Xiaoying Zhou1, Wei Liu2, Min Gu3, Hongwen Zhou4, Guoxin Zhang5. 1. Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China. zhouxiaoying0926@sina.cn. 2. Department of Gastroenterology, The First People's Hospital of Suqian, Suqian, Jiangsu, China. 3. Department of Pediatrics, Changzhou Children's Hospital, Changzhou, Jiangsu, China. 4. Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China. 5. Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China. guoxinz@njmu.edu.cn.
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.
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. Diabeticmice 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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