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Mechanistic insights of soluble uric acid-induced insulin resistance: Insulin signaling and beyond

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Abstract

Hyperuricemia is a metabolic disease caused by purine nucleotide metabolism disorder. The prevalence of hyperuricemia is increasing worldwide, with a growing trend in the younger populations. Although numerous studies have indicated that hyperuricemia may be an independent risk factor for insulin resistance, the causal relationship between the two is controversial. There are few reviews, however, focusing on the relationship between uric acid (UA) and insulin resistance from experimental studies. In this review, we summarized the experimental models related to soluble UA-induced insulin resistance in pancreas and peripheral tissues, including skeletal muscles, adipose tissue, liver, heart/cardiomyocytes, vascular endothelial cells and macrophages. In addition, we summarized the research advances about the key mechanism of UA-induced insulin resistance. Moreover, we attempt to identify novel targets for the treatment of hyperuricemia-related insulin resistance. Lastly, we hope that the present review will encourage further researches to solve the chicken-and-egg dilemma between UA and insulin resistance, and provide strategies for the pathogenesis and treatment of hyperuricemia related metabolic diseases.

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Abbreviations

Akt:

Protein kinase B

AMPK:

Adenosine monophosphate-activated protein kinase

BMDMs:

Bone marrow-derived macrophages

CVDs:

Cardiovascular diseases

eNOS:

Endothelial nitric oxide synthase

ENPP1:

Ectonucleotide pyrophosphatase/phosphodiesterase 1

ERK:

Extracellular signal-regulated kinase

FFA:

Free fatty acids

GLUT4:

Glucose transporter 4

HF:

Heart failure

HFD:

High-fat diet

HMGB1:

High mobility group box 1

HO-1:

Heme oxygenase 1

HUA:

High level of uric acid

HUVECs:

Human umbilical vein endothelial cells

IR:

Insulin receptor

IRS:

Insulin receptor substrates

MCP-1:

Monocyte chemotactic protein-1

mTOR:

Mammalian target of rapamycin

NAFLD:

Non-alcoholic fatty liver disease

NLRP3:

NOD-like receptor family pyrin domain containing 3

NO:

Nitric oxide

Nrf2:

Nuclear factor erythroid 2-related factor 2

PI3K:

Phosphatidylinositol-3-kinase

PMs:

Peritoneal macrophages

RAGE:

Receptor for advanced glycation end products

RBP4:

Retinol binding protein 4

ROS:

Reactive oxygen species

SGLT-2:

Sodium-glucose co-transporter 2

sUA:

Serum uric acid

T2DM:

Type 2 diabetes mellitus

TXNIP:

Thioredoxin-interacting protein

UA:

Uric acid

ULT:

Urate-lowering therapy

URAT-1:

Urate transporter-1

Uox-KO:

Uricase gene knockout

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Acknowledgements

The authors would like to thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript.

Funding

This work was supported by grants from the Natural Science Foundation of China (82260163), the Natural Science Foundation of Fujian Province (2020J01018) and the Gout Research Foundation (Japan, 2022).

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Authors and Affiliations

  1. Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China

    Wei Yu, De Xie & Jidong Cheng

  2. Health Evaluation Center, Osaka Gyoumeikan Hospital, Osaka, Japan

    Tetsuya Yamamoto

  3. Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo Medical University, Nishinomiya, Hyogo, Japan

    Hidenori Koyama & Jidong Cheng

  4. Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, Fujian, China

    Jidong Cheng

  5. Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, People’s Republic of China

    Jidong Cheng

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  1. Wei Yu
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  2. De Xie
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  3. Tetsuya Yamamoto
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Contributions

Wei Yu and Jidong Cheng identified and interpreted the literature sources and drafted the manuscript. Wei Yu, De Xie, Tetsuya Yamamoto, and Hidenori Koyama collected relevant research and review papers, designed the figures, and prepared the content of the tables. Wei Yu and Jidong Cheng completed the proofreading and final editing of the manuscript.

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Correspondence to Jidong Cheng.

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Highlights

• Hyperuricemia is closely associated with insulin resistance, however, their true interaction has long been debated and remains unclear.

• An increasing number of experimental studies have demonstrated soluble UA-induced insulin resistance in the pancreas and peripheral tissues, including skeletal muscle, adipose tissue, liver, heart/cardiomyocytes, vascular endothelial cells, and macrophages.

• The molecular mechanism of UA-induced insulin resistance is mainly via impaired insulin signaling, including IR, IRS, PI3K/Akt, and GLUT4.

• The activation of TXNIP, RBP4, AMPK, ENPP1, and NLRP3 inflammasome, M1 macrophage polarization, and autophagy defects may be potential novel mechanisms and intervention targets for UA-induced insulin resistance.

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Yu, W., Xie, D., Yamamoto, T. et al. Mechanistic insights of soluble uric acid-induced insulin resistance: Insulin signaling and beyond. Rev Endocr Metab Disord 24, 327–343 (2023). https://doi.org/10.1007/s11154-023-09787-4

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