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 ab-

normalities 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 degenera-
tive changes eventually resulting in nerve fiber loss. In comparison, the
late structural phase of DPN affects type 1 diabetes more severely. Pro-
gressive 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 af-
fecting 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 neuropa-
thy 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 inves-
tigations, 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: 235–249 (2006). 

C 2006 New York Academy of Sciences.

doi: 10.1196/annals.1372.004

235
236 ANNALS NEW YORK ACADEMY OF SCIENCES

The prevalence of DPN varies with an average prevalence of about 30% in

the diabetic population.4 DPN accompanying type 1 diabetes occurs more pre-
dictably 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.15–17
Our understanding of DPN has in general been gained from streptozotocin-
induced 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 short-
comings with the STZ-D rat as a model of the human disorders is that al-
though 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/Wor-
rat develops acute onset of diabetes at around 70–75 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 20.0–25.0 mmol glucose.
The type 2 counterpart, the BBZDR/Wor-rat, in which the fa/fa allele is out-
bred 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
SIMA & KAMIYA: DIABETIC NEUROPATHY 237

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

Body Glucose Insulin C-peptide IGF-1
weight (g) (mM) (pmol/L) (pmol/L) (ng/mL)
Control 501 ± 10 5.0 ± 0.2 430 ± 20 733 ± 45 1188± 32
BB/Wor 383 ± 7∗∗ 23.9 ± 1.3∗∗ 52 ± 6∗∗ <25∗∗ 771 ± 85∗∗
BBZDR/Wor 586 ± 31# 23.8 ± 3.1 ∗∗ 586 ± 26∗,# 810 ± 81# 880 ± 72∗∗
BB/Wor + C-peptide 386 ± 12∗∗ 24.0 ± 1.3 ∗∗ 40 ± 7∗∗ 710 ± 66# 839 ± 50∗∗
∗ 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 patho-

genetic 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 dia-
betic 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 neces-
sary 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 dia-
betes 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
238 ANNALS NEW YORK ACADEMY OF SCIENCES

Type 1 and Type 2 Diabetes Type 1 Diabetes

Hyperglycemia Insulin / C-peptide
Acute
Reversible NO
NCV-Slowing Polyol Pathway
Na+/K+- ATPase

Oxidative Stress

Nonenzymatic Glycation

Neurotrophism

Chronic Apoptosis ?
Irreversible
NCV-Slowing

Axonal Impaired Regeneration Nodal /Paranodal

Degeneration /Loss 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 expla-
nation see text. (Redrawn from Sima an Kamiya.61 )

proposed that the consequences of hyperglycemia come together causing mi-

tochondrial dysfunction, superoxide overproduction, and oxidative and ni-
trosative stress contributing to the depletion of NO and impaired nerve per-
fusion33–35 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/Wor-
rat 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 conse-
quence 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,
SIMA & KAMIYA: DIABETIC NEUROPATHY 239

(A) 70

Motor Nerve Conduction Velocity

60 Hyperglycemic
Component
(m/sec)

50 Insulin/C-peptide
Deficiency
Component
40

onset 1wk 1mo 2mo 4mo 5mo 6mo 7mo 8mo

Duration of Diabetes
(B) 45
Sensory Nerve Conduction Velocity

40 Hyperglycemic
Component
(m/sec)

Insulin/C-peptide
35
Deficiency
Component

30
6W 2mo 4mo 6mo 8mo
Duration of Diabetes
(C)
Latencies of thermal hyperalgesia

25

20
(seconds)

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.
240 ANNALS NEW YORK ACADEMY OF SCIENCES

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 dia-
betes 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+ per-
meability 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 ax-
onal 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 myeli-
nated 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 laten-
cies 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.44–46 The varying de-
gree 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 degen-
eration 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,47–50 it is not to-
tally surprising that insulinomimetic C-peptide significantly ameliorates these
changes in type 1 diabetes (FIG. 3).49
To summarize, the metabolic abnormalities underlying early functional ab-
normalities in DPN show obvious differences between the two types of di-
abetes. No doubt, hyperglycemia plays an important role in the develop-
ment of DPN, we would argue though, that impaired insulin availability,
a potent neurotrophic agent in itself, and consequent aberrant signal trans-
duction may play an equally important role in the pathophysiology of these
changes.
SIMA & KAMIYA: DIABETIC NEUROPATHY 241

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/Wor-
rats 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 signifi-
cantly 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-peptide-
treated 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.
242 ANNALS NEW YORK ACADEMY OF SCIENCES

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 signifi-
cantly (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 para-
nodal 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/Wor-
rats21 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 trans-
port and progressive axonal atrophy evident in the type 1 BB/Wor-rat after 4
months of diabetes.54–56 The axonal atrophy shows a proximal to distal gra-
dient54 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 neuro-
filament and their assembly.52,58–61
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 at-
rophy 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
SIMA & KAMIYA: DIABETIC NEUROPATHY 243

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 insuli-
nomimetic 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 exper-
imental diabetes is the progressive degeneration of the node and paranodal
apparatus.15,67 These changes will affect nerve conduction velocity in a ma-
jor way. They consist of progressive disruption of the paranodal apparatus
allowing for lateralization of nodal voltage-gated Na+ -channels, thereby di-
minishing 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 protein–protein interactions.62,68 The paranodal molecules
colocalize with the insulin receptor, the expression of which is downregu-
lated 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 di-
abetes.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, noci-
ceptive neuropathy with C-fiber degeneration occurs.69 In the type 1 BB/Wor-
rat 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 leav-
ing 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 sup-
pressed 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
244 ANNALS NEW YORK ACADEMY OF SCIENCES

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. Un-
myelinated 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 com-
pared 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 sub-
stance 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 differ-
ences in insulin action and its downstream regulatory effect on neurotrophic
factors and their receptors.41 This is confirmed by the beneficial effects of C-
peptide 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 auto-
nomic neuropathy is characterized by neuroaxonal dystrophic changes of ter-
minal 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 in-
sulin 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
SIMA & KAMIYA: DIABETIC NEUROPATHY 245

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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