Glial cell alterations in diabetes-induced neurodegeneration

Abstract

Diabetic retinopathy; Glial cells; Neurodegeneration

Retinopatía diabética; Células gliales; Neurodegeneración

Retinopatia diabètica; Cèl·lules glials; Neurodegeneració

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.

This work was supported by a Miguel Servet Fellowship from the Spanish Health Institute Carlos III (CP21/00032 to AGF), a grant from the Spanish State Research Agency corresponding to “Plan Nacional 2021” (PID2021-124465OA-I00 to AGF), the Maria Zambrano fellowship from Spanish Ministry of Science, Innovation and Universities, financed by European Union “NextGenerationEU” (Universitat Autònoma de Barcelona, to MLS), a Miguel Servet Fellowship from the Spanish Health Institute Carlos III (CP22/00078 to JAGS), a grant from the Spanish State Research Agency corresponding to “Plan Nacional 2022” (PID2022-143269OB-I00 to JAGS) and a grant from the “X Convocatoria Intramural 2023” from ISABIAL (Modality F to AGF).