Disrupting insulin signaling in Schwann cells impairs myelination and induces a sensory neuropathy

Abstract

Although diabetic mice have been studied for decades, little is known about the cell type specific contributions to diabetic neuropathy (DN). Schwann cells (SCs) myelinate and provide trophic support to peripheral nervous system axons. Altered SC metabolism leads to myelin defects, which can be seen both in inherited and DNs. How SC metabolism is altered in DN is not fully understood, but it is clear that insulin resistance underlies impaired lipid metabolism in many cell types throughout the body via the phosphoinositide 3‐kinase/protein kinase b (PKB)/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Here, we created an insulin resistant SC by deleting both insulin receptor (INSR) and insulin‐like growth factor receptor 1 (IGF1R), to determine the role of this signaling pathway in development and response to injury in order to understand SC defects in DN. We found that myelin is thinner throughout development and adulthood in INSR/IGF1R Schwann cell specific knock out mice. The nerves of these mutant mice had reduced expression of key genes that mediate fatty acid and cholesterol synthesis due to reduced mTOR–sterol regulatory element‐binding protein signaling. In adulthood, these mice show sensory neuropathy phenotypes reminiscent of diabetic mice. Altogether, these data suggest that SCs may play an important role in DN and targeting their metabolism could lead to new therapies for DN.

Genome-wide profiling of DNA methylation and gene expression identifies candidate genes for human diabetic neuropathy

“…Impaired insulin signaling in DPN may induce myelination deficits in Schwann cells and insulin resistance in sensory neurons [66,67]. Our results show that insulin signaling pathway genes such as IRS2 are differentially methylated and that IGF-I is downregulated, indicating impaired insulin signaling in the sural nerves of patients with higher HbA1c.…”

“…Insulin and IGF-I both signal through the PI3K-Akt pathway, which in turn exerts multiple cellular actions through downstream effectors, including the mammalian target of rapamycin complex 1 (mTORC1) [68]. PI3K-Akt-mTORC1 signaling is heavily implicated in Schwann cell lipid synthesis, a critical mechanism for myelination [66], whose disruption is associated with impaired nerve function [69]. Consistent with these findings, our KEGG-based analysis revealed a dysregulated PI3K-Akt pathway at both the DNA methylation and gene expression levels, and suggests that DNA methylation may be a new mechanism for regulating PI3K-Akt in peripheral nerves.…”

Considerations for a Reliable In Vitro Model of Chemotherapy-Induced Peripheral Neuropathy

“…The application of hiPSCs to generate a variety of cell types found in the peripheral nervous system presents an exciting opportunity to explore the interactions of these various cell types (Schwann cells, satellite glial cells) in a controlled fashion. Advancements in understanding the role of Schwann cells in the pathology of neuronal disease, including peripheral neuropathy [121][122][123][124][125][126][127], highlight their consideration for development of more complex in vitro models of CIPN. In the meantime, a hiPSC-derived PSN cell model is urgently needed to advance the understanding of the pathogenesis of CIPN and identify gaps requiring deeper exploration for the prevention and treatment of CIPN.…”

Schwann cell interactions during the development of the peripheral nervous system

“…Mice lacking the LRP1 in Schwann cells have mildly thinner myelin, Remak bundle deformities, and present with mechanical allodynia (Orita et al, 2013). Other molecules exogenous to the nervous system such as insulin and insulin-like growth factor have also been suggested to help shape proper PNS development since mice lacking the insulin receptor and the insulin-like growth factor receptor 1 in Schwann cells have thinner myelin and radial sorting defects (Hackett, Strickland, & Milbrandt, 2019). Therefore, Schwann cell communication beyond the traditionally considered axons and ECM, is likely to contribute to the generation of the functionally sound nerve unit.…”