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High uric acid directly inhibits insulin signalling and induces insulin resistance
Authors:Yuzhang Zhu  Yaqiu Hu  Tianliang Huang  Yongneng Zhang  Zhi Li  Chaohuan Luo  Yinfeng Luo  Huier Yuan  Ichiro Hisatome  Tetsuya Yamamoto  Jidong Cheng
Affiliation:1. Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China;2. Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan;3. Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
Abstract:

Background and aim

Accumulating clinical evidence suggests that hyperuricemia is strongly associated with abnormal glucose metabolism and insulin resistance. However, how high uric acid (HUA) level causes insulin resistance remains unclear. We aimed to determine the direct role of HUA in insulin resistance in vitro and in vivo in mice.

Methods

An acute hyperuricemia mouse model was created by potassium oxonate treatment, and the impact of HUA level on insulin resistance was investigated by glucose tolerance test, insulin tolerance test and insulin signalling, including phosphorylation of insulin receptor substrate 1 (IRS1) and Akt. HepG2 cells were exposed to HUA treatment and N-acetylcysteine (NAC), reactive oxygen species scavenger; IRS1 and Akt phosphorylation was detected by Western blot analysis after insulin treatment.

Results

Hyperuricemic mice showed impaired glucose tolerance with insulin resistance. Hyperuricemia inhibited phospho-Akt (Ser473) response to insulin and increased phosphor-IRS1 (Ser307) in liver, muscle and fat tissues. HUA induced oxidative stress, and the antioxidant NAC blocked HUA-induced IRS1 activation and Akt inhibition in HepG2 cells.

Conclusion

This study supplies the first evidence of HUA directly inducing insulin resistance in vivo and in vitro. Increased uric acid level may inhibit IRS1 and Akt insulin signalling and induce insulin resistance. The reactive oxygen species pathway plays a key role in HUA-induced insulin resistance.
Keywords:Akt, protein kinase B   GTT, glucose tolerance test   HUA, high uric acid   IRS, insulin receptor substrate   ITT, insulin tolerance test   NAC, N-acetyl-l-cysteine   ROS, reactive oxygen species
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