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Helicobacter pylori infection causes hepatic insulin resistance by the c-Jun/miR-203/SOCS3 signaling pathway

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Abstract

Background

Epidemiological studies have indicated that patients with chronic Helicobacter pylori infection have an increased risk of developing type 2 diabetes mellitus, but the underlying mechanisms remain largely unknown. This study aimed to investigate whether H. pylori infection contributes to the development of insulin resistance, as well as the underlying mechanisms both in vivo and in vitro.

Methods

The effect of H. pylori infection on glucose metabolism was evaluated in humans and mouse models. The role of the c-Jun/miR-203/suppressor of cytokine signaling 3 (SOCS3) pathway in H. pylori-induced insulin resistance was determined in vitro and was validated in vivo.

Results

Average fasting glucose levels were increased in patients (P = 0.012) and mice (P = 0.004) with H. pylori infection. Diabetic mice with H. pylori infection showed impaired glucose metabolism and insulin tolerance and hyperinsulinemia. Furthermore, H. pylori infection impaired insulin signaling in primary hepatocytes. H. pylori infection could upregulate SOCS3, a well-known insulin signaling inhibitor, by downregulating miR-203. SOCS3 overexpression interfered with insulin signaling proteins, and knockdown of SOCS3 alleviated H. pylori-induced impairment of insulin signaling. The transcription factor c-Jun, which affects gene expression, was induced by H. pylori infection and suppressed miR-203 expression.

Conclusions

Our results demonstrated that H. pylori infection induced hepatic insulin resistance by the c-Jun/miR-203/SOCS3 signaling pathway and provide possible implications with regard to resolving insulin resistance.

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Acknowledgments

This research was supported by grants from the National Natural Science Foundation of China (81270476 and 81072032). The authors thank Hong Lu from the Department of Gastroenterology in Shanghai Renji Hospital for her kind help in providing H. pylori SS1 strain. Xiaoying Zhou performed the in vitro experiments and wrote the first draft of the manuscript. Wei Liu and Min Gu performed the in vivo study. Guoxin Zhang reviewed and revised the manuscript. Xiaoying Zhou is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China

    Xiaoying Zhou & Guoxin Zhang

  2. Department of Gastroenterology, The First People’s Hospital of Suqian, Suqian, Jiangsu, China

    Wei Liu

  3. Department of Pediatrics, Changzhou Children’s Hospital, Changzhou, Jiangsu, China

    Min Gu

  4. Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China

    Hongwen Zhou

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  1. Xiaoying Zhou
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  2. Wei Liu
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  3. Min Gu
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Corresponding author

Correspondence to Xiaoying Zhou.

Electronic supplementary material

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535_2015_1051_MOESM1_ESM.tif

Supplementary material 1 (TIFF 500 kb). Fig. S1 a Body weight of mice in different groups. b Food intake of mice in different groups. c Effect of Helicobacter pylori infection on oral glucose tolerance in mice. Mice in all groups received glucose orally, and blood samples were collected at 0, 30, 60, 90, and 120 min. d Mice fasted overnight for 16 h, and blood samples were collected 0, 2, 5, 15, 30, 60, and 120 min after the injection of glucose, and serum insulin levels were determined. Each point is the mean ± the standard error for five or six separate mice

535_2015_1051_MOESM2_ESM.tif

Supplementary material 2 (TIFF 801 kb). Fig. S2 a The locations of the predicted miRNA binding sites within the 3′ UTR of SOCS3 mRNA (top) and qRT-PCR assays for the miRNAs (bottom). b Phosphorylation states of IRS-1, Akt, and GSK3β in cells transfected with miR-203 mimics/inhibitors with or without Helicobacter pylori infection. Significantly different compared with the control, asterisk P < 0.05

535_2015_1051_MOESM3_ESM.tif

Supplementary material 3 (TIFF 461 kb). Fig. S3 a The effect of Helicobacter pylori infection on miR-203 3′ UTR luciferase activities. b The effect of H. pylori infection on SOCS3 3′ UTR luciferase activities. c Immunofluorescence analysis of SOCS3 protein expression level in cells transfected with miR-203 mimics or inhibitors. Significantly different compared with the control, asterisk P < 0.05

535_2015_1051_MOESM4_ESM.tif

Supplementary material 4 (TIFF 283 kb). Fig. S4 Expression of a miR-203, b c-Jun, and c SOCS3 in cells with culture medium of Helicobacter pylori infection compared with the control. Significantly different as compared with control, one asterisk P < 0.05, two asterisks P < 0.01

Supplementary material 5 (DOCX 21 kb)

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Zhou, X., Liu, W., Gu, M. et al. Helicobacter pylori infection causes hepatic insulin resistance by the c-Jun/miR-203/SOCS3 signaling pathway. J Gastroenterol 50, 1027–1040 (2015). https://doi.org/10.1007/s00535-015-1051-6

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  • DOI: https://doi.org/10.1007/s00535-015-1051-6

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