Glial cell alterations in diabetes-induced neurodegeneration

Abstract

Type 2 diabetes mellitus is a global epidemic that due to its increasing prevalence worldwide will likely become the most common debilitating health condition. Even if diabetes is primarily a metabolic disorder, it is now well established that key aspects of the pathogenesis of diabetes are associated with nervous system alterations, including deleterious chronic inflammation of neural tissues, referred here as neuroinflammation, along with different detrimental glial cell responses to stress conditions and neurodegenerative features. Moreover, diabetes resembles accelerated aging, further increasing the risk of developing age-linked neurodegenerative disorders. As such, the most common and disabling diabetic comorbidities, namely diabetic retinopathy, peripheral neuropathy, and cognitive decline, are intimately associated with neurodegeneration. As described in aging and other neurological disorders, glial cell alterations such as microglial, astrocyte, and Müller cell increased reactivity and dysfunctionality, myelin loss and Schwann cell alterations have been broadly described in diabetes in both human and animal models, where they are key contributors to chronic noxious inflammation of neural tissues within the PNS and CNS. In this review, we aim to describe in-depth the common and unique aspects underlying glial cell changes observed across the three main diabetic complications, with the goal of uncovering shared glial cells alterations and common pathological mechanisms that will enable the discovery of potential targets to limit neuroinflammation and prevent neurodegeneration in all three diabetic complications. Diabetes and its complications are already a public health concern due to its rapidly increasing incidence, and thus its health and economic impact. Hence, understanding the key role that glial cells play in the pathogenesis underlying peripheral neuropathy, retinopathy, and cognitive decline in diabetes will provide us with novel therapeutic approaches to tackle diabetic-associated neurodegeneration.

Keywords: Astrocytes; Cognitive decline; Diabetes; Diabetic neuropathy; Diabetic retinopathy; Glial cells; Microglia; Muller; Neurodegeneration; Schwann cells.

Fig. 1

Glial cells across the nervous system are implicated in diabetic complications. Schematic summary of the different central nervous system, peripheral nervous system, and enteric nervous system glial cells which functions are described in this review. This figure was created with BioRender.com

Fig. 2

Summary of the glial cell alterations described in the most common neural diabetic complications. Glial cells show altered functions in the retina, as well as the peripheral and enteric nervous system, where they share common and unique alterations in response to diabetes. This figure was created with BioRender.com. AQP4 aquaporin-4, BDNF brain-derived growth factor, CNS central nervous system, CXCL C-X-C motif chemokine ligand, DRG dorsal root ganglia, ENS enteric nervous system, GFAP glial fibrillary acidic protein, GLAST glutamate aspartate transporter, GLT-1 glutamate transporter-1, GS glutamine synthase, IFN interferon, IL- interleukin, NGF nerve growth factor, NT neurotrophin, PNS peripheral nervous system, TNF tumor necrosis factor, VEGF vascular endothelial growth factor