Oligodendroctyes: the forgotten players of diabetes pathophysiology

Juan Antonio López-Villodres,Beatriz García-Díaz

Oligodendrocytes (OLs),glial cells that provide myelin sheaths to axons in the central nervous system (CNS),have a dual role.First,this myelin fatty cover around the axons protects the nerves and is crucial for the saltatory propagation of action potentials.Second and not less important,OLs provide trophic support to neurons and axons.Thus,OL metabolism is important for OL wellbeing and the proper accomplishment of their functions,and OL metabolism energetics directly affect the energy metabolism of neighboring neurons.

Unlike their counterparts in the peripheral nervous system,OLs myelinate more than one axon;sometimes OLs myelinate as many as 50 axons.Therefore,any alteration in OL energy physiology has a broad impact on CNS physiology and pathology and is an important cause of CNS neurodegeneration.

Despite the relevant importance of OLs in the proper function of the CNS and the symptomatic consequences that white matter alterations and neurodegeneration can have on patient quality of life,the effects of the chronic hyperglycemia of diabetes on OLs and myelin patterns have been neglected for years.In this article,we summarize the recent data on the pathogenic effects of high glucose levels on the oligodendroglial cells and white matter of diabetic patients to shed some light on the unexplored aspects of this pathology that remains to be elucidated.More in-depth study of this novel feature of diabetic pathogenesis will open up new avenues for treatments to improve patients’ quality of life.

White matter alterations in diabetes:Diabetes conditions refer to a group of diseases characterized by high blood glucose levels.It has long been known that uncontrolled hyperglycemia over time causes,among other consequences,central neurological damage in humans due to changes in brain transport,blood flow,metabolism,and microstructural brain alterations(Dolatshahi et al.,2023).

Among the systemic causes of diabetes physiopathogenesis,the overall impact of diabetes lies in the combination of its metabolic and vascular effects.These two factors have an outstanding effect on white matter development and maintenance.New studies have shown that the cognitive decline and dementia observed in diabetic patients are associated with CNS white matter alterations (O’Grady et al.,2019;Wang et al.,2022).Moreover,imaging studies have shown a reduction in the connectivity and function of CNS white matter tracts.

Glucose metabolism in oligodendrocyte differentiation:In adults,OLs differentiate from the OL progenitor cell (OPC) pool that is present in the CNS parenchyma.These precursor cells represent 4–5% of the total CNS cells and promote myelin turnover throughout life,both in physiological states (such as myelin plasticity and learning) and in pathological conditions (during CNS repair of any lesion).In addition,adult OLs are also responsible for new myelin formation,primarily enabling myelin plasticity through experience and,to a lesser extent,repairing myelin damage.

Therefore,oligodendroglial cells,both OPCs and mature OLs,have high energy demands constantly throughout life to endure as much as a 6500-fold increase in membrane area needed to ensheathe multiple axons.OPCs need to consume high levels of energy during their differentiation and myelination to produce myelin (lipid and protein synthesis).Mature OLs are not less energyconsuming.Managing constant and dynamic myelin maintenance and plasticity,OLs need to yield constant protein and lipid synthesis.Moreover,their role in coping with the trophic support of the axons necessitates an extra energy investment (Tepavcevic,2021).

These insights have indicated that OL metabolism is an important aspect to analyze in many neurodegenerative diseases in recent years.Among the energy substrates,glucose is the preferred fuel source of brain cells,including OLs and OPCs.Glucose is primarily catabolized via aerobic glycolysis,producing substrates to enter into different pathways: the first intermediate(glucose-6-phosphate,G-6-p) can be converted into the pentose phosphate pathway or continue down the pathway to decompose into pyruvate.Pyruvate might either fuel the mitochondrial respiratory chain or be converted into lactate and shuttled out to the periaxonal space (via the myelin-expressed MCT1 transporter) to feed neurons (Tepavcevic,2021;Figure 1).

Figure 1｜Proposed effects of high levels of glucose in myelin formation in healthy conditions versus diabetes.

Hence,the oligodendroglial cell need for this main substrate is tremendous.Not surprisingly,energy deprivation causes myelin alterations in pathological conditions such as vascular diseases,stroke,and secondary ischemia associated with some injuries.The underlying reason is that low levels of glucose have a significant role in arresting OL differentiation,as observed in anin vitrostudy(Rinholm et al.,2011).

Importantly,physiological levels of substrates are always in a range,but outside of the physiological range,the effects of any factor might be noxious.Glucose does not escape this homeostatic principle,and high blood glucose levels,such as those present in diabetic patients,have also been shown to have deleterious effects on oligodendroglial cells and are responsible for neurobehavioral and sensory-motor deficits (Wang et al.,2022).

Oligodendrocyte impairment in diabetes:Despite the growing knowledge about the pathophysiologic mechanisms of diabetes,the causes of CNS defects,particularly regarding oligodendroglial cells,remain largely unknown.Animal model studies have started to discern the involvement of each cell type.Specifically,the role of glucose levels in OL differentiation has started to be analyzed (Rinholm et al.,2011).However,whether the oligodendroglial damage caused by hyperglycemia is direct or indirect and whether these alterations affect every region equally or specific regions more than others remain largely unclear.

Anin vitroexperiment has undoubtedly shown that OL differentiation increases with increasing glucose levels in culture (Rinholm et al.,2011),and in this study,a maximum glucose concentration of 41.5 mM or 747.66 mg/dL was observed,which are higher levels than those observed in diabetic patients and diabetes model animals.Furthermore,OPCs and myelinating OLs are closely associated with the vascular network,indicating that during their differentiation process,OLs have direct access to glucose in the blood stream by glucose transporters such as Glut1.Thus,anin vitrostudy suggests that hyperglycemic conditions favor myelin plasticity or repair,contrary to what occurs in the ischemic lesions of diabetes patients and model animals (Ma et al.,2018).

Some diabetes model rodents with blood glucose concentrations lower than those assessed in culture (30 mM) show a decreased number of OPCs,with a reduced capacity of OPCs to migrate and survive and a diminution of myelin expression and OL ultrastructural alterations(Wang et al.,2022).Moreover,OPC proliferation and OL formation of new myelin after ischemia are dampened under high glucose conditions (Ma et al.,2018).In contrast,other diabetes model animals have shown no differences in OL numbers(Lietzau et al.,2020),highlighting the need for a better understanding of the mechanism underlying white matter dysfunction in hyperglycemic conditions.

The first rationale that emerged from this apparent disagreement between thein vitroandin vivoanalyses was the role of microglia in OL differentiation.Extensive studies have documented a shift from the M2/proregenerative phenotype toward the M1/proinflammatory phenotype of CNS-resident microglia associated with diabetes (Vargas-Soria et al.,2023).While M2 microglia favor OL differentiation,an environment influenced by M1 microglia impairs this process.

In addition,blood-brain barrier permeability is also increased in diabetes.This increased permeability facilitates the infiltration of monocyte-derived macrophages that,together with the effects of hyperglycemia on proinflammatory microglia,burst into exacerbated CNS chronic inflammation and therefore impair OL differentiation.

Other factors developed during the disease might have a direct effect on OPC/OL physiology.For instance,high glucose levels induce microvasculature alterations in the diabetic brain,causing alterations in blood supply and a higher risk of developing atherosclerosis.Vascular atrophy might allow enough glucose substrate supply to be present in hyperglycemic conditions,but the resulting reduction in blood flow diminishes oxygen perfusion in the brain.Under favorable and nutrient-rich conditions,OPCs and OLs both rely significantly more on glycolysis than OXPHOS to generate ATP (Narine and Colognato,2022),escaping their need for oxygen.However,during OL differentiation,oligodendroglial cells need more active metabolism and oxidative respiration.As mentioned,OPCs and OLs are activated both under physiological conditions(myelin plasticity and maintenance) and after white matter injury.Then,oxygen is needed to carry out the mitochondrial respiration necessary for the progression of OL maturation.Blocking oxidative respiration has been shown to impair OL differentiation (Ziabreva et al.,2010).Thus,the imbalance between glucose availability and oxygen presence might disturb OPC/OL metabolism and the myelination process.Nevertheless,more studies are needed to elucidate the effect of glucose/oxygen imbalance on OL differentiation.

Insights from the altered signaling pathways in peripheral myelinating Schwann cells during diabetes,such as increased polyol pathway signaling,suggest another pathogenic aspect of the effect of hyperglycemia on OLs.In Schwann cells,high glucose levels activate aldose reductase,the first enzyme in the polyol pathway,which converts glucose to sorbitol.Aldose reductase activity drives Schwann cells toward an immature phenotype and increases the flux through the polyol pathway,depleting cytosolic NADPH and leaving Schwann cells more vulnerable to reactive oxygen species.Aldose reductase is also present in OLs,raising the hypothesis that an increased influx toward this polyol pathway might be an unexplored component in CNS myelin disruption due to hyperglycemia (Goncalves et al.,2017;Figure 1).

High glucose levels in Schwann cells also cause the excessive formation of advanced glycation end-products,activating the receptor for advanced glycosylation end products and inducing modifications to proteins,lipids,and nucleic acids(such as DNA methylation) (Goncalves et al.,2017).These pathogenic factors already described in peripheral myelinating cells suggest that similar alterations may occur in OLs;nevertheless,these aspects remain understudied.

On the other hand,the presence of proper oxygen levels in diabetic conditions induces long-term hyperactivation of mitochondria and consequent escalation of oxidative stress.This glucose overload results in mitochondrial dysfunction.Although OLs rely less on mitochondrial respiration after myelination is complete,mitochondrial disruption can diminish the potential of OLs to respond to brain plasticity or injury.Notably,mitochondria are also present within the myelin sheath and are able to respond to Ca2+entry through NMDA receptors (Meyer and Rinholm,2021),suggesting a persistent role of these organelles in mature OLs.Finally,oxidative stress and the high levels of reactive oxygen species in OPCs and OLs might damage the DNA/RNA of these cells,ensuring their malfunction (Figure 1).Although much is still unknown about the roles of OL mitochondria in brain plasticity and repair,it is reasonable to think that their malfunction might impair the wellbeing of these cells,altering the trophic support that they provide to the axons and diminishing their neuroprotective role,therefore causing neurodegeneration and the consequent associated neurological symptoms of diabetes.

Insulin resistance in oligodendrocytes:An early feature of type II diabetes,the most common type of diabetes to develop in conditions of overweight or physical inactivity,is insulin resistance.Imaging studies have also shown that even in the initial stages of the disease,higher insulin resistance has been associated with significant myelin alterations in the human brain,diminishing or increasing the white matter content in specific areas (O’Grady et al.,2019).Insulin resistance is defined as the altered response to insulin by the cells.Regarding OLs,both insulin and insulin-like growth factor-1 stimulate OL development,most likely due to their effects on lipogenesis and cholesterologenesis,which are essential for myelin synthesis.Thus,the loss of insulin sensitivity and/or the reduction in insulin levels observed in the cerebrospinal fluid of diabetic patients (O’Grady et al.,2019) may trigger the white matter alterations observed in these patients.

In short,many aspects of the effects of chronic hyperglycemia and diabetes on the development and maintenance of oligodendroglial cells and their involvement in the CNS dysfunction observed in diabetic patients remain unclear.A better understanding of the effects of chronic high glucose levels on oligodendroglial cells might lead to the design of new strategies to alleviate extrinsic or intrinsic harmful cues in these cells,such as anti-inflammatory or antioxidant treatments.Therefore,the growing evidence about this aspect of diabetes pathogenesis encourages hope for the ability to counteract another aspect of the disease and the exploration of novel therapeutic approaches to ameliorate the clinical course of this pathological condition.

This work has been funded by Instituto de Salud Carlos III(ISCIII)through the project“CP20-0049”and co-funded by the European Union(to BGD).

Juan Antonio López-Villodres,Beatriz García-Díaz*

Departamento Fisiología Humana,Histología Humana,Anatomía Patológica y Educación Física y Deportiva,Facultad de Medicina,Universidad de Málaga,Málaga,Spain (López-Villodres JA)UGC Neurociencia.Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (IBIMA Plataforma Bionand),Málaga,Spain (García-Díaz B)

*Correspondence to:Beatriz García-Díaz,PhD,beatriz.garcia@ibima.eu.

https://orcid.org/0000-0003-2655-571X(Beatriz García-Díaz)

Date of submission:October 24,2023

Date of decision:December 6,2023

Date of acceptance:December 24,2023

Date of web publication:January 31,2024

https://doi.org/10.4103/NRR.NRR-D-23-01754

How to cite this article:López-Villodres JA,García-Díaz B(2024)Oligodendroctyes:the forgotten players of diabetes pathophysiology.Neural Regen Res 19(11):2349-2350.

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