Gout and Metabolic Syndrome: a Tangled Web
Purpose of review
The complexity of gout continues to unravel with each new investigation. Gout sits at the intersection of multiple intrinsically complex processes, and its prevalence, impact on healthcare costs, and association with important co-morbidities make it increasingly relevant. The association between gout and type 2 diabetes, hypertension, hyperlipidemia, cardiovascular disease, renal disease, and obesity suggest that either gout, or its necessary precursor hyperuricemia, may play an important role in the manifestations of the metabolic syndrome. In this review, we analyze the complex interconnections between gout and metabolic syndrome, by reviewing gout’s physiologic and epidemiologic relationships with its major co-morbidities.
Increasing evidence supports gout’s association with metabolic syndrome. More specifically, both human studies and animal models suggest that hyperuricemia may play a role in promoting inflammation, hypertension and cardiovascular disease, adipogenesis and lipogenesis, insulin and glucose dysregulation, and liver disease. Fructose ingestion is associated with increased rates of hypertension, weight gain, impaired glucose tolerance, and dyslipidemia and is a key driver of urate biosynthesis. AMP kinase (AMPK) is a central regulator of processes that tend to mitigate against the metabolic syndrome. Within hepatocytes, leukocytes, and other cells, a fructose/urate metabolic loop drives key inhibitors of AMPK, including AMP deaminase and fructokinase, that may tilt the balance toward metabolic syndrome progression. Preliminary evidence suggests that agents that block the intracellular synthesis of urate may restore AMPK activity and help maintain metabolic homeostasis.
Gout is both an inflammatory and a metabolic disease. With further investigation of urate’s role, the possibility of proper gout management additionally mitigating metabolic syndrome is an evolving and important question.
KeywordsGout Metabolic syndrome Uric acid Diabetes Fructose Hypertension
Dr. Pillinger is supported in part by NYU CTSA grant 1UL1TR001445 from the National Center for the Advancement of Translational Science (NCATS), NIH. Dr. Krasnokutsky is supported in part by an Investigator Award from the Rheumatology Research Foundation.
Compliance with Ethical Standards
Conflict of Interest
None of the authors have any direct conflict of interest regarding this manuscript. However, for the purpose of full disclosure, we note the following: Dr. Pillinger serves and/or has served as a consultant for Horizon, Ironwood and SOBI, and has been an investigative site for a sponsored, FDA-mandated trial by Takeda. Dr. Krasnokutsky has served as a consultant for Horizon and Ironwood. Dr. Thottam has no disclosures to report.
Human and Animal Rights Informed Consent
This review article did not directly involve any clinical research or human subjects. We do reference currently unpublished data from an ongoing study, and note that the study in question has been approved by the Institutional Review Board of New York University School of Medicine.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 16.• Saddekni MB, Saag KG, Dudenbostel T, et al. The effects of urate lowering therapy on inflammation, endothelial function, and blood pressure (SURPHER) study design and rationale. Contemp Clin Trials. 2016;50:238–44. This manuscript reports the study design of an improtant trial, currently recruiting patients for participation in an assessment of the potential of urate-lower therapy to control blood pressure in adults with essential hypertension. CrossRefPubMedPubMedCentralGoogle Scholar
- 17.United States. Department of Health and Human Services., Center for Disease Control., National Center for Health Statistics (U.S.). Health, United States, 2015 : with special feature on racial and ethnic health disparities, vol. xv. Hyattsville: National Center for Health Statistics; 2016. 449 pages p Google Scholar
- 19.•• Chen JH, Lan JL, Cheng CF, et al. Effect of urate-lowering therapy on all-cause and cardiovascular mortality in hyperuricemic patients without gout: a case-matched cohort study. PLoS One. 2015;10(12):e0145193. This study reports the results of an extremely large, “big data”-based study of all-cause and cardiovascular mortality in untreated hyperuricemic patients compared with those receiving urate-lowering therapy on mortality risk. Treated hyperuricemic patients experienced a lower rate of all cause and cardiovascular death, suggesting that uarate lowering therapy may affect survival. CrossRefPubMedPubMedCentralGoogle Scholar
- 27.• Kuo CF, Grainge MJ, Mallen C, et al. Comorbidities in patients with gout prior to and following diagnosis: case-control study. Ann Rheum Dis. 2016;75(1):210–7. This article reports that patients with gout tend to have increasing development of co-morbidities after their gout diagnosis, suggesting a possible direction of causality between gout and metabolic syndrome. CrossRefPubMedGoogle Scholar
- 34.•• Takir M, Kostek O, Ozkok A, et al. Lowering uric acid with allopurinol improves insulin resistance and systemic inflammation in asymptomatic hyperuricemia. J Investig Med. 2015;63(8):924–9. This small clinical trial tests the possibility that urate lowering in patients with asymptomatic hyperuricemia may directly improve their metabolic state, in the form of decreased insulin resistance, as well as systemic inflammation. CrossRefPubMedGoogle Scholar
- 37.• Dalbeth N, Chen P, White M, et al. Impact of bariatric surgery on serum urate targets in people with morbid obesity and diabetes: a prospective longitudinal study. Ann Rheum Dis. 2014;73(5):797–802. Dalbeth et al report that weight loss surgery results in clinically relevant reductions in serum urate. CrossRefPubMedGoogle Scholar
- 39.•• Baldwin W, McRae S, Marek G, et al. Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes. 2011;60(4):1258–69. This study analyzes the effect of urate on a mouse model of metabolic syndrome. The study found that alterations in urate could affect components of the metabolic syndrome, including including insulin resistance and systemic and adipose inflammation. CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Sirota JC, McFann K, Targher G, et al. Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: liver ultrasound data from the National Health and Nutrition Examination Survey. Metabolism. 2013;62(3):392–9.CrossRefPubMedGoogle Scholar
- 50.• Wang Y, Viollet B, Terkeltaub R, et al. AMP-activated protein kinase suppresses urate crystal-induced inflammation and transduces colchicine effects in macrophages. Ann Rheum Dis. 2016;75(1):286–94. This study underlines the important role of AMPK’s on inflammatory response, and suggests a novel mechanism of colchicine as a stimulator of AMPK. CrossRefPubMedGoogle Scholar