Diabetic Neuropathy Differs in Type 1 and Type 2 Diabetes

ANDERS A.F. SIMA AND HIDEKI KAMIYA Departments of Pathology and Neurology, Wayne State University, Detroit, Michigan 48201, USA

ABSTRACT: In this article we describe differences in early metabolic abnormalities between type 1 and type 2 diabetic polyneuropathy (DPN), and how these differences lead to milder initial functional defects in type 2 diabetes, despite the same hyperglycemic exposures. This early reversible metabolic phase is progressively overshadowed by structural degenerative changes eventually resulting in nerve fiber loss. In comparison, the late structural phase of DPN affects type 1 diabetes more severely. Progressive axonal atrophy and loss is hence expressed to a larger extent in type 1 diabetes. In addition, type 1 DPN is characterized by paranodal degenerative changes not seen in type 2 DPN. These differences can be related to the differences in insulin action and signal transduction affecting the expression of neurotrophic factors and their receptors in type 1 diabetes. Downstream effects on neuroskeletal and adhesive proteins, their posttranslational modifications, and nociceptive peptides underlie the more severe resultant pathology in type 1 DPN. These differences in underlying mechanisms should be seriously considered in the future design of interventional paradigms to combat these common conditions. KEYWORDS: type 1 and type 2 diabetes; neuropathy; nerve conduction; neuropathology

INTRODUCTION
Diabetic neuropathy includes several distinct syndromes. Symmetric, mainly sensory polyneuropathy often accompanied by autonomic neuropathy is the most common form and is referred to as diabetic polyneuropathy (DPN). DPN is the most common late complication affecting both type 1 and type 2 diabetic patients.1,2 Despite decades of clinical and experimental investigations, the mechanisms underlying DPN are not fully understood and are sometimes controversial.3

Address for correspondence: Anders A.F. Sima, Department of Pathology, Wayne State University, 540 E. Canfield Ave. Detroit, MI 48201. Voice: 313-577-1150; fax: 313-577-0057. e-mail: asima@med.wayne.edu Ann. N.Y. Acad. Sci. 1084: 235249 (2006). doi: 10.1196/annals.1372.004
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The prevalence of DPN varies with an average prevalence of about 30% in the diabetic population.4 DPN accompanying type 1 diabetes occurs more predictably and progresses more rapidly resulting in a more severe neuropathy.1,5,6 Close to 100% of type 1 patients eventually develop DPN.7 Despite the common occurrence of DPN, there is no accepted or effective therapy available. In the last several decades numerous clinical trials employing various aldose reductase inhibitors,8,9 antioxidants,10 or substitution of nerve growth factor (NGF)11,12 have been disappointing, whereas strict glycemic control has revealed beneficial effects.13,14 In retrospect, the reasons for these disappointing outcomes are related to initiation of therapy too late in the natural history of the disease, suboptimal potencies of employed drugs and one may argue that the duration of treatments has been too short.8,9 Equally important is the fact that DPN in type 1 and type 2 patients has been regarded as one and the same disease, implying the same underlying mechanisms, namely hyperglycemia.13,14 The discrepancies in the epidemiology of DPN in type 1 and type 2 diabetes correspond to differences in underlying neuropathology as well as pathogenetic mechanisms.1517 Our understanding of DPN has in general been gained from streptozotocininduced diabetes (STZ-D) in rats, which develops within weeks of diabetes induction, nerve conduction velocity abnormalities, increased activity of the polyol pathway, and decreased endoneurial blood flow. However, despite these early functional and metabolic abnormalities, they do not develop structural deficits, such as progressive nerve fiber loss, even after prolonged duration of diabetes, which is the very hallmark of human DPN.18,19 Part of the shortcomings with the STZ-D rat as a model of the human disorders is that although it develops severe hyperglycemia, it does not reflect other aspects of the human conditions, like lack of circulating insulin and C-peptide as in type 1 diabetes, or hyperinsulinemia and insulin resistance as in type 2 diabetes. Our laboratory has taken a different approach utilizing rat models that mimic more closely the human conditions. The type 1 spontaneously diabetic BB/Worrat develops acute onset of diabetes at around 7075 days of age, as a result of an immune-mediated destruction of pancreatic cells, with total depletion of insulin and C-peptide. It therefore requires daily insulin injections titrated in such a way that it maintains a blood sugar level of 20.025.0 mmol glucose. The type 2 counterpart, the BBZDR/Wor-rat, in which the fa/fa allele is outbred on the BB background, develops spontaneous onset of hyperinsulinemic insulin-resistant hyperglycemia preceded by obesity.20 Overt diabetes occurs at the same age as in the type 1 model and hyperglycemia is maintained at the same levels without insulin substitution (TABLE 1). It is associated with hyperlipidemia and hypercholesterolemia.20 Employing these two models of the main types of human diabetes, several functional, metabolic, molecular, and structural differences have emerged, indicating that different treatment paradigms may apply to type 1 and type 2 DPN.21,22

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TABLE 1. Animal data in 8-month-old diabetic rats

Body weight (g) Control BB/Wor BBZDR/Wor BB/Wor + C-peptide

Glucose (mM)

Insulin (pmol/L)

C-peptide (pmol/L)

IGF-1 (ng/mL) 1188 32 771 85 880 72 839 50

501 10 5.0 0.2 430 20 733 45 383 7 23.9 1.3 52 6 <25 # 586 26,# 810 81# 586 31 23.8 3.1 386 12 24.0 1.3 40 7 710 66#

P < 0.01, P < 0.001 vs. control-rats; # P < 0.001 vs. BB/Wor-rats. NOTE: Decreased body weight in type 1 BB/Wor-rats and increased body weight in type 2 BBZDR/Wor-rats. Both animal models show the same magnitude of hyperglycemia. BB/Wor-rats are severely insulinopenic and C-peptidopenic, whereas insulin plasma levels are increased in the BBZDR/Wor-rats. Systemic IGF-1 is decreased in all diabetic groups.

DPN is the result of complicated sequential, interacting, and dynamic pathogenetic mechanisms (FIG. 1). Some mechanisms may be prominent at one point in its natural history, later to be replaced by other mechanisms.2,9,22 In both diabetic subjects and in experimental diabetes there is an initial metabolic phase causing nerve dysfunction, which is amendable to metabolic corrections.2,23,24 This is progressively replaced by a structural phase, which with the duration of diabetes becomes increasingly nonresponsive to metabolic interventions.2,9 The Metabolic Phase of DPN Several early metabolic abnormalities have been identified in the diabetic nerve. Shunting of excessive glucose through the activated polyol pathway leads to intracellular accumulation of sorbitol and fructose with consequent depletion of other organic osmolytes such as taurine and myo-inositol.25,26 Depletion of the myo-inositol pool interferes with phosphoinositide turnover resulting in insufficient diacylglycerol to maintain protein kinase C necessary for activation of Na+ /K+ -ATPase (FIG. 1).25,27 The type 1 BB/Wor-rat shows activation of the polyol pathway, with consequent impairment of neural Na+ /K+ -ATPase, which is corrected by aldose reductase inhibition.28 In the type 2 BBZDR/Wor-rat, which shows the same magnitude of hyperglycemia (TABLE 1) and hence activation of the polyol pathway, the impairment of Na+ /K+ -ATPase activity is significantly less.21 This difference in Na+ /K+ ATPase activity is accounted for by impaired insulin signaling in type 1 diabetes adding to the polyol pathway-induced defect. This has been confirmed by the insulinomimetic effect of proinsulin C-peptide.29,30 When BB/Wor-rats are substituted with C-peptide they show a dose-dependent correction of neural Na+ /K+ -ATPase activity and the acute nerve conduction defect.31 Therefore, the more severe defect in Na+ /K+ -ATPase activity can be accounted for by insulinopenia and perturbed insulin signal transduction (FIG. 1).32 Endoneurial hypoxemia secondary to impaired endoneurial blood flow has been ascribed to impaired expression of eNOS and NO activity. It has been

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Type 1 and Type 2 Diabetes

Hyperglycemia Acute Reversible NCV-Slowing NO

Type 1 Diabetes
Insulin / C-peptide

Polyol Pathway

Na+/K+- ATPase Oxidative Stress Nonenzymatic Glycation Neurotrophism Chronic Irreversible NCV-Slowing Apoptosis ?

Axonal Degeneration /Loss

Impaired Regeneration

Nodal /Paranodal Degeneration

FIGURE 1. Scheme of pathogenetic mechanisms involved in DPN of type 1 and type 2 diabetes. The early metabolic abnormalities underlying the acute functional deficits are reversible. However, these become increasingly superimposed by progressive structural abnormalities, which become less reversible after metabolic corrections. For further explanation see text. (Redrawn from Sima an Kamiya.61 )

proposed that the consequences of hyperglycemia come together causing mitochondrial dysfunction, superoxide overproduction, and oxidative and nitrosative stress contributing to the depletion of NO and impaired nerve perfusion3335 and that these defects contribute to nerve dysfunction. In the type 1 BB/Wor-rat both endoneurial perfusion and nerve conduction are decreased and oxidative stress is increased. On the other hand, in the type 2 BBZDR/Worrat endoneurial nutritive blood flow and oxidative stress are similarly increased, whereas nerve conduction is not affected.36 C-peptide substitution of type 1 rats corrects the NO-sensitive neurovascular function and nerve conduction velocity, without effecting oxidative stress or hyperglycemia.36 These findings therefore suggest that nerve conduction deficits are not inevitably a consequence of increased oxidative stress and decreased nerve perfusion and indicate a dissociation between oxidative stress and endoneurial blood flow. These early metabolic abnormalities are associated with functional defects (FIG. 1). In the BB/Wor-rat there is a progressive decrease in motor nerve conduction velocity (MNCV) to 70% of normal values after a 5-week duration of diabetes. The MNCV defect is significantly milder in the BBZDR/Wor-rat, which shows a 12% deficit at 5 weeks of diabetes (FIG. 2 A).21 Sensory nerve conduction velocity (SNCV) in the type 1 BB/Wor-rat shows a 10% decrease,

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Motor Nerve Conduction Velocity (m/sec)

(A)

70

60

Hyperglycemic Component

50

Insulin/C-peptide Deficiency Component

40

onset 1wk 1mo 2mo 4mo 5mo 6mo 7mo 8mo Sensory Nerve Conduction Velocity (m/sec)

(B)

45

Duration of Diabetes

40

Hyperglycemic Component

35

Insulin/C-peptide Deficiency Component

30 6W 2mo 4mo 6mo 8mo

Duration of Diabetes
Latencies of thermal hyperalgesia (seconds)

(C)

25 20

15

10

5 1W 2mo 4mo 6mo 8mo

Duration of Diabetes
:Control, :BB/Wor, :BB/Wor+C-peptide, :BBZDR/Wor

FIGURE 2. (A). Longitudinal measurements of MNCV in type 1 BB/Wor- and type 2 BBZDR/Wor-rats. Also indicated is the effect of C-peptide replacement, which does not influence hyperglycemia. Therefore the components of the nerve conduction deficits can be divided into a hyperglycemic component and an insulin/C-peptide deficiency component. (B). SNCV measurements. In type 1 BB/Wor-rats this is decreased after 2 months of diabetes and decreases progressively. Type 2 BBZDR/Wor-rats show normal conduction velocity for 6 months and becomes decreased only after 8 months of diabetes. C-peptide replaced BB/Wor-rats show a pattern similar to that of BBZDR/Wor-rats. (C). Latencies to withdrawal from thermal stimuli, thermal hyperalgesia, decrease progressively in the type 1 model up to 6 months duration of diabetes and then increase by 8 months. This increase correlates with profound C-fiber loss and reflects early analgesia. The defect in the type 2 model is significantly milder. Type 1 rats replaced with C-peptide show a pattern similar to that of type 2 rats.

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whereas in the type 2 BBZDR/Wor-rat it is unaltered at the same duration of diabetes (FIG. 2 B).36 These differences between type 1 and type 2 diabetes can be related to differences in neural Na+ /K+ -ATPase activities. Since the excitation of the nodal membrane underlying the impulse propagation is caused by an inward flux of Na+ , NCV velocity is related directly to nodal Na+ permeability. In the BB/Wor-rat there is a progressive increase in the abnormal inactivation of Na+ and a decline in the maximal peak of Na+ permeability resulting in decreased nodal Na+ equilibrium potentials.37 These changes are directly associated with the decreased Na+ /K+ -ATPase activity causing intra-axonal Na+ accumulation.37,38 Interestingly, these biophysical abnormalities are corrected by insulin in acutely diabetic rats.38 Nodal axonal swelling, an early structural abnormality, is more prominent in type 1 than in type 2 BB-rats.21 It correlates with intra-axonal Na+ accumulation and is reversed following insulin or C-peptide treatment.29,39 However, the expression of voltage-gated -Na+ -channels is not altered in the sciatic nerve of diabetic rats.40 Therefore, these early metabolic dysfunctions of myelinated fibers can be directly related to the Na+ /K+ -ATPase defect, whereas the impact of impaired endoneurial blood flow is probably less as alluded to above. Unmyelinated fiber dysfunction is reflected by thermal hyperalgesia. Again, the type 1 BB/Wor-rat shows a significantly more rapid decrease in the latencies to thermal stimuli (FIG. 2 C).36,41 Damage to small myelinated A and unmyelinated C-fibers underlies hyperalgesia and allodynia.42,43 Damage to axonal membranes of C-fibers induces increased formation of Na+ -channels and -adrenergic receptors facilitating ectopic discharges.4446 The varying degree of hyperalgesia in the two models correlates with significant differences in the expression NGF and NT-3 in the sciatic nerve and of insulin receptor, IGF-1 receptor, high-affinity NGFR-TrkA, and TrkC in dorsal root ganglia (DRGs) and consequent suppression of nociceptive peptides and synthesis of neuroskeletal proteins (FIG. 3).19,41,47 These changes eventually lead to degeneration and loss of nociceptive C-fibers.41 The abnormalities leading up to this series of events either do not occur or are significantly milder in the type 2 BBZDR/Wor-rat.41 Since the expression of neurotrophic factors and their receptors is intimately related to insulin signal transduction,4750 it is not totally surprising that insulinomimetic C-peptide significantly ameliorates these changes in type 1 diabetes (FIG. 3).49 To summarize, the metabolic abnormalities underlying early functional abnormalities in DPN show obvious differences between the two types of diabetes. No doubt, hyperglycemia plays an important role in the development of DPN, we would argue though, that impaired insulin availability, a potent neurotrophic agent in itself, and consequent aberrant signal transduction may play an equally important role in the pathophysiology of these changes.

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FIGURE 3. In A and B, sciatic nerve contents of NGF and NT-3 are significantly (P < 0.005) decreased in BB/Wor-rats of 8 months diabetes duration. In the BBZDR/Worrats the levels are not significantly different from controls. C-peptide replacement of BB/Wor-rat resulted in significantly increased levels of NGF and NT-3 levels (both P < 0.05). In C and D Western blots of their respective receptors in DRGs showed significantly decreased expression in BB/Wor-rats (both P < 0.005) and were not significantly altered in BBZDR/Wor-rats. The expressions were significantly increased in C-peptidetreated rats compared to untreated BB/Wor-rats (both P < 0.05). In E and F the expression of the insulin receptor and IGF-1R were both significantly (P < 0.005) decreased in DRGs from BB/Wor-rats, and not significantly different from control rats in BBZDR/Wor-rats or C-peptide replaced BB/Wor-rats.

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FIGURE 4. Myelinated axon area (A) were significantly (P < 0.001) decreased in 8 months diabetic BB/Wor-rats, but unaltered in type 2 BBZDR/Wor-rats and in C-peptide replaced type 1 BB/Wor-rats. Myelinated fiber numbers (B) in the sural nerve was significantly (P < 0.001) decreased in BB/Wor-rats and not significantly different from controls in type 2 BBZDR/Wor-rats or C-peptide replaced BB/Wor-rats.

The Structural Phase of DPN From the acute metabolic abnormalities emerge progressive structural changes, which become decreasingly responsive to metabolic interventions. One of the earliest detectable changes in myelinated fibers is nodal and paranodal axonal swelling, which correlates with the early Na+ /K+ -ATPase defect and increased intra-axonal [Na+ ]i .37,38 It is more expressed in type 1 BB/Worrats21 and is reversible.31,38 Other early abnormalities consist of malalignment of cytoskeletal structures51 reflecting aberrant synthesis, phosphorylation, and assembly of neurofilaments.52,53 These changes lead to perturbed axonal transport and progressive axonal atrophy evident in the type 1 BB/Wor-rat after 4 months of diabetes.5456 The axonal atrophy shows a proximal to distal gradient54 and ultimately results in distal axonal degeneration with secondary myelin breakdown and fiber loss (FIG. 4).54,57 Axonal degeneration has been associated with impaired neurotrophic support by insulin itself, IGF-1, and neurotrophins (FIG. 3), resulting in impaired synthesis of tubulins and neurofilament and their assembly.52,5861 Significant fiber loss of 10% is already detectable in sural nerves of type 1 BB/Wor-rats after 4 months of diabetes increasing to 33% after 11 months.54 In contrast, the type 2 BBZDR/Wor-rat exhibits significantly milder axonal atrophy and fiber loss (FIG. 4) amounting to 11% after 14 months of diabetes.21 Primary segmental demyelination is rare in these models but is nevertheless

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more common in type 2 diabetic rats.21 Differences in axonal degeneration and loss are also reflected by differences in the chronic nerve conduction defects (FIG. 2 A,B). C-peptide substitution of type 1 BB/Wor-rats prevents and improves significantly the nerve conduction defects, reflecting its insulinomimetic effects.29,60 However, these defects are not totally prevented but show residual defects similar to the defects encountered in the type 2 model (FIG. 2A,B). This has led us to suggest that the chronic functional defects in DPN consist of a hyperglycemic component, not responsive to insulinomimetic C-peptide, and an insulin/C-peptide deficiency component not present in type 2 diabetes (FIG. 2).61,62 It has recently been suggested that DRG cell apoptosis may be an underlying mechanism in DPN.35,63,64 However, these findings have not been substantiated.57,65,66 A characteristic structural change occurring in type 1 human and experimental diabetes is the progressive degeneration of the node and paranodal apparatus.15,67 These changes will affect nerve conduction velocity in a major way. They consist of progressive disruption of the paranodal apparatus allowing for lateralization of nodal voltage-gated Na+ -channels, thereby diminishing the initial Na+ current of the nodal membrane. The abnormality of the paranodal ion-channel barrier is caused by decreased expression of key adhesive molecules and their insulin-mediated posttranslational modifications that underlie their proteinprotein interactions.62,68 The paranodal molecules colocalize with the insulin receptor, the expression of which is downregulated in chronically type 1 diabetic BB/Wor-rats. It is therefore not totally surprising that C-peptide replacement prevents these abnormalities.62 These abnormalities do not occur in the type 2 model even after 14 months of diabetes.21 Therefore, this degenerative process is specific for type 1 diabetes and contributes to the more severe conduction defect seen in type 1 diabetic rats (FIG. 2 A,B). As often misquoted, these abnormalities are not related to the Na+ /K+ -ATPase defect. The peripheral unmyelinated fiber population represents sympathetic and nociceptive sensory fibers. This fiber population appears to be specifically sensitive to diabetic environments. Even under prediabetic conditions as in the GK-rat, which shows impaired glucose tolerance and cell dysfunction, nociceptive neuropathy with C-fiber degeneration occurs.69 In the type 1 BB/Worrat increased hyperalgesia to thermal stimulation is already present at 2 months duration of diabetes and increases progressively thereafter (FIG. 2 C).41 This is accompanied by degenerative changes of C-fibers consisting of type 2 Schwann cell/axon relationships, whereby the mesaxon degenerates leaving the axon directly exposed to the endoneurial environment (FIG. 5). This is followed by axonal atrophy and loss, leaving behind collagen pockets and denervated Schwann cells (FIG. 5).41 This series of events is preceded by suppressed expression of the insulin receptor in DRG cells, impaired exposure to NGF, IGF-1, NT-3, and their respective receptors NGF-RTrkA, IGF-1R, and

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FIGURE 5. Unmyelinated fiber size (A) was significantly (P < 0.05) decreased in BB/Wor-rats but not in BBZDR/Wor-rats or in C-peptide-substituted BB/Wor-rats. Unmyelinated fiber numbers in the sural nerve (B) was markedly decreased (P < 0.001) in type 1 rats, whereas they were not significantly different from nondiabetic control rats in BBZDR/Wor-rats or in C-peptide-replenished BB/Wor-rats. The frequency of type 2 axon/Schwann cell relationship (C) was significantly more common in BB/Wor-rats compared to control rats (P < 0.0001), C-peptide replaced BB/Wor-rats (P < 0.0001) and to BBZDR/Wor-rats (P < 0.005).

TrkC (FIG. 3).41,49 The consequences of this impairment of wide neurotrophic support are impaired synthesis of nociceptive neuropeptides, such as substance P and GRRP, axonal atrophy, and loss of their parent DRG cells.41,49 The neuronal loss is not apoptosis-induced but correlates with progressive degeneration of the Golgi apparatus resulting in vacuolar degeneration and eventually neuronal loss (Kamiya et al., unpublished data). These changes progress at a significantly slower pace in the type 2 BBZDR/Wor-rat, which correlates with an almost normal expression of neurotrophic receptors in DRG cells (FIG. 3) and milder suppression of nociceptive neuropeptides.41 Hence, these differences between the two models can be traced to the profound differences in insulin action and its downstream regulatory effect on neurotrophic factors and their receptors.41 This is confirmed by the beneficial effects of Cpeptide replacement on nociceptive sensory neuropathy in the type 1 rat model (FIG. 3).49 In the type 1 diabetic BB/Wor-rat the development of sympathetic autonomic neuropathy is characterized by neuroaxonal dystrophic changes of terminal axons.70,71 In comparison, such changes do not develop in the type 2 BBZDR/Wor-rat.72 As to whether these changes bear any relationship to insulin action and/or neurotrophic support is not known. In summary, this review has demonstrated marked differences in metabolic factors and their magnitudes in type 1 and type 2 experimental diabetes models, which closely mimic the human conditions. The subsequent development of structural changes relates to different sets of underlying molecular changes and differences in the severities of neurotrophic support, which can be directly

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related to differences in insulin action. Therefore, despite exposure to the same magnitude of hyperglycemia over prolonged periods of time the resultant outcome is markedly different. This means that apart from hyperglycemia, perturbations of insulin action and signaling play equally important roles in the development of type 1 DPN. Such differences have to be taken into account in future approaches to treating and/or preventing this common complication of diabetes.

ACKNOWLEDGMENTS
Our own studies referred to in this article were supported by the Medical Research Council of Canada, Canadian Diabetes Association, the Juvenile Diabetes Research Foundation, the National Institute of Health, the Morris Hood Diabetes Center, and the Thomas Foundation. Dr. H. Kamiya is presently a postdoctoral fellow supported by the Thomas Foundation.

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