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      Relationship Between Circulating Netrin-1 Concentration, Impaired Fasting Glucose, and Newly Diagnosed Type 2 Diabetes

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          Background: The protein netrin-1 has demonstrated anti-inflammatory, tissue regeneration, and immune modulation properties. Although inflammation is a major contributing factor in the development of insulin resistance and type 2 diabetes, little is known about a possible relationship between serum netrin-1 and type 2 diabetes. Therefore, we investigated the association between circulating levels of netrin-1 and glycometabolic parameters predictive of type 2 diabetes.

          Methods: Serum samples were collected from 41 normal controls, 85 subjects with impaired fasting glucose (IFG), and 92 subjects with newly diagnosed type 2 diabetes. Clinical and laboratory parameters were assessed and netrin-1 levels were measured by commercial enzyme-linked immunosorbent assay. Spearman correlation analyses and multivariable-adjusted regression analyses were conducted to examine the relationship between serum netrin-1 levels and glycometabolic parameters.

          Results: Serum netrin-1 levels in subjects with type 2 diabetes or IFG were significantly higher compared to normal controls (441.0, 436.6, and 275.9 pg/mL, respectively; P for trend < 0.001). Serum netrin-1 levels were significantly positively correlated with fasting glucose, HbA 1c, and insulin resistance index (all Ps < 0.01). Serum netrin-1 levels were independently associated with IFG or type 2 diabetes (standardized β = 0.405, P < 0.001) after adjusting for covariates and potential confounders. In addition, the receiver operating characteristic (ROC) analysis showed that serum netrin-1 levels could identify the presence of IFG and type 2 diabetes with the area under the ROC curve (AUC) of 0.784 ( P < 0.001).

          Conclusions: Our results suggest that elevated serum netrin-1 levels are significantly associated with the presence of IFG and type 2 diabetes.

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          Most cited references 37

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          Inflammation: the link between insulin resistance, obesity and diabetes.

          Recent data have revealed that the plasma concentration of inflammatory mediators, such as tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), is increased in the insulin resistant states of obesity and type 2 diabetes, raising questions about the mechanisms underlying inflammation in these two conditions. It is also intriguing that an increase in inflammatory mediators or indices predicts the future development of obesity and diabetes. Two mechanisms might be involved in the pathogenesis of inflammation. Firstly, glucose and macronutrient intake causes oxidative stress and inflammatory changes. Chronic overnutrition (obesity) might thus be a proinflammatory state with oxidative stress. Secondly, the increased concentrations of TNF-alpha and IL-6, associated with obesity and type 2 diabetes, might interfere with insulin action by suppressing insulin signal transduction. This might interfere with the anti-inflammatory effect of insulin, which in turn might promote inflammation.
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            The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6.

            In vertebrates, commissural axons pioneer a circumferential pathway to the floor plate at the ventral midline of the embryonic spinal cord. Floor plate cells secrete a diffusible factor that promotes the outgrowth of commissural axons in vitro. We have purified from embryonic chick brain two proteins, netrin-1 and netrin-2, that each possess commissural axon outgrowth-promoting activity, and we have also identified a distinct activity that potentiates their effects. Cloning of cDNAs encoding the two netrins shows that they are homologous to UNC-6, a laminin-related protein required for the circumferential migration of cells and axons in C. elegans. This homology suggests that growth cones in the vertebrate spinal cord and the nematode are responsive to similar molecular cues.
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              Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia.

              The neuronal guidance molecule netrin-1 is linked to the coordination of inflammatory responses. Given that mucosal surfaces are particularly prone to hypoxia-elicited inflammation, we sought to determine the function of netrin-1 in hypoxia-induced inflammation. We detected hypoxia-inducible factor 1alpha (HIF-1alpha)-dependent induction of expression of the gene encoding netrin-1 (Ntn1) in hypoxic epithelia. Neutrophil transepithelial migration studies showed that by engaging A2B adenosine receptor (A2BAR) on neutrophils, netrin-1 attenuated neutrophil transmigration. Exogenous netrin-1 suppressed hypoxia-elicited inflammation in wild-type but not in A2BAR-deficient mice, and inflammatory hypoxia was enhanced in Ntn1(+/-) mice relative to that in Ntn1(+/+) mice. Our studies demonstrate that HIF-1alpha-dependent induction of netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces.

                Author and article information

                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                23 November 2018
                : 9
                1Department of Laboratory Medicine, Yonsei University College of Medicine , Seoul, South Korea
                2Division of Special Chemistry, Green Cross Reference Laboratory , Yongin-si, South Korea
                3Department of Laboratory Medicine, Veterans General Hospital , Incheon, South Korea
                4Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul, South Korea
                5Department of Internal Medicine, Yonsei University College of Medicine , Seoul, South Korea
                6Institute of Endocrine Research, Yonsei University College of Medicine , Seoul, South Korea
                7Department of Systems Biology, Glycosylation Network Research Center, Yonsei University , Seoul, South Korea
                Author notes

                Edited by: Tarunveer Singh Ahluwalia, Steno Diabetes Center Copenhagen (SDCC), Denmark

                Reviewed by: Eusebio Chiefari, Dipartimento di Scienze della Salute, Università degli Studi Magna Graecia di Catanzaro, Italy; Daniela Patrizia Foti, Università degli studi Magna Græcia di Catanzaro, Italy

                *Correspondence: Sang-Guk Lee comforter6@

                This article was submitted to Genomic Endocrinology, a section of the journal Frontiers in Endocrinology

                †These authors have contributed equally to this work

                Copyright © 2018 Yim, Kim, Lee, Kang, Cha, Kim, Cho, Lee and Lee.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 46, Pages: 8, Words: 6246
                Funded by: National Research Foundation of Korea 10.13039/501100003725
                Award ID: NRF-2016R1A5A1010764
                Award ID: NRF-2017R1C1B5015044
                Funded by: Korean Diabetes Association 10.13039/100007687
                Award ID: Y.-h.L., 2015
                Funded by: Yonsei University College of Medicine 10.13039/501100008005
                Award ID: 6-2017-0051
                Original Research


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