High uric acid directly inhibits insulin signalling and induces insulin resistance.
OBJECTIVE
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.


CONCLUSIONS
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.
Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Yuzhang
Y
Zhu
Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Yaqiu
Y
Hu
Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Tianliang
T
Huang
Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Yongneng
Y
Zhang
Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Zhi
Z
Li
Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Chaohuan
C
Luo
Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Yinfeng
Y
Luo
Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Huier
H
Yuan
Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan.
Ichiro
I
Hisatome
Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Tetsuya
T
Yamamoto
Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China. Electronic address: jidongcheng36@hotmail.com.
Jidong
J
Cheng
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D004195:Disease Models, Animal; D018149:Glucose Intolerance / Q000209:etiology / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D033461:Hyperuricemia / Q000150:complications / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014527:Uric Acid / Q000378:metabolism*
D000975:Antioxidants; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D017382:Reactive Oxygen Species; D014527:Uric Acid; D051057:Proto-Oncogene Proteins c-akt; D000111:Acetylcysteine
Akt; IRS1; Insulin resistance; Reactive oxygen species; Uric acid