Abstract
BackgroundA reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Neuronal insulin resistance is associated with several neurological disorders and recent evidence has indicated that dorsal root ganglion (DRG) neurons in primary culture display altered insulin signaling, yet in vivo results are lacking. Here, experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis.ResultsThe results indicate that insulin signaling abnormalities documented in other “insulin sensitive” tissues (i.e. muscle, fat, liver) of ob/ob mice are also present in the PNS. A robust increase in Akt activation was observed with insulin and IGF-1 stimulation in nondiabetic mice in both the sciatic nerve and DRG; however this response was blunted in both tissues from ob/ob mice. The results also suggest that upregulated JNK activation and reduced insulin receptor expression could be contributory mechanisms of PNS insulin resistance within sensory neurons.ConclusionsThese findings contribute to the growing body of evidence that alterations in insulin signaling occur in the PNS and may be a key factor in the pathogenesis of diabetic neuropathy.
Highlights
A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy
While altered insulin signaling is known to be the key factor in the development of diabetes, the role that it plays in diabetic neuropathy (DN) is not well understood
Statistical analysis of the data revealed that ob/ob mice maintained elevated glucose levels compared to nondiabetic controls throughout most of the study, and that the area under the curve (AUC) was significantly higher for diabetic ob/ob mice (Figure 1D)
Summary
A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis. Recent evidence suggests that cultured sensory neurons from insulinresistant mice display classic signs of insulin resistance and that insulin resistance may be contributing to mitochondrial dysfunction and increased ROS in DN [5,6,7]. While the exact mechanisms through which insulin promotes these functions remain unclear, insulin is considered a potent neurotrophic factor key to maintaining proper neuronal function
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