title: Dual actions of Netrin-1 on islet insulin secretion and immune modulation.
abstract: Netrin-1 is typically known as a neural guidance cue, which has been implicated in pancreas development. Since regenerative, angiogenic and anti-inflammatory properties of Netrin-1 have been reported in multiple tissues, we have investigated the potential role of Netrin-1 in the endocrine islet and its implication in mice with high-fat diet (HFD)/streptozotocin (STZ)-induced diabetes. Effects of exogenous Netrin-1 on β-cell [Ca(2+)]i, cyclic AMP (cAMP) and insulin production were assessed in vitro The long-term impact of Netrin-1 treatment was then evaluated in HFD/STZ-induced diabetic mice by subcutaneous implantation of osmotic minipumps which release Netrin-1 in a sustained manner for 4 weeks. Immunostaining of pancreases of Netrin-1-treated and control animals were employed to examine islet morphology, vascularization and macrophage infiltration. Plasma insulin, glucagon and pro-inflammatory cytokine concentrations were quantified by ELISA. Expression of endogenous Netrin-1 was also assessed by PCR and immunohistochemistry. We observed a stimulatory effect of Netrin-1 on in vitro insulin secretion by promoting β-cell Ca(2+) influx and cAMP production. After 4-week continuous exposure, a hypoglycaemic property of Netrin-1 was demonstrated, which is probably attributable to improved β-cell function, shown as increased insulin content and preproinsulin mRNA expression. Enhanced islet vascularization, reduced islet macrophage infiltration and ameliorated systemic inflammation were detected from HFD/STZ-induced diabetic mice after Netrin-1 administration. We propose a dual action of Netrin-1 in islets during pathophysiological hyperglycaemia: by maintaining insulin secretion while attenuating inflammation.
authors: Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China Medical Experiment Centre, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors: Shan
authors: S
authors: Gao
authors: Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
authors: Xiuyuan
authors: X
authors: Zhang
authors: Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
authors: Yibo
authors: Y
authors: Qin
authors: Medical Experiment Centre, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors: Shixin
authors: S
authors: Xu
authors: Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
authors: Ju
authors: J
authors: Zhang
authors: Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
authors: Zhihong
authors: Z
authors: Wang
authors: Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
authors: Weiwei
authors: W
authors: Wang
authors: Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
authors: Deling
authors: D
authors: Kong
authors: Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China cli0616826@126.com.
authors: Chen
authors: C
authors: Li
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009414:Nerve Growth Factors / Q000235:genetics / Q000276:immunology*; D000075388:Netrin-1; D010179:Pancreas / Q000276:immunology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D000242:Cyclic AMP; D002118:Calcium
keywords: Netrin-1; diabetes; insulin secretion; islets; macrophage infiltration