BackgroundPancreatic β-cell dysfunction resulting from inflammation has been recognized to contribute to type 2 diabetes mellitus (T2DM). Netrin-1 is a new indicator of subclinical inflammation and it has a role in β-cell apoptosis. This study evaluated the level of netrin-1 in newly diagnosed T2DM patients and explored whether netrin-1 is a reliable marker or a key factor in the development of T2DM.MethodsNetrin-1 level was determined using a commercially available human enzyme-linked immune sorbent assay (ELISA) kit. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as an index to measure insulin resistance. The sample consisted of 30 patients with newly diagnosed T2DM who had a glycosylated hemoglobin (HbA1c) level ranging from 7.5 % (58 mmol/mol) to 10.5 % (91 mmol/mol). The control group consisted of 26 healthy individuals matched for age and body mass index.ResultsThe netrin-1 level of T2DM patients was significantly lower than that of healthy controls (p < 0.01). Logistic regression analysis showed that the level of netrin-1 was negatively correlated with HOMA-IR, fasting blood glucose, postprandial blood glucose, fasting insulin and HbA1c.ConclusionsPlasma netrin-1 levels were decreased in patients with newly diagnosed T2DM, and the levels of netrin-1 were negatively associated with IR and glucose homeostasis. Future studies on the precise mechanism will offer new insights into the prevention and treatment of T2DM.

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This study examines the effect and mechanism of action of Netrin-1 on bone marrow mesenchymal stem cells in angiogenesis. Tube formation and migration of bone marrow mesenchymal stem cells were observed in cell culture. Bone marrow mesenchymal stem cells or Netrin-1-bone marrow mesenchymal stem cells were injected into the ischaemic area of the rat hind limb on the first day after surgery. Laser Doppler perfusion imaging was performed to analyse the levels of vascular endothelial growth factor in plasma and muscles, and immunohistochemistry and immunofluorescence were used to analyse angiogenesis. Bone marrow mesenchymal stem cells in medium containing Netrin-1 markedly increased the number of tubes formed and the migration of bone marrow mesenchymal stem cells compared with the untreated control group. The function of Netrin-1 in tube formation and migration is similar to vascular endothelial growth factor, and combined with vascular endothelial growth factor, Netrin-1 has more enhanced effect than in the other three groups. The Netrin-1-bone marrow mesenchymal stem cell group had better augmented blood-perfusion scores and vessel densities, as well as improved function of the ischaemic limb than that of the group injected with bone marrow mesenchymal stem cells (treated with bone marrow mesenchymal stem cells individually) or the control group (treated with medium). These results suggest that Netrin-1 has the ability to augment the angiogenesis of bone marrow mesenchymal stem cells and improve the function of the ischaemic hind limb by increasing the level of vascular endothelial growth factor.

Transplantation of bone marrow mesenchymal stem cells (BMSCs) has been developed as a new method of treating diseases of the peripheral nervous system. While netrin-1 is a critical molecule for axonal path finding and nerve growth, it may also affect vascular network formation. Here, we investigated the effect of transplanting BMSCs that produce netrin-1 in a rat model of sciatic nerve crush injury. We introduced a sciatic nerve crush injury, and then injected 1×106 BMSCs infected by a recombinant adenovirus expressing netrin-1 Ad5-Netrin-1-EGFP or culture medium into the injured part in the next day. At day 7, 14 and 28 after injection, we measured motor nerve conduction and detected mRNA expressions of netrin-1 receptors UNC5B and Deleted in Colorectal Cancer (DCC), and neurotrophic factors brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) by real-time PCR. We also detected protein expressions of BDNF and NGF by Western blotting assays and examined BMSCs that incorporated into myelin and vascellum. The results showed that BMSCs infected by Ad5-Netrin-1-EGFP significantly improved the function of the sciatic nerve, and led to increased expression of BDNF and NGF (P<0.05). Moreover, 28 days after injury, more Schwann cells were found in BMSCs infected by Ad5-Netrin-1-EGFP compared to control BMSCs. In conclusion, transplantation of BMSCs that produce netrin-1 improved the function of the sciatic nerve after injury. This method may be a new treatment of nerve injury.