Insulin resistance (IR) is the major feature of metabolic syndrome, including type 2 diabetes. IR studies are mainly focused on peripheral tissues, such as muscle and liver. There is, however, little knowledge about IR in neurons. In this study, we examined whether neurons develop IR in response to hyperinsulinemia. We first examined insulin signaling using adult dorsal root ganglion neurons as a model system. Acute insulin treatment resulted in time- and concentration-dependent activation of the signaling cascade, including phosphorylation of the insulin receptor, Akt, p70S6K, and glycogen synthase kinase-3β. To mimic hyperinsulinemia, cells were pretreated with 20 nM insulin for 24 h and then stimulated with 20 nM insulin for 15 min. Chronic insulin treatment resulted in increased basal Akt phosphorylation. More importantly, acute insulin stimulation after chronic insulin treatment resulted in blunted phosphorylation of Akt, p70S6K, and glycogen synthase kinase-3β. Interestingly, when the cells were treated with phosphatidylinositol 3-kinase pathway inhibitor, but not MAPK pathway inhibitor, chronic insulin treatment did not block acute insulin treatment-induced Akt phosphorylation. Insulin-induced Akt phosphorylation was lower in dorsal root ganglion neurons from BKS-db/db compared with control BKS-db+ mice. This effect was age dependent. Our results suggest that hyperinsulinemia cause IR by disrupting the Akt-mediated pathway. We also demonstrate that hyperinsulinemia increases the mitochondrial fission protein dynamin-related protein 1. Our results suggest a new theory for the etiology of diabetic neuropathy, i.e. that, similar to insulin dependent tissues, neurons develop IR and, in turn, cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury and the development of neuropathy.

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal disorder involving the degeneration and loss of motor neurons. The mechanisms of motor neuron loss in ALS are unknown and there are no effective treatments. Defects in the distal axon and at the neuromuscular junction are early events in the disease course, and zebrafish provide a promising in vivo system to examine cellular mechanisms and treatments for these events in ALS pathogenesis.ResultsWe demonstrate that transient genetic manipulation of zebrafish to express G93A-SOD1, a mutation associated with familial ALS, results in early defects in motor neuron outgrowth and axonal branching. This is consistent with previous reports on motor neuron axonal defects associated with familial ALS genes following knockdown or mutant protein overexpression. We also demonstrate that upregulation of growth factor signaling is capable of rescuing these early defects, validating the potential of the model for therapeutic discovery. We generated stable transgenic zebrafish lines expressing G93A-SOD1 to further characterize the consequences of G93A-SOD1 expression on neuromuscular pathology and disease progression. Behavioral monitoring reveals evidence of motor dysfunction and decreased activity in transgenic ALS zebrafish. Examination of neuromuscular and neuronal pathology throughout the disease course reveals a loss of neuromuscular junctions and alterations in motor neuron innervations patterns with disease progression. Finally, motor neuron cell loss is evident later in the disease.ConclusionsThis sequence of events reflects the stepwise mechanisms of degeneration in ALS, and provides a novel model for mechanistic discovery and therapeutic development for neuromuscular degeneration in ALS.

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Background Head and neck pain is an atypical presentation of acute aortic dissection. Classic teaching associates this pain with proximal dissections, but this has not been extensively studied. Methods Patients enrolled in the International Registry of Acute Aortic Dissection from January 1996 to March 2015 were included in this study. We analyzed the demographics, presentation, treatment, and outcomes of Type A aortic dissection patients presenting with head and neck pain (n = 812, 25.8%) and compared it with those without these symptoms (n = 2,341, 74.2%). Results Patients with head and neck pain were more likely to be white, female, with a family history of aortic disease. Patients with head and neck pain had higher percentages of back pain (43.3% vs. 37.5%, p = 0.005) and chest pain (87.6% vs. 79.3%, p < 0.001). On imaging, a higher percentage of those with head and neck pain had arch vessel involvement (44.3% vs. 38%, p = 0.010) and intramural hematoma (11.7% vs. 8.1%, p = 0.003). Surgical management was more common in patients with head and neck pain (89.8% vs. 85.2%, p = 0.001). Regarding outcomes, patients with head and neck pain had significantly higher rates of stroke than those without head and neck pain (13% vs. 9.9%, p = 0.016); however, overall mortality was lower for those with head and neck pain (19.5% vs. 23%, p = 0.038). Those with head and neck pain only had higher overall mortality compared to those with head and neck pain with chest or back pain (34.6% vs. 19.9%, p = 0.013). A logistic regression of mortality revealed that preoperative hypotension and age > 65 years were significantly associated with increased mortality. Conclusion Presence of head and neck pain in Type A dissection is associated with more arch involvement, intramural hematoma, and stroke. When isolating those with head and neck pain only, there appear to be a higher rate of comorbidity burden and higher overall mortality.