Effects of Liraglutide on Neuronal Insulin Resistance in in vitro

Abstract

Brain insulin resistance has been shown to be associated with cognitive impairment and Alzheimer’s disease (AD). Several studies have been demonstrated that AD and type 2 diabetes mellitus (T2DM) shared some risk factors including amyloidogenesis and brain insulin resistance. Liraglutide is a long-acting GLP-1 receptor agonist using in T2DM therapy. Several studies showed that liraglutide has beneficial effects on brain function including the cognitive improvement, decreased AD-like characteristics such as amyloid plaque and also has neuroprotective effects. However, the effect of liraglutide on the model of neuronal insulin resistance with AD-like characteristics has not been thoroughly investigated yet. In the present study, the model of neuronal insulin resistance with AD-like characteristics was established by using human neuroblastoma cell line (SH-SY5Y). Those cells were induced to be insulin resistance with 100 nM insulin for 2 days. The insulin resistant characteristics were indicated as an impairment of insulin signaling, including decreased phosphorylation of insulin receptor (IR) and the down-stream signaling; AKT and GSK3β. The AD-like characteristics as indicated by increased amyloid-β and Tau phosphorylation and the expression of extracellular insoluble plaques was also found in this model. Moreover, this chronic insulin resistant condition also increased cell death by increasing Bax/Bcl2 ratio. The application of 500 nM liraglutide onto the model of neuronal insulin resistance with AD-like characteristics improved neuronal insulin sensitivity and decreased AD characteristics but it could not improve cell death. These findings suggest that liraglutide is a promising therapy for AD with insulin resistant condition.