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World J Diabetes. Jul 15, 2025; 16(7): 107673
Published online Jul 15, 2025. doi: 10.4239/wjd.v16.i7.107673
Extra-renal role of urate transporter-1 in diabetes
Tian-Shu Yang, Min Du, Ling-Yun Luo, Li Lin, Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Xue-Lian Luo, Department of Oncology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
ORCID number: Xue-Lian Luo (0000-0003-1068-6061).
Co-first authors: Tian-Shu Yang and Min Du.
Co-corresponding authors: Li Lin and Xue-Lian Luo.
Author contributions: Yang TS wrote the original manuscript; Yang TS and Du M contributed equally to this article and are co-first authors of this manuscript; Yang TS, Du M, Luo LY, Lin L, and Luo XL wrote, reviewed and edited the manuscript; Lin L and Luo XL managed the project; they contributed equally to this article and are co-corresponding authors of manuscript; all authors thoroughly reviewed and endorsed the final manuscript.
Conflict-of-interest statement: The authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xue-Lian Luo, MD, PhD, Department of Oncology, The Third Affiliated Hospital of Chongqing Medical University, Huixing Street, Yubei District, Chongqing 401120, China. 806850653@qq.com
Received: March 28, 2025
Revised: April 20, 2025
Accepted: June 3, 2025
Published online: July 15, 2025
Processing time: 109 Days and 23.7 Hours

Abstract

The rising global incidence of diabetes mellitus (DM) and hyperuricemia presents a growing challenge to public health systems worldwide. Urate transporter-1 (URAT1), a key renal urate transporter, has emerged as a promising therapeutic target for managing DM and its associated complications. Growing evidence suggests that URAT1’s role in metabolic disorders extends beyond its function in the kidney. Specifically, URAT1 can influence uric acid metabolism in multiple tissues including neural, hepatic, vascular smooth muscle, cardiac, and adipose tissue, thereby contributing to insulin resistance, inflammation, and end-organ damage. In this review, we comprehensively examine the extra-renal functions of URAT1, focusing on its roles in the hematopoietic system, heart, liver, adipose tissue, and vascular endothelium in the context of DM. This analysis highlights the multi-organ mechanisms through which URAT1 exerts its effects, offering valuable insights into its potential as a therapeutic target for this complex systemic metabolic disorder.

Key Words: Diabetes mellitus; Insulin resistance; Extra-renal urate transporter-1; Urate transporter-1 inhibitor

Core Tip: Emerging evidence highlights the extra-renal roles of urate transporter-1 (URAT1) in diabetes mellitus, extending beyond its canonical function in renal urate reabsorption. URAT1-mediated uric acid uptake in tissues such as adipose, liver, heart, endothelium, and hematopoietic cells exacerbates insulin resistance, oxidative stress, and inflammation, driving diabetic complications. Pharmacological inhibition of URAT1 with agents like dotinurad, benzbromarone, or probenecid attenuates these pathological processes by reducing uric acid influx, restoring insulin signaling, and suppressing pro-inflammatory pathways. This review underscores URAT1 as a pivotal therapeutic target for mitigating multi-organ dysfunction in diabetes mellitus, offering novel strategies to address systemic metabolic and inflammatory derangements.



INTRODUCTION

Diabetes mellitus (DM) has emerged as a major global public health concern. In China alone, over 10% of the population is currently affected by DM, and projections suggest that more than 600 million individuals worldwide will be living with the disease by 2045[1]. Hyperuricemia is an independent risk factor for DM, and their co-prevalence has been rising annually[2,3]. The kidney serves as the primary route for uric acid (UA) excretion, and urate transporter-1 (URAT1, also known as SLC22A12, MIM #607096) plays a crucial role in renal UA reabsorption. Genetic mutations in URAT1 have been linked to familial renal hypouricemia (MIM #220150), a disorder characterized by defective UA reabsorption, further highlighting URAT1’s essential role in urate homeostasis[4]. Pharmacological inhibition of URAT1 with agents such as benzbromarone and dotinurad has been shown to effectively reduce UA levels while simultaneously improving DM-related metabolic disturbances[5-7].

To date, most research on URAT1 has concentrated on its physiological and pathological roles within the kidney, where it functions as a key mediator of UA reabsorption. However, there is a relative paucity of literature examining its expression, regulatory mechanisms, and functional significance in extra-renal tissues. Moreover, the implications of URAT1 activity in these peripheral tissues, particularly in the context of DM, remain largely underexplored. In this review, we aim to bridge this knowledge gap by systematically examining extra-renal URAT1 expression and its roles across various organ systems, including the liver, adipose tissue, heart, vascular endothelium, and hematopoietic compartments. We also highlight how URAT1-mediated alterations in UA metabolism within these tissues may contribute to DM pathogenesis, particularly through mechanisms involving insulin resistance, inflammation, oxidative stress, and metabolic dysfunction. Overall, by elucidating these multifaceted roles, our review provides novel insights into the systemic nature of URAT1’s functions and offers a more comprehensive understanding of its pharmacological relevance. The perspective elaborated here may inform future therapeutic strategies targeting URAT1 to more effectively treat DM and its complications.

THE EXTRA-RENAL ROLE OF URAT1 IN DM

In human tissues, URAT1 is predominantly expressed in the kidney, while its presence in extra-renal tissues is relatively limited[8]. Despite their lower abundance, extra-renal URAT1 proteins play important physiological and pathological roles that are often underappreciated in current research. In this section, we summarize the extra-renal roles of URAT1 (e.g., in the hematopoietic system, liver, heart, endothelium, and adipose tissue) in DM (Figure 1).

Figure 1
Figure 1 Relationship between extra-renal urate transporter-1 and diabetes mellitus. This figure illustrates the relationship between extra-renal urate transporter-1 (URAT1) and diabetes mellitus. Uric acid (UA) enters macrophages via URAT1, inducing pro-inflammatory polarization – a process suppressed by probenecid, which reduces chronic inflammation in diabetes. Diabetes mellitus upregulates URAT1 expression on erythrocyte membranes. A high-fat diet induces cardiac metabolic dysfunction and insulin resistance, which are mitigated by dotinurad through reduction of oxidative stress and inflammation. Dotinurad also reverses high-fat diet-driven URAT1 upregulation in white adipose tissue, alleviates insulin resistance, promotes white adipose tissue browning, and improves hepatic injury/insulin sensitivity. Additionally, uric acid inhibits endothelial phosphorylated protein kinase B/phosphorylated endothelial nitric oxide synthase, effects that are counteracted by probenecid, thereby restoring endothelial function and preventing diabetic complications. DM: Diabetes mellitus; URAT1: Urate transporter 1; WAT: White adipose tissue; BAT: Brown adipose tissue; UA: Uric acid; p-AKT: Phosphorylated protein kinase B; p-eNOS: Phosphorylated endothelial nitric oxide synthase; ROS: Reactive oxygen species; TNF-α: Tumor necrosis factor-α; IL-1β: Interleukin-1β; UCP1: Uncoupling protein 1; PGC1α: Coactivator 1-alpha; ALT: Alanine aminotransferase; CCL2: Chemokine ligand 2.
HEMATOPOIESIS

Inflammation is a key driver in the development and progression of DM, significantly contributing to both insulin resistance and β-cell dysfunction[9]. Studies reveal that UA can promote systemic inflammation by skewing macrophage polarization towards a proinflammatory M1 phenotype, while concurrently inhibiting the anti-inflammatory M2 phenotype. This imbalance in macrophage polarization is implicated in insulin resistance and atherosclerosis pathogenesis. Importantly, the URAT1 inhibitor probenecid has been shown to completely block UA-induced production of tumor necrosis factor-alpha (TNF-α) and markedly reduce M1 polarization by inhibiting URAT1-mediated UA uptake. These findings highlight the potential of targeting URAT1-dependent UA transport to suppress macrophage-driven inflammatory responses in metabolic diseases such as DM[10].

A separate study examined variations in URAT1 expression on erythrocyte membranes among different patient groups. The results demonstrated a significant upregulation of URAT1 on red blood cell membranes in individuals with DM compared to healthy controls. Interestingly, the highest levels of URAT1 expression were detected in patients with DM-related complications. Additionally, a strong positive correlation was observed between elevated hemoglobin A1c levels (> 6.5%) and increased URAT1 expression, indicating that persistent hyperglycemia may contribute to URAT1 overexpression in diabetic erythrocytes. These findings suggest that URAT1 could serve as a valuable biomarker for assessing disease progression and the risk of complications in type 2 DM (T2DM)[11].

LIVER

The liver plays a central role in regulating glucose and lipid metabolism under the influence of insulin[12]. Impaired hepatic insulin sensitivity disrupts glucose homeostasis and contributes to the development of T2DM, which is closely linked to metabolic dysfunction-associated fatty liver disease (MAFLD), a condition characterized by hepatic steatosis and insulin resistance[13]. In high-fat diet (HFD)-fed mice, Tanaka et al[14] were the first to uncover the involvement of URAT1 in MAFLD pathogenesis and insulin resistance. Their study demonstrated that treatment with the URAT1 inhibitor dotinurad significantly ameliorated hepatic steatosis, reduced hepatocellular ballooning, and suppressed inflammation, as evidenced by decreased mRNA expression of pro-inflammatory cytokines such as chemokine ligand 2 and TNFα without affecting hepatic URAT1 expression. These improvements were attributed to reduced hepatic UA uptake, leading to attenuation of oxidative stress and inflammation. Additionally, dotinurad improved glucose tolerance, enhanced insulin sensitivity, and lowered fasting glucose and insulin levels in HFD-fed mice[14]. Collectively, these findings support the potential of URAT1 inhibitors as a therapeutic approach for managing comorbid T2DM- MAFLD by targeting inflammatory and oxidative stress-related pathways.

HEART

Insulin resistance, hyperinsulinemia, and hyperglycemia are each recognized as independent risk factors for the onset of metabolic cardiomyopathy[15]. A 2023 study demonstrated that treatment with the URAT1 inhibitor dotinurad significantly improved HFD-induced cardiac dysfunction[16]. In subsequent in vitro experiments using neonatal rat cardiomyocytes, stimulation with palmitic acid and high glucose upregulated URAT1 expression and activated the mitogen-activated protein kinase signaling pathway, as evidenced by increased phosphorylation of extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase. This activation led to elevated reactive oxygen species (ROS) production, increased pro-inflammatory cytokine levels (e.g., TNF-α and interleukin-1β), and enhanced apoptosis. Importantly, dotinurad treatment significantly attenuated these pathological responses, underscoring its protective role in reducing cardiomyocyte injury induced by metabolic stress via URAT1 inhibition[16].

ENDOTHELIUM

Endothelial dysfunction is widely acknowledged as a key contributor to the development of diabetes-related complications[17], while endothelial glucose uptake and metabolic disorders are also closely linked to the development of T2DM[18]. In human umbilical vein endothelial cells, UA has been shown to promote the interaction between ectonucleotide pyrophosphatase/phosphodiesterase 1 and the insulin receptor, thereby impairing insulin receptor phosphorylation and disrupting downstream insulin signaling. Importantly, treatment with the URAT1 inhibitor probenecid normalized ectonucleotide pyrophosphatase/phosphodiesterase 1-IR binding and restored insulin signaling by preventing UA-induced interference[19]. These findings highlight the therapeutic potential of URAT1 inhibitors in mitigating insulin resistance and managing diabetes and its vascular complications.

ADIPOSE TISSUE

The conversion of white adipose tissue (WAT) into brown adipose tissue (BAT) promotes thermogenesis, enhances insulin sensitivity, and reduces inflammation, making it a promising strategy for addressing obesity-related diabetes by improving glucose metabolism and mitigating insulin resistance[20]. In HFD-fed mice, Tanaka et al[14] reported that URAT1 expression was significantly upregulated in both epididymal WAT and BAT, where it contributed to increased ROS and inflammation through enhanced UA uptake. Treatment with the URAT1 inhibitor dotinurad effectively reduced UA influx, lowered ROS levels, and reactivated the thermogenic protein UCP1 in BAT[14]. This intervention reversed HFD-induced “whitening” of BAT characterized by lipid accumulation and restored its thermogenic, “browned” phenotype. In WAT, URAT1 inhibition similarly elevated UCP1 expression, promoted partial browning, and improved insulin sensitivity[21]. Furthermore, URAT1 upregulation in adipose tissue has been associated with aggravated metabolic dysfunction through the activation of inflammatory pathways involving chemokine ligand 2 and TNFα[22]. Collectively, these findings underscore URAT1 as a promising therapeutic target for treating obesity-associated diabetes.

THE ROLE OF EXTRA-RENAL URAT1 AND OTHER DISEASES

In addition to its established involvement in DM, extra-renal URAT1 also plays a crucial role in the pathogenesis of several other diseases. Within the nervous system, URAT1 is localized to the basolateral membrane of choroid plexus epithelial cells and ependymal cells in humans, where it facilitates UA transport to help maintain cerebral UA homeostasis. In murine models, URAT1 has neuroprotective effects by suppressing microglial inflammation and preserving dopaminergic neurons[23-25]. Although the presence of hepatic URAT1 in humans remains controversial, its expression is well-characterized in mice. Notably, URAT1 deficiency in murine livers exacerbates acetaminophen-induced liver injury through disruptions in lipid metabolism, activation of the nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 inflammasome and nuclear factor kappa B signaling and increased oxidative stress[26]. In vascular smooth muscle cells, URAT1 facilitates UA uptake and contributes to the progression of abdominal aortic aneurysms via activation of the extracellular signal-regulated kinase/ matrix metalloproteinase-9 signaling pathway[27]. These findings underscore the broader pathophysiological significance of URAT1 beyond its renal and metabolic functions.

URAT1 INHIBITOR AND DM

Currently, the main URAT1 inhibitors approved for clinical use include dotinurad, benzbromarone, and probenecid, while verinurad has shown promising results in ongoing clinical trials[28]. Additionally, several novel URAT1 inhibitors are under active development[29,30]. Dotinurad has strong anti-inflammatory, anti-diabetic, and vaso-protective effects in both preclinical and clinical studies[6,14,16,31]. Benzbromarone similarly exhibits significant hypoglycemic properties and can prevent the onset of DM[32,33]. Probenecid not only reduces inflammation in macrophages and endothelial cells but also enhances pancreatic β-cell function, thereby improving insulin resistance in diabetic models[10,19,34]. Another selective URAT1 inhibitor Lesinurad has been evaluated in clinical trials for the treatment of hyperuricemia and gout. Although its primary use has focused on lowering UA levels, emerging evidence suggests potential metabolic benefits beyond urate control. However, concerns regarding its safety profile, particularly the risk of nephrotoxicity, have limited its wide clinical use and led to market withdrawal in some regions. As such, further investigation is warranted to assess its suitability for use in diabetic populations[35].

In comparative clinical studies, dotinurad has demonstrated superior selectivity for URAT1 and reduced risk of hepatotoxicity compared to benzbromarone. Verinurad, currently undergoing phase II clinical trials, has demonstrated potential in treating patients with hyperuricemia and chronic kidney disease, offering enhanced potency and increased urinary urate excretion. Additionally, novel agents like SHR4640 have also entered clinical pipelines, exhibiting strong urate-lowering and anti-inflammatory properties. These advancements highlight the growing interest in URAT1 inhibitors not only as treatments for hyperuricemia, but also as promising therapeutic options for addressing the metabolic and cardiovascular complications commonly associated with diabetes.

RETROSPECT AND FUTURE PERSPECTIVES

This article provides a comprehensive analysis of URAT1 expression and function, shedding light on its mechanistic involvement in T2DM onset and progression. In addition, by integrating findings from molecular, cellular, and clinical research, it underscores how URAT1-mediated dysregulation of UA metabolism in extra-renal tissues contributes to insulin resistance, systemic inflammation, and various diabetic complications. These insights are pivotal for the advancement of precision medicine approaches in DM management. Importantly, the article highlights that the role of URAT1 extends beyond its canonical function in renal urate transport as it also exerts significant regulatory effects in non-renal tissues by modulating local UA homeostasis and activating downstream signaling pathways[36]. In endothelial cells, adipose tissue, cardiomyocytes, and hepatocytes, URAT1-mediated intracellular uptake of urate promotes ROS generation, nuclear factor kappa B signaling pathway activation, and the release of pro-inflammatory cytokines such as TNF-α and interleukin-1β[37]. This pro-oxidative and pro-inflammatory cellular environment disrupts insulin signaling, contributes to pathological tissue remodeling, and drives metabolic dysfunction. These observations highlight URAT1 as a critical upstream regulator of inflammation and oxidative stress, playing a central role in diabetes-associated organ damage.

In the context of DM, hyperinsulinemia stimulates URAT1 to enhance UA reabsorption, while URAT1 activation further exacerbates insulin resistance. Simultaneously, the accumulation of intracellular UA acts as a pro-oxidant, promoting ROS generation and the release of pro-inflammatory cytokines, which disrupt insulin signaling pathways[6,38,39]. This establishes a self-amplifying feedback loop that intensifies tissue damage in diabetic patients, particularly within the cardiovascular, renal, and hepatic systems, through ongoing oxidative stress and chronic inflammation[40].

Current research on DM and its complications has largely concentrated on the benefits of lowering serum UA levels, while the extra-renal roles and mechanistic functions of URAT1 remain relatively understudied. A deeper understanding of potential contributions of URAT1 beyond the kidney is essential, particularly given its emerging relevance in multiple organ systems affected by DM. To advance this field, future research should adopt a multifaceted experimental approach, integrating genetic, dietary, and pharmacological models that replicate the complex metabolic disturbances observed in diabetes. These models should be used to systematically assess URAT1 expression patterns and functional roles, as well as those of other urate transporters, across various organ systems such as the liver, heart, adipose tissue, endothelium, and central nervous system.

The use of selective pharmacological inhibitors or gene-editing technologies (e.g., CRISPR/Cas9) targeting specific urate transporters can help delineate their precise mechanistic contributions to insulin resistance, inflammation, oxidative stress, and organ dysfunction. However, translating findings from animal models to human physiology presents notable challenges. Rodents possess functional uricase, an enzyme that rapidly metabolizes UA. In contrast, humans lack this enzyme, resulting in fundamentally different urate homeostasis. Moreover, species-specific differences in URAT1 expression and urate handling further complicate direct extrapolation of results from rodent studies to human pathophysiology. Therefore, while rodent models offer foundational insights, their translational relevance may be limited.

Humanized URAT1 transgenic mice and 3D organoid co-culture systems (e.g., hepatocyte–adipocyte–endothelial tri-cultures) may better recapitulate human pathophysiology and enable mechanistic dissection of inter-organ interactions mediated by URAT1[41]. Moreover, future studies should incorporate innovative technologies including multi-omics (e.g., transcriptomics, proteomics, metabolomics), single-cell transcriptomics, and spatial transcriptomics to gain a comprehensive understanding of functional dynamics of URAT1 in various tissues and disease stages. High-resolution imaging platforms, such as intravital microscopy and organ-specific fluorescent probes, can further illuminate the spatial localization and real-time activity of URAT1 in different cellular contexts. Overall, a combination of sophisticated modeling systems, high-throughput molecular techniques, and integrative analytics will be crucial to unravel the complex roles of URAT1 in extra-renal tissues, ultimately guiding the development of more targeted and effective therapeutic strategies for diabetes and its associated complications.

CONCLUSION

This review establishes URAT1 as a pivotal systemic regulator in DM pathogenesis, extending far beyond its classical renal role. In extra-renal tissues, URAT1-mediated UA influx triggers oxidative stress, nuclear factor kappa B activation, and pro-inflammatory cytokine release (TNF-α, interleukin-1β), directly impairing insulin signaling. Critically, hyperinsulinemia and URAT1 activation form a self-amplifying loop that accelerates multi-organ damage. Pharmacological URAT1 inhibition (e.g., dotinurad, probenecid) demonstrates therapeutic promise by disrupting this cycle, improving insulin sensitivity, and attenuating diabetic complications across organ systems. Future research must prioritize human-relevant models (e.g., organoids) and advanced multi-omics approaches to fully elucidate URAT1’s tissue-specific mechanisms and translate these insights into targeted clinical strategies for diabetes and its systemic sequelae.

Footnotes

Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Endocrinology and metabolism

Country of origin: China

Peer-review report’s classification

Scientific Quality: Grade B, Grade B, Grade C, Grade C

Novelty: Grade A, Grade C, Grade C

Creativity or Innovation: Grade B, Grade C, Grade C

Scientific Significance: Grade B, Grade C, Grade C

P-Reviewer: Cardona F; Pappachan JM; Shen YP S-Editor: Bai Y L-Editor: Filipodia P-Editor: Xu ZH

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