urate levels, and the difficulty of maintaining such improvement in the long term.

Weight-reducing, calorie restricted diet, with moderate carbohydrate restriction and increased proportional intake of protein and unsaturated fats. Given the strong association between the IRS, hyperuricemia, and gout, a weight-reducing calorie restricted diet with moderate carbohydrate restriction and increased proportional intake of protein and unsaturated fat has recently been advocated in patients with primary gout39. Low purine foods are often rich in both carbohydrate and saturated fat. These tend to further decrease insulin sensitivity, leading to higher plasma levels of insulin, glucose, triglycerides, and small, dense LDL-C particles and decreased HDL-C levels, thereby increasing the risk of CAD in these patients39,57. By contrast, a low energy, calorie restricted, high protein, high unsaturated fat, low carbohydrate diet improves insulin sensitivity and decreases plasma glucose, insulin, and triglyceride levels, with a reduction in the incidence and mortality of CAD39,57,58. Recently reported in 13 middle aged men with gout39 is a study of a calorie restricted (1600 kcal/day or 6690 kj/day), weight-reducing diet with restriction of carbohydrate (40% of energy/day), increased proportional intake of protein (30% of energy or 120 g/day, compared to 80-90 g/day generally recommended in diets of Western countries), and replacement of saturated by unsaturated fat (30% of energy/day). Unsaturated fats included both monounsaturated (nuts, olive and canola oils) and polyunsaturated fats (fish). Purine-rich foods were not restricted, but patients were encouraged to limit dairy products (milk, cheese, butter) that, although low in purine content, are high in saturated fat39. The 16 week trial resulted in a mean weight loss of 5.4 kg, significant reductions in serum urate, triglycerides, LDL-C, and total cholesterol, and a significant decrease in the frequency of gouty attacks. The beneficial effects of the diet are mediated through improving insulin sensitivity, with reduction of insulin plasma levels, an increase in the renal excretion of urate, and lowering of serum urate levels39. These preliminary observations, which need to be confirmed in larger, longer term controlled studies, raise concerns about the usefulness of the traditional low purine diet in the management of gout. Such a diet, with its unlimited intake of carbohydrate and saturated fat, will not benefit a patient with both gout and IRS. A weight-reducing diet, with moderate carbohydrate restriction and increased proportional intake of both protein and unsaturated fats, is clearly preferred, but there are no longterm studies of the efficacy of such an approach.

Experimental fish oil and plant seed oil dietary supplementation. There is some experimental evidence to indicate that diets enriched in both gamma-linolenic acid (GLA) in plant seed oil (evening primrose oil) and eicosapentaenoic acid (EPA) in fish oil significantly suppress urate crystal induced inflammation in the Sprague-Dawley rat subcutaneous air pouch model59. GLA is metabolized into prostaglandin E1 (PGE1, which is antiinflammatory), whereas EPA is metabolized into both PGE3 (which is less inflammatory than PGE2) and leukotriene B5 (which suppresses both LKB4 production by neutrophils and interleukin 1 generation by macrophages)59. The effects on the course of clinical gout of a diet enriched with both fish oil and plant seed oil have not been studied.

CONCLUSION

While dietary restriction of purines has long been superseded by more effective urate-lowering drugs, recent data suggest that dietary measures may play a much greater role in the treatment of metabolic disorders commonly associated with gout: obesity, IRS, and dyslipidemia. Before commencing lifelong urate-lowering drug therapy, it is important to identify and treat any of these underlying disorders that may be contributing to the hyperuricemia. In light of its clinical and therapeutic implications, it is important to recognize the strong association of IRS (abdominal obesity, dyslipidemia, raised serum insulin levels, and glucose intolerance) with hyperuricemia and gout. Although the exact frequency of IRS in patients with gout is not known, estimates range between 76% for IRS and 95% for hyperinsulinemia39. An elevated serum urate level may serve as a surrogate marker of IRS, and hence an indicator of risk of CAD. Given the prognostic ramifications of IRS in terms of cardiovascular morbidity, dietary intervention is strongly recommended in these patients.

There is growing evidence that a low energy, calorie restricted, low carbohydrate (40% of energy), high protein (120 g/day, or 30% of energy) diet, with unsaturated fat (30% of energy) and high dietary fiber, is more beneficial in terms of lowering serum urate, insulin, LDL-C, and triglyceride levels, and hence reducing CAD risk, than the conventional low purine diet, with its unlimited intake of carbohydrates and saturated fat8,13,39,57,58. Restriction of alcoholic beverages is key in the management of gout; a continued high intake of alcohol can result in refractoriness to urate-lowering effects of both allopurinol and uricosurics31.

Dieting of any kind is burdensome for most patients, and urging patients to change longstanding, ingrained habits can prove fruitless. Only 20% of patients seeking medical care are ready to change unhealthy behaviors, including hazardous alcohol use and bad eating habits60. Sustaining a lifestyle change can also be both difficult and impractical and the relapse rate is high60. Given the renewed interest in the importance of dietary measures in the management of gout and its associated metabolic disorders, particularly the IRS, new strategies are needed to motivate patients and improve the physician's effectiveness in counselling patients to initiate and adhere to a lifestyle change, including longterm dietary interventions60.

REFERENCES

Search PubMed for:

1. Roubenoff R. Gout and hyperuricemia. Rheum Dis Clin North Am 1990;16:539-50. [MEDLINE]

2. Ross GA, Seegmiller JE. Hyperuricemia and gout: classification, complications and management. N Engl J Med 1979;300:1459-68.

3. Fam AG. Pathogenesis of hyperuricemia in patients with primary gout. Primary Care Canada 1997;8:9-10.

4. Fam AG. Managing problem gout. Ann Acad Med Singapore 1998;27:93-9. [MEDLINE]

5. Tickly M, Bellinger A, Lincoln D, Russell A. Risk factors for gout: a hospital-based study in urban black South Africans. Rev Rhum Engl Ed 1998;65:225-31. [MEDLINE]

6. McGill NW. Gout and other crystal-associated arthropathies. Ballieres Clin Rheumatol 2000;14:445-60. [MEDLINE]

7. Emmerson B. Hyperlipidemia in hyperuricemia and gout. Ann Rheum Dis 1998;57:509-10. [MEDLINE]

8. Vuorinen-Markkola H, Yki-Jarvinen H. Hyperuricemia and insulin resistance. J Clin Endocrinol Metab 1994;78:25-9. [MEDLINE]

9. Kersley GD. A short history of gout. In:Gutman AB, Fessel WJ, Hall AP, et al, editors. Gout: a clinical comprehensive. New York: Medcom Inc.; 1971:8-13.

10. Rodnan GP. Treatment of the gout and other forms of crystal-induced arthritis. Bull Rheum Dis 1982;32:43-53. [MEDLINE]

11. Myers AR, Epstein FH, Dodge HJ, Mikkelsen WM. The relationship of serum uric acid to risk factors in coronary heart disease. Am J Med 1968;45:520-8.

12. Roubenoff R, Klag MJ, Mead LA, Liang KY, Seidler AJ, Hochberg MC. Incidence and risk factors for gout in white men. JAMA 1991;266:3004-7. [MEDLINE]

13. Emmerson BT. The management of gout. N Engl J Med 1996; 334:445-51. [MEDLINE]

14. Yu T-F. Milestones in the treatment of gout. Am J Med 1974; 56:676-85.

15. Healey LA. The epidemiology of Filipino hyperuricemia. In: Smyth CJ, Holers VM, editors. Gout, hyperuricemia and other crystal-associated arthropathies. New York: Marcel Dekker; 1999:121-6.

16. Garrod AB. A treatise on gout and rheumatic gout. 3rd ed. London: Longmans; 1876:218-45.

17. Sharpe CR. A case-control study of alcohol consumption and drinking behaviour in patients with acute gout. Can Med Assoc J 1984;131:563-7. [MEDLINE]

18. Drum DE, Goldman PA, Jankowski CB. Elevation of serum uric acid as a clue to alcohol abuse. Arch Intern Med 1981;141:477-9. [MEDLINE]

19. Gibson T, Rodgers AV, Simmonds HA, Court-Brown F, Todd E, Meilton V. A controlled study of diet in patients with gout. Ann Rheum Dis 1983;42:123-7. [MEDLINE]

20. Rodnan GP. The pathogenesis of aldermanic gout: procatarctic role of fluctuations in serum urate concentration in gouty arthritis provoked by feast and alcohol [abstract]. Arthritis Rheum 1980;23 Suppl:737.

21. Machlachlan MJ, Rodnan GP. Effects of food, fast and alcohol on serum uric acid and acute attacks of gout. Am J Med 1967;42:38-57.

22. Vandenberg MK, Moxley G, Breitbach SA, Roberts WN. Gout attacks in chronic alcoholics occur at lower serum urate levels than in nonalcoholics. J Rheumatol 1994;21:700-4. [MEDLINE]

23. Eastmond CJ, Garton M, Robins S, Riddoch S. The effects of alcoholic beverages on urate metabolism in gout sufferers. Br J Rheumatol 1995;34:756-9. [MEDLINE]

24. Faller J, Fox IH. Ethanol-induced hyperuricemia: evidence for increased urate production by activation of adenine nucleotide turnover. N Engl J Med 1982;307:1598-602. [MEDLINE]

25. Puig JG, Fox IH. Ethanol-induced activation of adenine nucleotide turnover. Evidence for a role of acetate. J Clin Invest 1984; 74:936-41. [MEDLINE]

26. Gibson T, Rodgers AV, Simmonds HA, Toseland P. Beer drinking and its effect on uric acid. Br J Rheumatol 1984;23:203-9. [MEDLINE]

27. Halla JT, Ball GV. Saturnine gout: a review of 42 patients. Semin Arthritis Rheum 1982;11:307-14. [MEDLINE]

28. Lin JL, Huang PT. Body lead stores and urate excretion in men with chronic renal disease. J Rheumatol 1994;21:705-9. [MEDLINE]

29. Shadick NA, Kim R, Weiss S, Liang MH, Sparrow D, Hu H. Effect of low level lead exposure on hyperuricemia and gout among middle aged and elderly men: the Normative Aging Study. J Rheumatol 2000;27:1708-12. [MEDLINE]

30. Kaneko K, Fujimori S, Akaoka I. Changes caused by ethanol intake on metabolism of hypouricemic agents (combination of allopurinol and benzbromarone). Adv Exp Med Biol 1991;309A:139-42. [MEDLINE]

31. Ralston SH, Capell HA, Sturrock RD. Alcohol and response to treatment of gout. BMJ 1988;296:1641-2. [MEDLINE]

32. Ferns GAA, Lanham J, Dieppe P, Galston DJ. A DNA polymorphism of an apoprotein gene associates with the hypertriglyceridemia of primary gout. Hum Genet 1988;78:55-9. [MEDLINE]

33. Moriwaki Y, Yamamoto T, Takahashi S, Tsutsumi Z, Higashino K. Apolipoprotein E phenotypes in patients with gout: relation with hypertriglyceridaemia. Ann Rheum Dis 1995;54:351-4. [MEDLINE]

34. Takahashi S, Yamamoto T, Moriwaki Y, Tsutsumi Z, Higashino K. Impaired lipoprotein metabolism in patients with primary gout — influence of alcohol intake and body weight. Br J Rheumatol 1994;33:731-4. [MEDLINE]

35. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607. [MEDLINE]

36. Godsland IF, Stevenson JC. Insulin resistance: syndrome or tendency? Lancet 1995;346:100-3. [MEDLINE]

37. Davidson MB. Clinical implications of insulin resistance syndromes. Am J Med 1995;99:420-6. [MEDLINE]

38. Carey DGP. Abdominal obesity. Curr Opin Lipidol 1998;9:35-40. [MEDLINE]

39. Dessein PH, Shipton EA, Stanwix AE, Joffe BI, Ramokgadi J. Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study. Ann Rheum Dis 2000;59:539-43. [MEDLINE]

40. Facchini F, Ida Chen YD, Hollenbeck CB, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance and plasma uric acid concentration. JAMA 1991;266:3008-11. [MEDLINE]

41. Muscelli E, Natali A, Bianchi S, et al. Effect of insulin on renal sodium and uric acid handling in essential hypertension. Am J Hypertens 1996;9:746-52. [MEDLINE]

42. Ter Maaten JC, Voorburg A, Heine RJ, Ter Wee PM, Donker AJ, Gans RO. Renal handling of urate and sodium during acute physiological hyperinsulinaemia in healthy subjects. Clin Sci Lond 1997;92:51-8. [MEDLINE]

43. Tinahones JF, Perez-Lindon G, C-Soriguer FJ, Pareja A, Sanchez-Guijo P, Collantes E. Dietary alterations in plasma very low density lipoprotein levels modify renal excretion of urates in hyperuricemic-hypertriglyceridemic patients. J Clin Endocrinol Metab 1997;82:1188-91. [MEDLINE]

44. Tooke JE, Hannemann MM. Adverse endothelial function and the insulin resistance syndrome. J Intern Med 2000;247:425-31. [MEDLINE]

45. Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP. Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol 2000;152:897-907. [MEDLINE]

46. Istok R, Kovalancik M, Rovensky J. Total plasma homocysteine in patients with gout [letter]. J Rheumatol 1999;26:2068-9. [MEDLINE]

47. Lee J, Sparrow D, Vokonas PS, Landsberg L, Weiss ST. Uric acid and coronary heart disease risk: evidence for a role of uric acid in the obesity-insulin resistance syndrome. The Normative Aging Study. Am J Epidemiol 1995;142:288-94. [MEDLINE]

48. Puig JG, Ruilope LM. Uric acid as a cardiovascular risk factor in arterial hypertension. J Hypertens 1999;17:869-72. [MEDLINE]

49. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999;131:7-13. [MEDLINE]

50. Ross R, Dagnone D, Jones PJ, et al. Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med 2000;133:92-103. [MEDLINE]

51. Vuksan V, Sievenpiper JL, Owen R, et al. Beneficial effects of viscous dietary fiber from Konjac-mannan in subjects with the insulin resistance syndrome: results of a controlled metabolic trial. Diabetes Care 2000;23:9-14. [MEDLINE]

52. Sunayama S, Watanabe Y, Daida H, Yamaguchi H. Thiazolidinediones, dyslipidaemia and insulin resistance syndrome. Curr Opin Lipidol 2000;11:397-402. [MEDLINE]

53. Fam AG. Strategies and controversies in the treatment of gout and hyperuricemia. Ballieres Clin Rheumatol 1990;4:177-91. [MEDLINE]

54. Matzkies F, Berg G, Madl H. The uricosuric action of protein in man. Adv Exp Med Biol 1980;122A:227-31. [MEDLINE]

55. Yamakita J, Yamamoto T, Moriwaki Y, Takahashi S, Tsutsumi Z, Higashino K. Effect of tofu (bean curd) ingestion and on uric acid metabolism in healthy and gouty subjects. Adv Exp Med Biol 1998;431:839-42. [MEDLINE]

56. Nicholls A, Scott JT. Effect of weight-loss on plasma and urinary levels of uric acid. Lancet 1972;2:1223-4.

57. Parillo M, Rivellese AA, Ciardullo AV, et al. A high monounsaturated-fat/low carbohydrate diet improves peripheral insulin sensitivity in non-insulin-dependent diabetic patients. Metabolism 1992;41:1373-8. [MEDLINE]

58. Piatti PM, Monti F, Fermo I, et al. Hypocaloric high protein diet improves glucose oxidation and spares lean body mass: comparison to hypocaloric high carbohydrate diet. Metabolism 1994;43:1481-7. [MEDLINE]

59. Tate GA, Mandell BF, Karmali RA, et al. Suppression of monosodium urate crystal-induced acute inflammation by diets enriched with gamma-linolenic acid and eicosapentaenoic acid. Arthritis Rheum 1988;31:1543-51. [MEDLINE]

60. Levinson W, Cohen MS, Brady D, Duffy FD. To change or not to change: "Sounds like you have a dilemma". Ann Intern Med 2001;135:386-91. [MEDLINE]



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