role of neuropoietic cytokines in development and...

Experimental Diab. Res., 4:303–312, 2003Copyright c© Taylor and Francis Inc.ISSN: 1543-8600 print / 1543-8619 onlineDOI: 10.1080/15438600390249736

Role of Neuropoietic Cytokines in Developmentand Progression of Diabetic Polyneuropathy: From GlucoseMetabolism to Neurodegeneration

Dusanka S. Skundric and Robert P. Lisak

Department of Neurology, Division of Neuroimmunology, and Department of Immunologyand Microbiology, Wayne State University School of Medicine, Detroit Medical Centre, Detroit,Michigan, USA

Diabetic neuropathy develops as a result of hyper-glycemia-induced local metabolic and microvascularchanges in both type I and type II diabetes mellitus. Diabeticneuropathy shows slower impulse conduction, axonal de-generation, and impaired regeneration. Diabetic neuropa-thy affects peripheral, central, and visceral sensorimotorand motor nerves, causing improper locomotor and vis-ceral organ dysfunctions. The pathogenesis of diabetic neu-ropathy is complex and involves multiple pathways. Lackof success in preventing neuropathy, even with successfultreatment of hyperglycemia, suggests the presence of earlymediators between hyperglycemia-induced metabolic andenzymatic changes and functional and structural proper-ties of Schwann cells (SCs) and axons. It is feasible thatonce activated, such mediators can act independently of theinitial metabolic stimulus to modulate SC-axonal communi-cation. Neuropoietic cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), leukemia inhibitory factor (LIF),ciliary neurotrophic factor (CNTF), tumor necrosis factoralpha (TNF-α), and transforming growth factor beta (TGF-β), exhibit pleiotrophic effects on homeostasis of glia andneurons in central, peripheral, and autonomic nervous sys-tem. These cytokines are produced locally by resident andinfiltrating macrophages, lymphocytes, mast cells, SCs, fi-broblasts, and sensory neurons. Metabolic changes inducedby hyperglycemia lead to dysregulation of cytokine control.Moreover, their regulatory roles in nerve degeneration and

Received 13 February 2003; accepted 11 June 2003.Address correspondence to Dusanka S. Skundric, MD, PhD, De-

partment of Neurology, Wayne State University School of Medicine,421 E. Canfield, 3141 Elliman Building, Detroit, MI 48201, USA.E-mail: [email protected]

regeneration may potentially be utilized for the preventionand/or therapy of diabetic neuropathy.

Keywords Cytokines; Diabetic Neuropathy; Schwann Cell

INTRODUCTIONDiabetic polyneuropathy is a chronic complication of both

type I and type II diabetes mellitus. It affects peripheral, cen-tral, and visceral sensorimotor and motor nerves. Diabetic neu-ropathy develops as a result of hyperglycemia-induced localmetabolic and microvascular changes. Chronic complications,including neuropathy, retinopathy, and nephropathy, are majorcauses of morbidity and mortality in patients with type I andtype II diabetes (review by Sheetz and King, 2002; Williamset al., 2002).

In peripheral nerve, abnormalities of the Na+ and K+ trans-port along myelinated axons lead to impairment of the nervefunction. Insufficient function of the peripheral nerve is mani-fested as slower conduction velocity, which develops early af-ter the onset of diabetes. This early functional abnormality isfollowed by more pronounced changes in the morphology ofSchwann cells (SCs), axons, and sensory neurons, which ulti-mately lead to axonal degeneration. Studies from experimentalmodels that resemble the patterns of human pathology provideinsights into the metabolic and molecular pathways underly-ing diabetic neuropathy (Sima et al., 2000, Sima, 2001; reviewby Eckersley, 2002). Homeostasis of myelinated peripheralnerve fibers is maintained through the SC-axonal contacts andcommunications. This includes, but is not limited to, production

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of neuropoietic cytokines and neurotrophic factors, expressionof cell adhesion molecules (CAMs) and deposition of extra-cellular matrix (ECM) by SCs. In diabetic neuropathy, manyaspects of SC-axonal communication are compromised. Dis-turbed local homeostasis leads to axonal degeneration accom-panied by impaired ability to regenerate (Xu et al., 2002). Con-ventional therapy of diabetes and maintenance of euglycemiclevels combined with auxiliary therapies to increase perfusionand/or prevent aberrant pathways of glucose metabolism havefailed to halt and/or restore functional and structural changesof peripheral nerve, in both humans and experimental ani-mals. This striking lack of success in preventing neuropathy,even with successful treatment of hyperglycemia, suggests thepresence of early mediators between hyperglycemia-inducedmetabolic and enzymatic changes and functional and structuralproperties of SCs and axons. It is feasible that once activated,such mediators can act independently of the initial metabolicstimulus to modulate SC-axonal communication. Partial suc-cess of some therapies in abrogating signs of already devel-oped diabetic neuropathy argues against the development ofcompletely irreversible changes, and provides hope for the dis-covery of novel therapies targeting early factors involved inpathogenesis of diabetic neuropathy. It is clear that the patho-genesis of diabetic neuropathy is complex and involves mul-tiple pathways. Therefore, early therapeutic intervention withcombined therapies aimed at modulation and/or blocking ofaberrant pathways might prove to be beneficial in the preven-tion and/or reversal of diabetic neuropathy. Such an approachis further emphasized by findings that combined blocking ofseveral pathways, independently induced by high glucose, isneeded for restoration of the metabolic abnormalities that un-derlie microvascular complications in diabetes. This therapeu-tic strategy has proved successful in the treatment of experi-mental diabetic retinopathy (Nishikawa, 2000; Hammes et al.,2003).

In this article we will briefly summarize major properties of aspecific group of mediators called neuropoietic cytokines withinthe peripheral nervous system (PNS) and present evidence fortheir role in the regulation of homeostasis, glucose metabolism,degeneration, and regeneration of the peripheral nerve. Neu-ropoietic cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), ciliary neurotrophicfactor (CNTF), tumor necrosis factor alpha (TNF-α) and trans-forming growth factor beta (TGF-β), are potent regulators ofhomeostatic properties of peripheral nerve. These cytokinesare produced locally by resident and infiltrating macrophages,lymphocytes, mast cells, SCs, fibroblasts, and sensory neurons.Metabolic changes induced by hyperglycemia lead to dysregu-lation of cytokine control.

METABOLIC CHANGES IN THE DIABETICPERIPHERAL NERVE

Elevated blood glucose levels activate aberrant pathways ofglucose metabolism, such as the polyol pathway. Activation ofsuch metabolic pathways leads to accumulation of their specificend products, such as sorbitol and fructose, and secondarilyperturbs phosphoinositide turnover and diacylglycerol (DAG),which in turn may directly or indirectly cause damage to glia andneurons. Furthermore, local accumulation of these end productsinduces changes in cell signaling in glia and neurons, perturbingvarious homeostatic functions regulated by those cell-signalingpathways (review by Sheetz and King, 2002).

The hallmarks of glucose metabolism through the polyolpathway are activation of the enzyme aldose reductase (AR) andaccumulation of sorbitol. Depending on its intracellular concen-tration, sorbitol may have either toxic or hyperosmotic effectson cells. Increased intracellular osmotic pressure, together withperturbed balances and exchange of cations and anions, affectstranscription of numerous genes, including genes of proinflam-matory cytokines IL-1, IL-6, and TNF-α. However, therapiesaimed at inhibiting AR used for the treatment and/or preven-tion of diabetic neuropathy in humans have failed to achievedesired effects. Similar therapies, if started early in differentanimal models of diabetic neuropathy, have, however, shownpromising results in ameliorating neuropathy (review by Sima,2001; Simmons and Feldman, 2002).

Hyperglycemia leads to accelerated phosphoinositideturnover, activation of phospholipase D and changes of DAGlevels (Sugimoto et al., 2000). Although hyperglycemia inperipheral nerve leads to overall impaired phosphoinositideturnover, DAG accumulation and total protein kinase C (PKC)expression (Eichberg, 2000), there is evidence to suggest thatvascular PKC-β isoforms are increased in diabetic nerve. Ac-tivated phospholipase D and DAG induce changes in the ac-tivation of PKC and expression of its isoforms in peripheralnerve. Changes in PKC activation and/or PKC isoform ex-pression can modulate the activity of Na+, K+-ATPase. TheNa+,K+-ATPase pump actively regulates intracellular concen-trations of these two cations important for the function ofcellular enzymes and transcription factors, such as activatorprotein-1 (AP-1) and nuclear factor kappa B (NF-κB). Tran-scription factors AP-1 and NF-κB are involved in the initia-tion of the transcription of numerous genes, including proin-flammatory and neuropoietic cytokines (IL-1, IL-6, TNF-α).In SCs, stimulation of PKC through extracellular signal regu-lated kinase (ERK) activation regulates the levels of LIF mRNA(Nagamoto-Combs et al., 1999). Neuropoietic cytokines havepleiotrophic effects on glia and neurons, either directly orindirectly through regulation of neurotrophic factors. The

NEUROPOIETIC CYTOKINES IN DPN 305

binding of cytokines to the gp130 receptor activates the signaltransducer and activators of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK), MAPK kinase (MEK), phos-phatidylinositol 3-kinase (PI3K), and serine/threonine kinasescalled Akt (protein kinase B) signaling pathways. These signal-ing pathways play important roles in the regulation of cellularglucose metabolism and cell survival. STAT3 and PI3K/Akt sig-naling play major roles in mediating the survival response ofneurons to cytokines (Alonzi et al., 2001). The same signalingpathways may be activated by insulin itself and synergisticallyso by C-peptide (Grunberger et al., 2001; Li et al., 2002).

Lack of neurotrophic support by nerve growth factor (NGF),neurotropin-3 (NT-3), brain-derived nerve factor (BDNF),insulin-like growth factor-I (IGF-I), and vascular endothelialgrowth factor (VEGF) is implicated in apoptosis of dorsalroot ganglia sensory neurons and axonal degeneration in di-abetes (Thrailkill, 2000; Carmeliet and Storkebaum, 2002;Nitta et al., 2002). Systemic therapies aimed to supplementlocal trophic factor deficiency have shown limited or no ef-fects (Pradat et al., 2001; Wellmer et al., 2001) in the pro-tection and/or repair of diabetic peripheral nerve. In vitro ex-periments in which SCs were cultured in the presence of el-evated glucose concentration revealed alterations in arachi-donic acid metabolism. Decreased content of glycerophos-pholipid arachidonoyl-containing molecular species (ACMS),decreased free cytosolic nicotinamide adenine dinucleotide(NAD+/NADH), increased malondialdehyde, depleted glu-tathione levels, and reduced cytosolic superoxide dismutaseactivity suggest that high glucose level elicit oxidative stressin SCs cultures (Miinea et al., 2002; Vincent et al., 2002). Ox-idative stress and inflammatory cytokines influence the bidirec-tional relationship between iron metabolic pathways and glu-cose metabolism, amplifying and potentiating hyperglycemia-induced events (Fernandez-Real et al., 2002). In peripheralnerve, cytokines regulate functions essential for SC-axonalhomeostasis and nerve regeneration, such as production ofECM, expression of CAMs, and organization of the cytoskele-ton (Chandross et al., 1996). Lack of CAM expression bySCs and/or dysregulation of ECM production and deposi-tion by SCs lead to improper contact between SCs and ax-ons (Stewart et al., 1997). If not corrected, these abnormal-ities may cause degenerative changes such as fiber loss andperinodal demyelination (Fu and Gordon, 1997). Regulationof Na+ and K+ voltage-gated channel expression and func-tion by proinflammatory cytokines has been reported in cen-tral nervous system (CNS) (Vega et al., 2002). The exis-tence of similar mechanisms in peripheral nerve and theirrelevance for impulse propagation remain to be investigated(Figure 1).

NEUROPOIETIC CYTOKINES: ROLE INHOMEOSTASIS, DEGENERATION, ANDREGENERATION OF PERIPHERAL NERVEAND RELATION TO GLUCOSE METABOLISM

Neuropoietic cytokines from the IL-1 and IL-6 families,TNF-α, and TGF-β exhibit pleiotrophic effects on glia cells andneurons important for the homeostasis of the peripheral, cen-tral, and autonomic nervous systems (Armati and Pollard, 1996;Benveniste, 1998; Chalazonitis et al., 1998; Charon et al., 1998;Geissen et al., 1998; Horton et al., 1998; Lisak et al., 1997). Inthis section, we will focus on cytokines produced locally bySCs and/or sensory neurons in the PNS and their effects on reg-ulation of homeostasis and degeneration and regeneration ofperipheral nerve. The effects of cytokines on similar functionsin the CNS and autonomic nerves have been studied to a lesserextent.

Cytokines produced in peripheral nerve originate from res-ident and infiltrating macrophages, lymphocytes, mast cells,SCs, fibroblasts, and probably neurons. Cytokines are involvedin the pathogenesis of nerve damage as well as repair. For ex-ample, TNF-α injected into nerve induces inflammatory de-myelination and wallerian degeneration, whereas IL-1 produc-tion promotes phagocytosis by scavenger macrophages and thesynthesis of neurotrophic factors nerve growth factor (NGF)and LIF (Lindholm et al., 1987; Carlson et al., 1996). Afterexperimental axotomy, other neuropoietic cytokines, includingIL-6, LIF, and TGF-β1, are overexpressed in nerve and pro-mote axonal growth until the contact with SCs is established.Proinflammatory cytokines are instrumental to the courseof inflammatory demyelinating neuropathies. They increasevascular permeability of the blood-nerve barrier, which favorstransmigration of leukocytes into nerve. They induce activa-tion and proliferation of lymphocytes and macrophages andmay have a direct myelinotoxic activity. In addition, down-regulation of the immunosuppressive cytokine TGF-β1 mayfavor the nerve inflammatory reactions (reviewed by Creangeet al., 1997).

Mechanisms leading to nerve degeneration and regenera-tion are essential in the pathogenesis of diabetic neuropathy.Compared to normal, the ability of diabetic peripheral nerveto regenerate is significantly diminished (Cameron and Cotter,1997). In a comparative analysis, Pierson et al. (2003) foundthat regenerative potentials in type I are affected to a greaterextent than in type II diabetic neuropathy. The regulatory rolesof cytokines in nerve degeneration and regeneration may po-tentially be utilized for the prevention and/or therapy of di-abetic neuropathy. Prior to attempting cytokine-based therapy,one needs to understand the effects of long-term hyperglycemiaon the local cytokine network. Data are still lacking regarding


FIGURE 1Schematic diagram of major aberrant metabolic pathways induced by hyperglycemia. The proposed role of proinflammatory

cytokines in relation to metabolic end products, activated enzymes, transcription factors, neuropoietic cytokines, and moleculesinvolved in Schwann cell–axonal communication.

the mechanisms involved in cytokine regulation by long-termhyperglycemia in peripheral nerve. Therefore, this review willfocus on bringing together existing knowledge about major reg-ulatory properties of neuropoietic cytokines in nerve degener-ation and regeneration, and how these may be of relevance fordiabetic neuropathy. Each cytokine family will be discussedseparately because of many shared properties within familymembers. Some properties are shared between different cy-tokines and therefore cytokine redundancy plays an importantrole in the local cytokine network. Finally we will incorporatedata from studies on cytokine regulation in diabetic neuropathy,which are still sparse but emerging. In different experimentalmodels of diabetic neuropathy, only a handful of laboratories,including ours, have directly studied the regulation of cytokines

and its role in the pathogenesis of diabetic neuropathy. There-fore, for the most part, we will summarize data from differ-ent models of nerve degeneration and regeneration, which arerelevant to diabetic neuropathy, attempting to underscore thesignificance of further understanding of cytokine regulation insimilar processes pertaining to diabetic neuropathy.

Autocrine Regulation of IL-1 in PeripheralNerve: Role in Homeostasis, Regenerationand the Pathogenesis of Diabetic Neuropathy

The SC is the myelin-producing glia of the PNS. It is respon-sible for myelination and ensheathment of myelinated periph-eral nerve, fibers. SCs also provide trophic support for neuronal


cells by regulation of neurotrophin, production in both normaland pathologic states. IL-1 is a proinflammatory and neuropoi-etic cytokine, locally produced by SCs, endoneurial and infil-trating macrophages and fibroblasts in peripheral nerve, andsensory neurons in dorsal root ganglia (Lisak et al., 1997). IL-1regulates the production of other cytokines, neurotrophins, andpain mediators by SCs and sensory neurons (Shadiack et al.,1993). IL-1 induces production of NGF (Lindholm et al., 1987).Operating as autocrine and paracrine factors, locally producedproinflammatory cytokines, including IL-1, IL-6 and TNF-α,interact through a cytokine-specific network in the PNS. Consti-tutive expression of IL-1α, IL-1β, interleukin beta–convertingenzyme (ICE, caspase-1), and type I IL-1 receptor (IL-1RI) hasbeen detected in normal adult sciatic nerve. Proinflammatorycytokines are up-regulated by peripheral nerve injury, includ-ing contusion, transection, toxicity, autoimmune, and metabolicinsults. Rapid up-regulation of cytokines following injury to pe-ripheral nerve precedes macrophage infiltration and secretion ofother products of inflammation. IL-1 is especially important forthe regulation of macrophage chemoattraction by stimulationof macrophage chemoattractant protein-1 (MCP-1, CCL2) bySCs. SCs of denervated nerves attract macrophages by secretionof MCP-1 in a process regulated by IL-6 and LIF (Tofaris et al.,2002). LIF mRNA is virtually undetectable in uninjured sensoryneurons but is induced by the inflammatory cytokine IL-1. Bio-logical properties of IL-1 are mediated through IL-1RI, whichhas been suggested to stimulate a ceramide-dependent proteinkinase pathway, much like TFN-α (Dinarello and Thompson,1991) IL-1 regulation of LIF mRNA, through stimulation ofthe endosomal, acidic sphingomyelinase pathway, leads to ce-ramide activation of PKC zeta (Carlson and Hart, 1996). IL-1β induction of LIF gene expression is at least partially tran-scriptional, but LIF mRNA increases to a greater extent thanLIF transcription, suggesting a post-transcriptional regulationas well (Carlson et al., 1996).

IL-1β, IL-6, and LIF affect dorsal root ganglia neurons interms of survival or neuritogenesis. Some of the effects are in-direct, probably mediated by NGF (Edoff and Jerregard, 2002).SCs regulate IL-1 production in an autocrine manner. Theyproduce both IL-1α and IL-1β and a natural antagonist, IL-1 receptor antagonist (IL-1RA). SCs also express IL-1R I, abiologically active IL-1 receptor (Skundric et al., 1997).

The ability of SCs to autoregulate IL-1 is activated in lo-cal immune regulation during autoimmune demyelinating neu-ritis (Figure 2) (Skundric et al., 2001). We investigated IL-1autoregulation in sciatic nerves of BB/W spontaneously dia-betic rats throughout the course of diabetic neuropathy. Ourresults showed activation of IL-1 signaling pathway in SCs,prior to and during the early stages of diabetic neuropathy, thussuggesting a role in the initiation of abnormal SC-axonal in-

teraction (Skundric et al., 2002a). Activation of ICE (caspase-1) corresponded to up-regulation of IL-1β production and re-cruitment of IL-1 receptor associated kinase (IRAK) by SCsat the early stages of neuropathy. Moreover, activation of IL-1signaling was occurring concomitantly with activation of IκBand subsequent translocation of NF-κB p65 in SCs (Skundricet al., 2002a). Activation of IL-1 signaling pathway may im-pact on the regulation of other proinflammatory cytokines indiabetic nerve. It may also be involved in the regulation ofoxidative metabolism through regulation of inducible nitricoxide synthase (iNOS) and therefore reactive oxygen species(ROS). Oxidative stress has been recently proposed as a mecha-nism responsible for apoptosis induction in diabetic neuropathy(Vincent et al., 2002).

Taken together, IL-1 is a potent regulator of both homeo-static mechanisms relevant for peripheral nerve function andIL-1 signaling, involved in pathogenic mechanisms implicatedin the development of diabetic neuropathy. Activation of IL-1signaling in diabetic nerve may thus represent initial compen-satory effects and, if sustained, may contribute to ongoing de-generation. Future experiments designed to examine functionaland structural changes in diabetic nerve induced by local mod-ulation of IL-1 signaling are needed to explore these potentialeffects. The IL-1 cytokine family and components of IL-1–specific signaling cascade have been thoroughly described andmany transgenic mice models have been generated to facilitatethe study of IL-1 pathways. Unfortunately, the utilization oftransgenic mice is of limited use for experiments required tounderstand the role of IL-1 in diabetic neuropathy. Such ex-periments have been mainly hampered by the significant roleof proinflammatory cytokines in the pathogenesis of type I di-abetes. Therefore, strategies to modulate cytokine productionand signaling locally need to be explored. Such approaches arefeasible in the case of IL-1; the basis for experimental therapiesmay include local use of the natural antagonist IL-1RA, specificsignaling blockers, and IL-1–specific traps.

NEUROPOIETIC PROPERTIES OF IL-6, LIF,AND CNTF: REGULATION IN DIABETICNERVE

IL-6, CNTF, LIF, and cardiotrophin-1 (CT-1) comprise agroup of structurally related cytokines that promote the sur-vival of subsets of neurons in the developing peripheral ner-vous system through activation of transcription factor NF-κB(Middleton et al., 2000). Constitutive expression of IL-6, IL-6receptors, and the signaling protein of the IL-6 receptor, gp130,suggests a role in the homeostasis of the peripheral nerve. IL-6 isinduced in peripheral nerve following injury and it is producedby SCs (Bolin et al., 1995). The role of neuropoietic cytokines


FIGURE 2Schematic diagram presenting IL-1 autoregulation by Schwann cells, macrophages (Mo), and T lymphocytes (Th1) in the

peripheral nerve during experimental autoimmune neuritis (EAN).

of the IL-6 family in the homeostasis and regeneration of theperipheral nerve can be modulated by neurotrophins. This reg-ulation is bidirectional and influences the regenerative abilityof the peripheral nerve. For example, NGF inhibits sympatheticneurons’ response to LIF through regulation of injury-inducedmolecules, such as galanin. Galanin expression is triggered bytwo consequences of nerve transection: the induction of LIFand the reduction in the availability of the target-derived factor,NGF (Shadiack et al., 1998). Similarly, damage-induced neu-ronal endopeptidase (DINE/ECEL) expression is regulated byLIF induction and deprivation of NGF in rat sensory gangliaafter nerve injury (Kato et al., 2002).

In human chronic inflammatory demyelinating polyneu-ropathy (CIDP), multiple neurotrophic growth factors andcytokines, NGF, glial cell line-derived neurotrophic factor(GDNF), LIF, and IL-6, are expressed together with their con-comitant receptors in the nerve lesions and play an importantrole particularly in nerve repair (Yamamoto et al., 2002). Thefact that the expression of neuropoietic cytokines and their re-ceptors correspond to similarities in pathologic, events, rather

than a specific disease, is clear from analyses of various hu-man peripheral neuropathies (Ito et al., 2001). LIF appears toregulate IGF-I expression in the peripheral nerve in the basalstate and early in the regeneration response in vivo (de Pabloet al., 2000). There is no direct evidence that LIF and CNTFare regulated by hyperglycemia. Future studies should reveal ifmechanisms of LIF and CNTF regulation in diabetic neuropa-thy correspond to patterns observed in other degenerative anddemyelinating neuropathies. Such data, combined with knownmechanisms of neurotrophic factor regulation in diabetic neu-ropathy, may be useful in considering combined therapies aimedat ameliorating degeneration and improving regeneration of di-abetic nerve.

Our results from gene array analysis of BB/W rats, whichspontaneously develop type I diabetes accompanied with di-abetic neuropathy, showed concomitant down-regulation ofvoltage-gated Na+ channel β subunits with IL-6 expressionand signaling through STAT3 at early stages of diabetic neu-ropathy (Skundric et al., 2002b; Sima et al., 2003). Similardown-regulation of Na+ channel β subunits was observed


in SCs cultured in hyperglycemic condition. Levels of Na+

channel β2 and β3 subunits were recovered by addition of IL-6to SCs cultures (Skundric et al., 2002c). These subunits playimportant roles as CAMs and in distribution and anchoringof voltage-gated Na+ channels at the nodal axolemma (Isom,2002; Sima et al., 2003). Lateralization of voltage-gated Na+

channels from the node and their spreading to the juxtapara-nodal and internodal regions have been observed in diabeticnerves of rats with type I diabetes (Cherian et al., 1996). There-fore, the potential of IL-6 to restore β-subunit expression mayprovide a basis for modulation of two processes essential forperipheral nerve integrity: one, related to voltage-gated Na+

channel anchoring in the membrane and, second, CAM expres-sion by SCs. IL-6 may play an important role in reestablish-ing CAM expression and binding to appropriate ECM ligands,which is profoundly perturbed in diabetic nerve (Merry et al.,1998) (see Figure 1). Proper contact between SCs through CAMexpression with ECM is necessary for SC-axonal homeostaticcommunication. We also found that IL-6 exhibits the potentialto regulate the expression of Na+,K+-ATPase in cultured SCs(Skundric, unpublished data). These findings underscore thesignificance of understanding the mechanisms of IL-6–specificregulation of voltage-gated Na+ channels and Na+,K+-ATPasein peripheral nerve. Future experiments will be required to re-veal if IL-6 modulates expression of only β subunits, withCAM-like properties, or if it also affects the expression andfunction of α subunits, directly engaged in Na+ and K+ trans-port. A recent report from Sima et al. (2003) suggests lackof significant differences in expression levels of α subunits ofvoltage-gated Na+ channels in diabetic neuropathy in rats.

Role of TNF in Peripheral Nerve Degeneration,Apoptosis, and Glucose Metabolism

Experiments in mice with genetically distinct patterns ofwallerian degeneration show that TNF-α and IL-1α initiatemolecular and cellular events in rapid-wallerian degeneration(e.g., the production of additional cytokines and NGF). TNF-α,IL-1α, and IL-1β may further regulate indirectly macrophagerecruitment, myelin removal, regeneration, and neuropathicpain. In contrast to rapid-wallerian degeneration, production ofTNF-α, IL-1α, and IL-1β proteins is deficient in slow-walleriandegeneration, although their mRNAs are expressed. mRNA ex-pression and protein production of TNF-α, IL-1α, and IL-1β

are differentially regulated during rapid-wallerian degeneration(normal) and slow-wallerian degeneration (delayed), suggest-ing that mRNA expression by itself is not an indication of thefunctional involvement of cytokines in wallerien degeneration(Shamash et al., 2002).

IL-1α and TNF-α markedly stimulate glucose utilization inprimary cultures of mouse cortical astrocytes. PI3K is essen-

tial for the effect of both IL-1α and TNF-α, whereas the actionof IL-1α also requires activation of the MAP kinase pathway.The Na+,K+-ATPase inhibitor ouabain prevents the IL-1α– andTNF-α–stimulated 2-deoxyglucose (2DG) uptake. These datasuggest that Na+ pump activity is a common target for thelong-term metabolic action of cytokines, promoted by the ac-tivation of distinct signaling pathways (Vega et al., 2002). Incultured myocytes, TNF-α decreased fatty-acid transport pro-tein 1 (FATP-1) mRNA, insulin receptor substrate-1 (IRS-1)–associated PI3K activity, and glucose uptake, resulting in severediet-induced insulin resistance (Maeda et al., 2002).

TNF-α is locally produced by SCs and has a role in periph-eral nerve regeneration and regulation of apoptosis (Armatiand Pollard, 1996). Our analysis of diabetic sciatic nerves inthe spontaneously diabetic BB/W rat revealed up-regulationof TNF-α as well as initiator and executive caspases at earlystages of diabetes. Activation of one of the major executivecaspases, caspase-3, was observed. These findings suggest arole of TNF-α in regulation of apoptosis in diabetic neuropathy(Skundric et al., 2003). Mitochondrial dysfunction and apop-tosis play important roles in the pathogenesis of diabetic neu-ropathy (Srinivasan et al., 2000). Revealing the mechanismsof TNF-α–specific modulations of degeneration, regeneration,and apoptosis in diabetic peripheral nerve will significantly fos-ter the development of appropriate therapies aimed to controlthese processes locally. TNF-α is a good candidate to be consid-ered as a possible therapeutic target because of the availabilityof TNF-α family proteins, soluble receptors, and blockers ofsome signaling components. TNF-α–related therapies have al-ready been used in treatment of other neurodegenerative andinflammatory processes.

Role of TGF-β in the Cytokine-SpecificNetwork in Peripheral Nerve: Implicationfor Diabetic Neuropathy

The TGF-β family of cytokines is involved in multiple path-ways regulating SC and neuronal development, SC prolifera-tion, production of neurotrophic factors, ECM deposition, andexpression of CAMs.

Treatment with TGF-β1 leads to induction of LIF mRNAin cultured SCs. This effect is mediated through PKC. The ef-fect of TGF-β1 on LIF induction is abrogated by experimentalconditions favoring SC-neuronal contact and myelination. Thisindicates that following lesions of peripheral nerve, SCs couldrespond to TGF-β1 by producing LIF, which in turn has neuro-protective effect and promotes regeneration. Once SC-axonalcontact is established, effect of TGF-β on LIF production sub-sides (Matsuoka et al., 1997). In contrast to induction of LIF,TGF-β has negative regulatory effect on the production of NT-3mRNA at the site of peripheral nerve injury (Cai et al., 1999).


TGF-β plays a role in SC communication with ECM by reg-ulating alpha1beta1 integrin expression (Stewart et al., 1997).Binding of alpha1beta1 integrin, expressed by SC, to ECMligands laminin/collagen, plays an essential role in SC devel-opment and differentiation. In regard to sensory neuronal de-velopment, endogenous TGF-β plays a significant role in regu-lation of ontogenetic neuron death. Experiments in developingchick embryo showed proapoptotic effects of TGF-β signalingon ontogenetic death of sensory and motor neurons. These ex-periments suggest a similar role of TGF-β in neuronal deathin a situation of target deprivation (Krieglstein et al., 2000).TGF-β1 and TNF-α induce SC death by apoptosis (Skoff et al.,1998). TGF-β also exhibits effect on SC differentiation (Lisaket al., 2001). Similar role for TGF-β, in control of develop-mentally regulated apoptosis of the SC lineage, has been de-scribed. This role is executed via TGF-β–specific phospho-rylation of the early response gene c-Jun in nondifferentiatedSCs, whereas more differentiated SCs are protected from thismechanism (Parkinson et al., 2001). In relation to SC plasticity,which is critical for peripheral nerve regeneration, TGF-β hasbeneficial effect by supporting the proliferating SC phenotypeinvolved in axonal regeneration. It is important that supportiveeffects of TGF-β on axonal regeneration overcome the nega-tive effects of long-term SC denervation (Sulaiman and Gordon,2002). Specific up-regulation of TGF-β, its receptors (type I andtype II), and intracellular second messengers, Smad 2/3 and 4,was observed in sensory neurons and satellite cells of dorsalroot ganglia following injury (Stark et al., 2001). Future exper-iments designed to reveal the molecular mechanisms of TGF-βregulation in diabetic nerve are needed in order to explore thepotential therapeutic utilization of TGF-β in the prevention andtreatment of diabetic neuropathy.

CONCLUSION AND FUTURE DIRECTIONSDiabetic polyneuropathy is a chronic debilitating complica-

tion of both type I and type II diabetes mellitus. It develops as aresult of hyperglycemia-induced local metabolic and microvas-cular changes. Neuropathy affects peripheral, central, and vis-ceral sensorimotor and motor nerves and causes impairment oflocomotor system and visceral organs. Neuropathy, along withother chronic complications, is the leading cause of morbidityand mortality of diabetes patients.

The pathogenesis of diabetic neuropathy is complex and in-volves multiple pathways. Therefore, early therapeutic inter-vention with combined therapies aimed at modulation and/orblocking of aberrant pathways might prove to be beneficial inthe prevention and/or reversal of diabetic neuropathy.

Neuropoietic cytokines from the IL-1 and IL-6 families,TNF-α, and TGF-β exhibit pleiotrophic effects on glia cells andneurons important for the homeostasis of the peripheral, central,

and autonomic nervous systems. Cytokines regulate degener-ation and regeneration of peripheral nerve, processes essentialin the pathogenesis of diabetic neuropathy. The contribution ofcytokines to homeostasis and repair is mediated through nu-merous functions, including regulation of neurotrophic factors,ECM, CAMs, and SC proliferation and differentiation.

The regulatory roles of cytokines in nerve degenerationand regeneration may potentially be utilized for the preven-tion and/or therapy of diabetic neuropathy. Prior to attemptingcytokine-based therapy, one needs to understand the effects oflong-term hyperglycemia on the local cytokine network. Neu-ropoietic cytokines and components of their specific signal-ing cascade have been thoroughly described and many trans-genic mice models have been generated to facilitate the studyof cytokine-specific pathways. Unfortunately, the utilization oftransgenic mice is of limited use for experiments required tounderstand their role in diabetic neuropathy. Such experimentshave been hampered mainly by the significant role of proin-flammatory cytokines in the pathogenesis of type I diabetes.Therefore, strategies to modulate cytokine production and sig-naling locally need to be explored. Such approaches are feasiblein the case of IL-1, IL-6, and TNF-α. The basis for experimentaltherapies may include local use of the natural antagonists, solu-ble receptors, blocking antibodies, specific signaling blockers,and specific cytokine traps.

REFERENCESAlonzi, T., Middleton, G., Wyatt, S., Buchman, V., Betz, U. A., Muller,

W., Musiani, P., Poli, V., and Davies, A. M. (2001) Role of STAT3and PI 3-kinase/Akt in mediating the survival actions of cytokineson sensory neurons. Mol. Cell Neurosci., 18, 270–282.

Armati, P. J., and Pollard, J. D. (1996) Immunology of the Schwanncell. Baillieres Clin Neurol., 5, 47–64.

Benveniste, E. N. (1998) Cytokine actions in the central nervous sys-tem. Cytokine Growth Factor Rev., 9, 259–275.

Bolin, L. M., Verity, A. N., Silver, J. E., Shooter, E. M., and Abrams,J. S. (1995) Interleukin-6 production by Schwann cells and inductionin sciatic nerve injury. J. Neurochem., 64, 850–858.

Cai, F., Campana, W. M., Tomlinson, D. R., and Fernyhough, P. (1999)Transforming growth factor-beta 1 and glial growth factor beta 2reduce neurotrophin-3 mRNA expression in cultured Schwann cellsvia a camp-dependent pathway. Brain Res. Mol. Brain Res., 71, 256–264.

Cameron, N. E., and Cotter, M. A. (1997) Metabolic and vascularfactors in the pathogenesis of diabetic neuropathy. Diabetes, 46(Suppl.), S31–S37.

Carlson, C. D., Bai, Y., Jonakait, G. M., and Hart, R. P. (1996)Interleukin-1 beta increases leukemia inhibitory factor mRNA lev-els through transient stimulation of transcription rate. Glia, 18, 141–151.

Carlson, C. D., and Hart, R. P. (1996) Activation of acidic sphin-gomyelinase and protein kinase C zeta is required for IL-1 inductionof LIF mRNA in a Schwann cell line. Glia, 18, 49–58.


Carmeliet, P., and Storkebaum, E. (2002) Vascular and neuronal ef-fects of VEGF in the nervous system: Implications for neurologicaldisorders. Semin. Cell Dev. Biol., 13, 39–53.

Chalazonitis, A., Rothman, T. P., Chen, J., Vinson, E. N., MacLennan,A. J., and Gershon, M. D. (1998) Promotion of the developmentof enteric neurons and glia by neuropoietic cytokines: Interactionswith neurotrophin-3. Dev. Biol., 198, 343–365.

Chandross, K., Spray, D., Cohen, R. I., Kumar, N. M., Kremer, M.,Dermietzel, R., and Kessler, J. A. (1996) TNF-a inhibits Schwanncell proliferation, connexin46 expression, and gap junctional com-munication. Mol. Cell Neurosci., 7, 479–500.

Charon, I., Zuin-Kornmann, G., Bataille, S., and Schorderet, M. (1998)Protective effect of neurotrophic factors, neuropoietic cytokines anddibutyryl cyclic AMP on hydrogen peroxide-induced cytotoxicityon PC12 cells: A possible link with the state of differentiation.Neurochem. Int., 33, 503–511.

Cherian, P. V., Kamijo, M., Angelides, K. J., and Sima, A. A. F.(1996) Nodal Na+ channel displacement is associated with nerve-conduction slowing in the chronically diabetic BB/Wrat: Preventionby aldose reductase inhibition. J. Diabetes Complications, 10, 192–200.

Creange, A., Barlovatz-Meimon, G., and Gherardi, R. K. (1997) Cy-tokines and peripheral nerve disorders. Eur. Cytokine Netw., 8, 145–151.

Dinarello, C. A., and Thompson, R. C. (1991) Blocking IL-1 inter-leukin 1 receptor antagonist in vivo and in vitro. Immunol. Today,12, 404–410.

Eckersley, L. (2002) Role of the Schwann cell in diabetic neuropathy.Int. Rev. Neurobiol., 50, 293–321.

Edoff, K., and Jerregard, H. (2002) Effects of IL-1beta, IL-6 or LIFon rat sensory neurons co-cultured with fibroblast-like cells. J. Neu-rosci. Res., 67, 255–263.

Eichberg, J. (2002) Protein kinase C changes in diabetes: Is the conceptrelevant to neuropathy? Int. Rev. Neurobiol., 50, 61–82.

Fernandez-Real, J. M., Lopez-Bermejo, A., and Ricart, W. (2002)Cross-talk between iron metabolism and diabetes. Diabetes, 51,2348–2354.

Fu, S. Y., and Gordon, T. (1997) The cellular and molecular basis ofperipheral nerve regeneration. Mol. Neurobiol., 14, 67–116.

Geissen, M., Heller, S., Pennica, D., Ernsberger, U., and Rohrer, H.(1998) The specification of sympathetic neurotransmitter phenotypedepends on gp130 cytokine receptor signaling. Development, 125,4791–4801.

Grunberger, G., Xiaolong, Q., Li, Z. G., Mathews, S. T., Sbriessa,D., Shisheva, A., and Sima, A. A. F. (2001) Molecular basis forthe insulimamimetic effects of C-peptides. Diabetologia, 44, 1247–1257.

Hammes, H. P., Edelstein, D., Taguchi, T., Matsumura, T., Ju, Q., Lin,J., Bierhaus, A., Nawroth, P., Hannak, D., Neumaier, M., Bergfeld,R., Giardino, I., and Brownlee, M. (2003) Benfotiamine blocks threemajor pathways of hyperglycemic damage and prevents experimen-tal diabetic retinopathy. Nat. Med., 9, 294–299.

Horton, A. R., Barlett, P. F., Pennica, D., and Davies, A. M. (1998)Cytokines promote the survival of mouse cranial sensory neuronesat different developmental stages. Eur. J. Neurosci., 10, 673–679.

Isom, L. (2002) The role of sodium channels in cell adhesion. Front.Biosci., 7, 12–33.

Ito, Y., Yamamoto, M., Mitsuma, N., Li, M., Hattori, N., and Sobue,G. (2001) Expression of mRNAs for ciliary neurotrophic factor

(CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), andtheir receptors (CNTFR alpha, LIFR beta, IL-6R alpha, and gp130)in human peripheral neuropathies. Neurochem. Res., 26, 51–58.

Kato, R., Kiryu-Seo, S., and Kiyama, H. (2002) Damage-inducedneuronal endopeptidase (DINE/ECEL) expression is regulated byleukemia inhibitory factor and deprivation of nerve growth factorin rat sensory ganglia after nerve injury. J. Neurosci., 22, 9410–9418.

Krieglstein, K., Richter, S., Farkas, L., Schuster, N., Dunker, N.,Oppenheim, R.W., and Unsicker, K. (2000) Reduction of endoge-nous transforming growth factors beta prevents ontogenetic neurondeath. Nat. Neurosci., 3, 1085–1090.

Li, Z.-G., Zhang, W., and Sima, A. A. F. (2002) C-peptide preventshippocampal apoptosis in type I diabetes. Int. J. Exp. Diabetes Res.,3, 241–246.

Lindholm, D., Heumann, R., Meyer, M., and Thoenen, H. (1987)Interleukin-1 regulates synthesis of nerve growth factor in non- neu-ronal cells of rat sciatic nerve. Nature, 330, 658.

Lisak, R. P., Bealmear, B., Benjamin, J. A., and Skoff, A. M. (2001)Interferon-gamma, tumor necrosis factor-alpha and transforminggrowth factor-beta inhibit cyclic AMP-induced Schwann Cell dif-ferentiation. Glia, 36, 354–363.

Lisak, R. P., Skundric, S., Bealmear, B. and Ragheb, S. (1997) Therole of cytokines in Schwann cell damage, protection and repair.J. Infect. Dis., 176 (Suppl. 2), S173–S179.

Maeda, N., Shimomura, I., Kishida, K., Nishizawa, H., Matsuda,M., Nagaretani, H., Furuyama, N., Kondo, H., Takahashi, M.,Arita, Y., Komuro, R., Ouchi, N., Kihara, S., Tochino, Y.,Okutomi, K., Horie, M., Takeda, S., Aoyama, T., Funahashi, T., andMatsuzawa, Y. (2002) Diet-induced insulin resistance in mice lack-ing adiponectin/ACRP30. Nat. Med., 8, 731–737.

Matsuoka, I., Nakane, A., and Kurihara, K. (1997) Induction of LIF-mRNA by TGF-beta 1 in Schwann cells. Brain Res., 776, 170–180.

Merry, A. L., Yamamoto, K., and Sima, A. A. F. (1998) Imbalances inN-CAM, SAM, and polysialic acid may underlie the paranodal ionchannel barrier defect in diabetic neuropathy. J. Diabetes Compli-cations, 40, 153–160.

Middleton, G., Hamanoue, M., Enokido, Y., Wyatt, S., Pennica, D.,Jaffray, E., Hay, R. T., and Davies, A. M. (2000) Cytokine-inducednuclear factor kappa B activation promotes the survival of develop-ing neurons. J. Cell Biol., 148, 325–332.

Miinea, C., Kuruvilla, R., Merrikh, H., and Eichberg, J. (2002) Alteredarachidonic acid biosynthesis and antioxidant protection mecha-nisms in Schwann cells grown in elevated glucose. J. Neurochem.,81, 1253–1262.

Nagamoto-Combs, K., Vaccariello, S. A., and Zigmond, R. E. (1999)The levels of leukemia inhibitory factor mRNA in a Schwann cellline are regulated by multiple second messenger pathways. J. Neu-rochem., 72, 1871–1881.

Nishikawa, T., Edelstein, D., Du, X. L., Yamagishi, S.,Matsumura, T., Kaneda, Y., Yorek, M. A., Beebe, D., Oates,P. J., Hammes, H. P., Giardino, I., and Brownlee, M. (2000)Normalizing mitochondrial superoxide production blocks threepathways of hyperglycaemic damage. Nature, 404, 787–790.

Nitta, A., Murai, R., Suzuki, N., Ito, H., Nomoto, H., Katoh, G.,Furukawa, Y., and Furukawa, S. (2002) Diabetic neuropathies inbrain are induced by deficiency of BDNF. Neurotoxicol. Teratol.,24, 695–701.


de Pablo, F., Banner, L. R., and Patterson, P. H. (2000) IGF-I expres-sion is decreased in LIF-deficient mice after peripheral nerve injury.Neuroreport, 11, 1365–1368.

Parkinson, D. B., Dong, Z., Bunting, H., Whitfield, J., Meier, C., Marie,H., Mirsky, R., and Jessen, K. R. (2001) Transforming growth factorbeta (TGFbeta) mediates Schwann cell death in vitro and in vivo:Examination of c-Jun activation, interactions with survival signals,and the relationship of TGFbeta-mediated death to Schwann cellsurvival. J. Neurosi., 21, 8572–8585.

Pierson, C. R., Zhang, W., Murakawa, Y., and Sima, A. A. (2002)Early gene responses of trophic factors in nerve regeneration dif-fer in experimental type 1 and type 2 diabetic polyneuropathies.J. Neuropathol. Exp. Neurol., 61, 857–871.

Pradat, P. F., Kennel, P., Naimi-Sadaoui, S., Finiels, F., Orsini, C.,Revah, F., Delaere, P., and Mallet, J. (2001) Continuous deliveryof neurotrophin 3 by gene therapy has a neuroprotective effect inexperimental models of diabetic and acrylamide neuropathies. Hum.Gene Ther., 12, 2237–2249.

Shadiack, A. M., Hart, R. P., Carlson, C. D., and Jonakait, G. M. (1993)Interleukin-1 induces substance P in sympathetic ganglia throughthe induction of leukemia inhibitory factor (LIF). J. Neurosci., 13,2601.

Shadiack, A. M., Vaccariello, S. A., Sun, Y., and Zigmond, R. E. (1998)Nerve growth factor inhibits sympathetic neurons’ response to aninjury cytokine. Proc. Natl. Acad. Sci. U. S. A., 95, 7727–7730.

Shamash, S., Reichert, F., and Rotshenker, S. (2002) The cytokinenetwork of Wallerian degeneration: Tumor necrosis factor-alpha,interleukin-1alpha, and interleukin-1beta. J. Neurosci., 22, 3052–3060.

Sheetz, M. J., and King, G. L. (2002) Molecular understanding ofhyperglycemia’s adverse effects for diabetic complications. JAMA,288, 2579–2588.

Sima, A. A. F. (2001) Diabetic neuropathy; polero genetic back-grounds, current and future therapies. Expert Rev. Neurotherapeut,1, 225–238.

Sima, A. A. F., Pierson, C. R., and Zhang, W. (2003) C-peptide pre-vents the molecular abnormalities of the paranode in type I diabeticpolyneuropathy. In: Proceedings of the 18th International DiabetesFederation Congress.

Sima, A. A. F., Zhang, W., Xu, G., Sugimoto, K., Guberski, D., andYorek, M. A. (2000) A comparison of diabetic polyneuropathy intype II diabetic BBZDR/Wor rats and in type I diabetic BB/Worrats. Diabetologia, 43, 786–793.

Simmons, Z., and Feldman, E. L. (2002) Update on diabetic neuropa-thy. Curr. Opin. Neurol., 15, 595–603.

Skoff, A. M., Lisak, R. P., Bealmear, B., and Benjamins, J. A. (1998)TNF alpha and TGF-beta act synergistically to kill Schwann cells.J. Neurosci. Res., 53, 747–756.

Skundric, D. S., Bealmear, B., and Lisak, R. P. (1997) Induced up-regulation of IL-1, IL-1RA and IL-1R type I gene expression bySchwann cells. J. Neuroimmunol., 74, 9–18.

Skundric, D. S., Dai, R., James, J., and Lisak, R. P. (2002a) Activa-tion of IL-1 signaling pathway in Schwann cells during diabeticneuropathy. Ann. N. Y. Acad. Sci., 951, 393–398.

Skundric, D. S., Dai, R., James, J., Sima, A. A. F., and Lisak, R. P.(2002b) Hyperglycemia induced activation of Stat3 signaling path-way in Schwann cells (SCs). Diabetes, Suppl. 2, A523 (Abstract).

Skundric, D. S., Dai, R. J., Mataverde, P., Lam, J. S., Kahn, D. E.,and Hart, R. P. (2002c) Role of IL-6 in modulation of Na+ and K+

transport at early stages of diabetic neuropathy. Diabetes Metab.Res. Rev., 18 (Suppl. 4), S23 (Abstract).

Skundric, D. S., Dai, R., and Mataverde, P. (2003) Regulation ofTNF-α and caspase-3 in diabetic neuropathy. In: Apoptosis 2003,From Signalling Pathways to Therapeutic Tools, Proceedings,Edited by Diederich, M., pp. 347 (Abstract). Luxembourg, Fon-dation de Recherche Cancer et Sang.

Skundric, D. S., Lisak, R. P., Rouhi, M., Kieseiner, B. C., Jung, S., andHartung, H. P. (2001) Schwann cell specific regulation of IL-1 andIL-1Ra during EAN: Possible relevance for immune regulation atparanodal regions. J. Neuroimmunol., 116, 74–82.

Srinivasan, S., Stevens, M., and Wiley, J. W. (2000) Diabetic peripheralneuropathy: Evidence for apoptosis and associated mitochondrialdysfunction. Diabetes, 49, 1932–1938.

Stark, B., Carlstedt, T., and Risling, M. (2001) Distribution of TGF-beta, the TGF-beta type I receptor and the R-II receptor in peripheralnerves and mechanoreceptors; observations on changes after trau-matic injury. Brain Res., 913, 47–56.

Stewart, H. J., Turner, D., Jassen, K. R., and Mirsky, R. (1997) Ex-pression and regulation of alpha1beta1 integrin in Schwann cells.J. Neurobiol., 33, 914–928.

Sugimoto, K., Murakawa, Y., and Sima, A. A. F. (2000) Diabeticneuropathy—a continuing enigma. Diabetes Metab. Res. Rev., 16,408–433.

Sulaiman, O. A., and Gordon, T. (2002) Transforming growth factor-beta and forskolin attenuate the adverse effects of long-termSchwann cell denervation on peripheral nerve regeneration in vivo.Glia, 37, 206–218.

Thrailkill, K. M. (2000) Insulin-like growth factor-I in diabetes melli-tus: Its physiology, metabolic effects, and potential clinical utility.Diabetes Technol. Ther., 2, 69–80.

Tofaris, G. K., Patterson, P. H., Jessen, K. R., and Mirsky, R. (2002)Denervated Schwann cells attract macrophages by secretion ofleukemia inhibitory factor (LIF) and monocyte chemoattractantprotein-1 in a process regulated by interleukin-6 and LIF. J. Neu-rosci., 22, 6696–6703.

Vega, C., Pellerin, L., Dantzer, R., and Magistretti, P. J. (2002) Long-term modulation of glucose utilization by IL-1alpha and TNF-alphain astrocytes: Na+ pump activity as a potential target via distinctsignaling mechanisms. Glia, 39, 10–18.

Vincent, A. M., Brownlee, M., and Russell, J. W. (2002) Oxidativestress and programmed cell death in diabetic neuropathy. Ann. N. Y.Acad. Sci., 959, 368–383.

Wellmer, A., Misra, V. P., Sharief, M. K., Kopelman, P. G.,and Anand, P. (2001) A double-blind placebo-controlled clini-cal trial of recombinant human brain-derived neurotrophic factor(rhBDNF) in diabetic polyneuropathy. J. Periph. Nerv. Syst., 6, 204–210.

Williams, R., Van Gaal, L., and Lucioni, C. (2002) Assessing the im-pact of complications on the costs of type II diabetes. Diabetologia,45, S13–S17.

Yamamoto, M., Ito, Y., Mitsuma, N., Li, M., Hattori, N., and Sobue, G.(2002) Parallel expression of neurotrophic factors and their recep-tors in chronic inflammatory demyelinating polyneuropathy. MuscleNerve, 25, 601–604.

Xu, G., Pierson, C. R., Murakawa, Y., and Sima, A. A. F. (2002) Alteredtubulin and neurofilament expression and impaired axonal growthin diabetic nerve regeneration. J. Neuropathol. Exp. Neurol., 61,164–175.

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