Uric Acid as a Causal Risk Factor for Cardiometabolic Syndrome: Insights from Recent Epidemiological and Experimental Evidence
Main Article Content
Abstract
Background: Uric acid is the end product of purine metabolism and serves as a major antioxidant in human plasma. While physiological concentrations may be protective, elevated serum uric acid has been increasingly associated with insulin resistance, type 2 diabetes mellitus, hypertension, dyslipidaemia, and non-alcoholic fatty liver disease. The role of uric acid as a causal factor in cardiometabolic syndrome remains controversial.
Methods: This narrative review examined evidence from epidemiological studies, experimental animal models, genetic analyses, and clinical trials that investigated the relationship between serum uric acid and cardiometabolic syndrome and its components. Emphasis was placed on mechanistic pathways and clinical implications of hyperuricemia.
Results: Most prospective and experimental studies indicate that elevated serum uric acid frequently precedes the development of insulin resistance and type 2 diabetes mellitus and is independently associated with cardiometabolic syndrome. Mechanistic evidence suggests that uric acid contributes to endothelial dysfunction through reduced nitric oxide bioavailability, increased oxidative stress, inflammation, and impaired insulin signaling. Hyperuricemia has also been linked to hypertension, renal dysfunction, and hepatic triglyceride accumulation via pathways involving mitochondrial dysfunction and inhibition of AMP-activated protein kinase. Pharmacological reduction of uric acid has been associated with improvement in cardiometabolic parameters in experimental models and selected clinical studies.
Conclusion: Current evidence supports a contributory role of elevated uric acid in the development of cardiometabolic syndrome. Uric acid may represent a modifiable risk factor and a potential therapeutic target in cardiometabolic disorders.
Downloads
Article Details
Section
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The Journal is owned, published and copyrighted by the Nigerian Medical Association, River state Branch. The copyright of papers published are vested in the journal and the publisher. In line with our open access policy and the Creative Commons Attribution License policy authors are allowed to share their work with an acknowledgement of the work's authorship and initial publication in this journal.
This is an open access journal which means that all content is freely available without charge to the user or his/her institution. Users are allowed to read, download, copy, distribute, print, search, or link to the full texts of the articles in this journal without asking prior permission from the publisher or the author.
The use of general descriptive names, trade names, trademarks, and so forth in this publication, even if not specifically identified, does not imply that these names are not protected by the relevant laws and regulations. While the advice and information in this journal are believed to be true and accurate on the date of its going to press, neither the authors, the editors, nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.
TNHJ also supports open access archiving of articles published in the journal after three months of publication. Authors are permitted and encouraged to post their work online (e.g, in institutional repositories or on their website) within the stated period, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access). All requests for permission for open access archiving outside this period should be sent to the editor via email to editor@tnhjph.com.
How to Cite
References
1.Rafael SF, Beatriz PM, Lucas MA, de Oliveira MB, de Araújo RM & de Oliveira KA (2022) Serum uric acid is independently associated with metabolic syndrome and systemic hypertension in women from northeast Brazil, Women & Health, 62:1, 68-74,
2.Mohammad HB, Amir B, Mohammad HG (2022) Investigating the relationship between serum uric acid to high-density lipoprotein ratio and metabolic syndrome Volume 5, Issue1 January 2022
3.Li J, He K, Fan J, et al. Serum uric acid and cardiometabolic syndrome among US adults: NHANES 1999–2020. Front Endocrinol (Lausanne). 2025;16:1527513.
4.Zhu Y, Zhang L, He S, et al. Serum uric acid as a causal risk factor for hypertension: evidence from genetic studies. Hypertens Res. 2025;48(2):123–32.
5.Kuwabara M, Niwa K, Nishi Y, et al. Asymptomatic hyperuricemia without comorbidities predicts cardiometabolic diseases: a 10-year Japanese cohort study. Eur Heart J. 2018;39(24):2321–8.
6.Johnson RJ, Bakris GL, Borghi C, et al. Hyperuricemia, acute and chronic kidney disease, hypertension, and cardiovascular disease: report of a scientific workshop organized by the National Kidney Foundation. Am J Kidney Dis. 2018;71(6):851–65.
7.Kim JH, Lee JE, Park SY, et al. Association between serum uric acid and metabolic risk in adolescents with obesity. Metabolites. 2025;15(4):237.
8.Sanchez-Lozada LG, Rodriguez-Iturbe B, Kelley EE, Nakagawa T, Madero M, Feig DI, et al. Uric Acid and Hypertension: An Update with Recommendations. Am J Hypertens. 2020;33(7):583-594.
9.El Ridi R, Tallima H. Physiological functions and pathogenic potential of uric acid: A review. J Adv Res. 2017;8(5):487–93.
10.Lanaspa MA, Epperson LE, Li N. Opposing activity changes in AMP deaminase and AMP-activated protein kinase in the hibernating ground squirrel. PLoS One. 2015;10(4):e0123509.
11.Johnson RJ, Merriman T, Lanaspa MA. Causal or noncausal relationship of uric acid with diabetes. Diabetes. 2015;64(8):2720–2.
12.Reaven GM. Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med. 1993;44:121–131.
13.Sluijs I, Holmes MV, van der Schouw YT, Beulens JW, Asselbergs FW, Huerta JM. A Mendelian randomization study of circulating uric acid and type 2 diabetes. Diabetes. 2015;64(8):3028–36.
14.Lv Q, Meng XF, He FF, Chen S, Su H, Xiong J, et al. High serum uric acid and increased risk of type 2 diabetes: a systemic review and meta-analysis of prospective cohort studies. PLoS One. 2013;8(2):e56864.
15.Liang CC, Lin PC, Lee MY, Chen SC, Shin SJ, Hsiao PJ, et al. Association of serum uric acid concentration with diabetic retinopathy and albuminuria in Taiwanese patients with type 2 diabetes mellitus. Int J Mol Sci. 2016;17(8).
16.Wang Y, et al. Effects of uric acid on endothelial dysfunction and mechanisms in early chronic kidney disease. Eur J Med Res. 2013;18:26.
17.Grundy SM (2008) Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol 28: 629-636.
18.Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, weight change, hypertension, diuretic use, and risk of gout in men: the health professionals follow up study. Arch Intern Med. 2005;165(7):742–748.
19.Fu CC, Wu DA, Wang JH, Yang WC, Tseng CH. Association of C-reactive protein and hyperuricemia with diabetic nephropathy in Chinese type 2 diabetic patients. Acta Diabetol. 2009;46(2):127-134.
20.Meigs JB, Mittleman MA, Nathan DM, et al. Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. JAMA. 2000;283(2):221-228.
21. Meshkani R, Zargari M, Larijani B. The relationship between uric acid and metabolic syndrome in normal glucose tolerance and normal 21.fasting glucose subjects. Acta Diabetol. 2011;48(1):79-88.
22.Misra A, Khurana L (2008) Obesity and the metabolic syndrome in developing countries. J Clin Endocrinol Metab 93: S9-30.
23.DeBoer MD, Dong L, Gurka MJ. Racial/ethnic and sex differences in the relationship between uric acid and metabolic syndrome in adolescents: an analysis of National Health and Nutrition Survey 1999–2006. Metabolism. 2012;61(4):554-561.
24.Ford ES, Li C, Cook S, Choi HK. Serum concentrations of uric acid and the metabolic syndrome among US children and adolescents. Circulation. 2007;115(19):2526-2532.
25.Dangana EO, Michael OS, Omolekulo TE, Areola ED, Olatunji LA. Enhanced hepatic glycogen synthesis and suppressed adenosine deaminase activity by lithium attenuates hepatic triglyceride accumulation in nicotine-exposed rats. Biomed Pharmacother. 2019;1417-1427.
26.Adeyanju OA, Michael OS, Soladoye AO, Olatunji LA. Blockade of mineralocorticoid receptor ameliorates oral contraceptive-induced insulin resistance by suppressing elevated uric acid and glycogen synthase kinase-3 instead of circulating mineralocorticoid. Arch Physiol Biochem. 2020;126(3):225-234.
27.Omolekulo TE, Michael OS, Olatunji LA. Dipeptidyl peptidase-4 inhibition protects the liver of insulin-resistant female rats against triglyceride accumulation by suppressing uric acid. Biomed Pharmacother. 2019;110:869-877.
28.Yu W, Cheng JD. Uric Acid and Cardiovascular Disease: An Update From Molecular Mechanism to Clinical Perspective. Front Pharmacol. 2020. Erratum in: Am J Hypertension. 2020 Dec 31;33(12):1150.
29.Freeman AM, Pennings N. Insulin Resistance. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.
30.Lee J, Kim B, Kim W. Lipid indices as simple and clinically useful surrogate markers for insulin resistance in the U.S. population. Sci Rep. 2021;11:2366.
31.Olatunji LA, Olaniyi KS, Usman TO, Abolarinwa BA, Achile CJ, Kim IK. Combined oral contraceptive and nitric oxide synthesis inhibition synergistically causes cardiac hypertrophy and exacerbates insulin resistance in female rats. Environ Toxicol Pharmacol. 2017;52:54-61.
32.Borghi C, Cicero AFG. Serum uric acid and acute coronary syndrome: Is there a role for functional markers of residual cardiovascular risk? Int J Cardiol. 2018;250:62-63.
33.Rathmann W, Funkhouser E, Dyer AR, Roseman JM. Relations of hyperuricemia with the various components of the insulin resistance syndrome in young black and white adults: the CARDIA study. Ann Epidemiol. 1998;8(4):250–261.
34.Takahashi S, Yamamoto T, Tsutsumi Z, Moriwaki Y, Yamakita J, Higashino K. Close correlation between visceral fat accumulation and uric acid metabolism in healthy men. Metabolism. 1997;46(10):1162–1165.
35.Feig DI, Kang DH, Johnson RJ (2008). Uric acid and cardiovascular risk. N Engl J Med. 359(17):1811–1821.
36.Gertler MM, Garn SM, Levine SA. Serum uric acid in relation to age and physique in health and in coronary heart disease. Ann Intern Med. 1951;34(6):1421–1431.
37.Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA. 2008;300(8):924–932.
38.Gaffo AL, Edwards NL, Saag KG. Gout. Hyperuricemia and cardiovascular disease: how strong is the evidence for a causal link? Arthritis Res Ther. 2009;11(4):240.
39.Feig DI, Johnson RJ. Hyperuricemia in childhood primary hypertension. Hypertension. 2003;42(3):247–252.
40.Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world--a growing challenge. N Engl J Med. 2007;356:213-215.
41.Facchini F, Chen YD, Hollenbeck CB, Reaven GM (1991). Relationship between resistance to insulin mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA.266(21):3008–3011.
42.Katsiki N, Papanas N, Fonseca VA, Maltezos E, Mikhailidis DP (2013). Uric acid and diabetes: Is there a link? Curr Pharm Des. 19(27):4930-7. doi: 10.2174/1381612811319270016. PMID: 23278493).
43.Martínez-Sánchez FD, Vargas-Abonce VP, Guerrero-Castillo AP, Santos-Villavicencio MD, Eseiza-Acevedo J, Meza-Arana CE, Gulias-Herrero A, Gómez-Sámano MA,(2021) Serum Uric Acid concentration is associated with insulin resistance and impaired insulin secretion in adults at risk for Type 2 Diabetes, Primary Care Diabetes, 15 (2); 293-299.
44.Katsiki N, Dimitriadis GD, Mikhailidis DP. Serum Uric Acid and Diabetes: From Pathophysiology to Cardiovascular Disease. Curr Pharm Des. 2021;27(16):1941-1951.
45.Bailey CJ. Uric acid and the cardio-renal effects of SGLT2 inhibitors. Diabetes Obes Metab. 2019;21(6):1291-1298.
46.Su H, Liu T, Li Y, Fan Y, Wang B, Liu M, Hu G, Meng Z, Zhang Q. Serum uric acid and its change with the risk of type 2 diabetes: A prospective study in China. Prim Care Diabetes. 2021;15(6):1002-1006.
47.De Becker B, Borgi C, Burnier M, van de Borne P, Uric acid and hypertension: focused review and practical recommendations. J Hypertens. 2019 May, 37(5): 878-883.
48.Cicero AF, Rosticci M, Bove M, et al. Serum uric acid change and modification of blood pressure and fasting plasma glucose in an overall healthy population sample: data from the Brisighella heart study. Ann Med. 2017; 49(4): 275- 282.
49.Cicero AF, Rosticci M, Fogacci F, Grandi E, D'Addato S, Borghi C. High serum uric acid is associated with poorly controlled blood pressure and higher arterial stiffness in hypertensive subjects. Eur J Int Med. 2017; 37: 38- 42.
50.Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11–20.
51.Kawano Y, Cohen DE. Mechanisms of hepatic triglyceride accumulation in nonalcoholic fatty liver disease. J Gastroenterol. 2013;48:434–441.
52.Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414:799–806.
53. Mantena SK, King AL, Andringa KK, Eccleston HB, Bailey SM. Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and 53.obesity-induced fatty liver diseases, Free Radic. Biol. Med. 2008; 44:1259–1272.
54.Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010; 7:251–264.
55.El-Sherbeeny NA, Nader MA, Attia GM, Ateyya H, Agmatine protects rat liver from nicotine-induced hepatic damage via antioxidative, antiapoptotic, and antifibrotic pathways, Naunyn Schmiedebergs Arch. Pharmacol. 2016; 389:1341–1351.
56.Tsushima Y, Nishizawa H, et al. Uric acid secretion from adipose tissue and its increase in obesity. J Biol Chem. 2013;288:27138–49.
57.Tsouli SG. Elevated serum uric acid levels in metabolic syndrome. Int J Cardiol. 2006.
58.Xu C, Yu C, Xu L, et al. High serum uric acid increases the risk for nonalcoholic fatty liver disease: A prospective observational study. PLoS One. 2010;5(7):e11578.
59.Shih MH, et al. Association between serum uric acid and nonalcoholic fatty liver disease in the US population. J Formos Med Assoc. 2015; 114:314–20.
60.Cicerchi C, Choi YJ, et al. Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes. Lab Invest. 2014;94(10):1114–25.
61.Lanaspa MA, Epperson LE, Li N. Opposing activity changes in AMP deaminase and AMP-activated protein kinase in the hibernating ground squirrel. PLoS One. 2015;10(4):e0123509.