Dual actions of Netrin-1 on islet insulin secretion and immune modulation

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 [Ca²⁺]_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 Ca²⁺ 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.