Painful and Painless Diabetic Neuropathies: What Is the Difference?

Abstract

Purpose of Review
The prevalence of diabetes mellitus and its chronic complications are increasing to epidemic proportions. This will unfortunately result in massive increases in diabetic distal symmetrical polyneuropathy (DPN) and its troublesome sequelae, including disabling neuropathic pain (painful-DPN), which affects around 25% of patients with diabetes. Why these patients develop neuropathic pain, while others with a similar degree of neuropathy do not, is not clearly understood. This review will look at recent advances that may shed some light on the differences between painful and painless-DPN.

Recent Findings
Gender, clinical pain phenotyping, serum biomarkers, brain imaging, genetics, and skin biopsy findings have been reported to differentiate painful- from painless-DPN.

Summary
Painful-DPN seems to be associated with female gender and small fiber dysfunction. Moreover, recent brain imaging studies have found neuropathic pain signatures within the central nervous system; however, whether this is the cause or effect of the pain is yet to be determined. Further research is urgently required to develop our understanding of the pathogenesis of pain in DPN in order to develop new and effective mechanistic treatments for painful-DPN.

Full text

MICROVASCULAR COMPLICATIONS—NEUROPATHY (R POP-BUSUI, SECTION EDITOR)
Painful and Painless Diabetic Neuropathies: What Is the Difference?
Pallai Shillo
1
&Gordon Sloan
1
&Marni Greig
1
&Leanne Hunt
1
&Dinesh Selvarajah
2
&Jackie Elliott
2
&Rajiv Gandhi
1
&
Iain D. Wilkinson
3
&Solomon Tesfaye
1,2
Published online: 7 May 2019
#The Author(s) 2019
Abstract
Purpose of Review The prevalence of diabetes mellitus and its chronic complications are increasing to epidemic
proportions. This will unfortunately result in massive increases in diabetic distal symmetrical polyneuropathy
(DPN) and its troublesome sequelae, including disabling neuropathic pain (painful-DPN), which affects around
25% of patients with diabetes. Why these patients develop neuropathic pain, while others with a similar degree of
neuropathy do not, is not clearly understood. This review will look at recent advances that may shed some light on
the differences between painful and painless-DPN.
Recent Findings Gender, clinical pain phenotyping, serum biomarkers, brain imaging, genetics, and skin biopsy findings have
been reported to differentiate painful- from painless-DPN.
Summary Painful-DPN seems to be associated with female gender and small fiber dysfunction. Moreover, recent brain imaging
studies have found neuropathic pain signatures within the central nervous system; however, whether this is the cause or effect of
the pain is yet to be determined. Further research is urgently required to develop our understanding of the pathogenesis of pain in
DPN in order to develop new and effective mechanistic treatments for painful-DPN.
Keywords Diabetes .Peripheral neuropathy .Neuropathic pain .Small fiber neuropathy .Painful diabetic neuropathy .Diabetic
neuropathy
Introduction
The worldwide prevalence of diabetes mellitus (DM) has
reached epidemic proportions, and is set to increase to 629
million by 2045 [1]. Rising population growth, aging, urban-
ization, and an increased prevalence of obesity and physical
inactivity are amongst the major contributing factors. Diabetic
neuropathies are one of the most common chronic
Pallai Shillo and Gordon Sloan are joint first authors
This article is part of the Topical Collection on Microvascular
Complications—Neuropathy
*Solomon Tesfaye
solomon.tesfaye@sth.nhs.uk; s.tesfaye@sheffiedl.ac.uk
Pallai Shillo
shillopr@yahoo.com
Gordon Sloan
Gordon.sloan@nhs.net
Marni Greig
Marni.Greig@sth.nhs.uk
Leanne Hunt
Leanne.Hunt@sth.nhs.uk
Dinesh Selvarajah
Dinesh.Selvarajah@sth.nhs.uk
Jackie Elliott
Jackie.Elliott@sth.nhs.uk
Rajiv Gandhi
Rajiv.Gandhi@sth.nhs.uk
Iain D. Wilkinson
i.d.wilkinson@sheffield.ac.uk
1
Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield
Teaching Hospitals NHS Foundation Trust, Glossop Road,
Sheffield S10 2JF, UK
2
Department of Oncology and Human Metabolism, University of
Sheffield, Sheffield, UK
3
Academic Unit of Radiology, University of Sheffield, Sheffield, UK
Current Diabetes Reports (2019) 19: 32
https://doi.org/10.1007/s11892-019-1150-5
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

complications of DM [2], and distal symmetrical
polyneuropathy (DPN) is the most prevalent form of diabetic
neuropathy, which may affect up to 50% of patients [2,3•,4•].
The Toronto Expert Group has defined DPN as “asymmetri-
cal, length dependent sensorimotor polyneuropathy attribut-
able to metabolic and micro-vessel alterations as a result of
chronic hyperglycaemia exposure and cardiovascular risk co-
variates”[5•]. A more recent definition of DPN in the
American Diabetes Association Position Statement is “the
presence of symptoms and/or signs of peripheral nerve dys-
function in people with diabetes after the exclusion of other
causes”[3•]. The rising numbers of patients diagnosed with
neuropathic disorders related to DM will have an immense
impact on health and social care provision [6].
DPN is a major risk factor for diabetic foot ulceration,
which remains a major cause of morbidity and is the leading
cause of non-traumatic amputations [7]. Although a large
number of patients with DPN may be entirely asymptomatic,
approximately 15–25% of people with DM present with neu-
ropathic pain (painful-DPN) [8–11,12•,13]. The neuropathic
pain is of varying degree of intensity [14] DPN and painful-
DPN has different clinical syndromes with the most common
of which is a mixed large and small fiber neuropathy. Small
nerve-fibers (SF) are small-caliber sensory fibers, which are
primarily responsible for peripheral nociception [15]. Pure SF
neuropathy may occur in DM and the clinical features include
symptoms of painful peripheral neuropathy with signs of SF
impairment (e.g., pinprick or thermal hypoalgesia or
allodynia) in a peripheral neuropathy distribution in the ab-
sence of large fiber impairment (e.g., impaired light touch,
vibration, proprioception or motor signs).
Painful-DPN often results in insomnia, mood disorders,
and a poor quality of life [12•]. The currently available thera-
pies for the pain associated with DPN remain inadequate,
given relatively modest pain relief and often troublesome side
effects [3•,16,17]. There is thus an urgent need to have a
better understanding of the pathogenesis of pain in DPN and
this has been the subject of a recent review (Fig. 1)[17].
Central to this understanding will be to develop new insights
as to why some patients develop disabling neuropathic symp-
toms while others with a similar degree of neuropathy do not.
This review will discuss the differences in risk factors, clinical
features, serum biomarkers, vascular alterations, quantitative
sensory testing (QST), skin biopsy parameters, genetics, and
brain imaging studies between painful- and painless-DPN.
Risk Factors
Several risk factors for DPN in general have been described and
confirmed in cohorts of type 1 and type 2 diabetes. The
EURODIAB Prospective Complications Study screened 3250
type 1 DM patients at baseline and followed 1172 patients
without DPN looking for risk factors that predicted the devel-
opment of DPN [4•]. The study found that in addition to gly-
cemic control, traditional vascular risk factors such as hyperten-
sion, raised triglycerides, obesity, and cigarette smoking were
independent risk factors for the development of new onset
DPN. Similar vascular risk factors were also found in T2DM
[18•,19,20]. However, the risk factors for neuropathic pain in
DM are less well known. This is partly because of the wide
variation in the diagnostic and population selection methods
employed by the epidemiological studies for painful-DPN
[21••,22]. The reported risk factors include increasing age [9,
10], elevated HbA1c [23••,24], duration of DM [9], and obesity
[10,25]. A high alcohol intake, type of diabetes, macro and
microvascular disease, and ethnicity have also been implicated
[21••]. Recent large studies have also suggested nephropathy
and female gender as risk factors for painful-DPN [26,27••,
28••]. Indeed, female gender was the only risk factor identified
in a large cross-sectional study (n= 816) performed by Truini
et al. which diagnosed painful-DPN using widely agreed
criteria [28••]. Thirteen percent were diagnosed with painful-
DPN and the only distinguishing risk factor from painless-DPN
was female gender. Gender differences are well recognized in
chronic pain conditions and neuropathic pain intensity has pre-
viouslybeenreportedtobemoresevereinfemales[29,30].
Recent advances in gene sequencing technology have led
to several studies examining genetic variants associated with
DPN and painful-DPN [31–34,35•,36]. Two recent studies
by Meng et al. conducted genome-wide association studies in
Tayside, Scotland [32,33]. Chr8p21.3, Chr1p35.1, and
Chr8p21.3 polymorphisms were associated with neuropathic
pain. However, the study did not use validated diagnostic
criteria for painful-DPN. Recently also, there has been great
interest in the role of voltage-gated sodium channels and their
role in neuropathic pain. The Na
v
1.7 sodium channel is well
recognized to be involved in pain signaling and “gain of func-
tion”mutations of its encoding gene, SCN9A, cause rare pain
disorders. Additionally, studies have identified Na
v
1.7 muta-
tions in idiopathic small fiber neuropathy [36] and painful-
DPN [34]. Blesneac et al. looked at the relationship between
Na
v
1.7 variants and painful-DPN and found that none of the
participants with painless-DPN (n= 78) were found to have a
genetic variant [35•]. However, a total of 12 rare Na
v
1.7
variants were identified in 10 out of 111 patients with pain-
ful-DPN. The subjects with these variants were found to have
a shorter duration of diabetes yet more severe burning pain.
Painful-DPN is a heterogeneous condition and subjects with
rare sodium channel gene variants may represent a subgroup
that may respond to a particular treatment.
In summary, while the risk factors for DPN are well recog-
nized, those for painful-DPN are less certain. This might in-
dicate the complexity of painful-DPN as many factors includ-
ing genetics, cultural, psycho-social, and gender may be
involved.
32 Page 2 of 13 Curr Diab Rep (2019) 19: 32
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Clinical Features
Neuropathic pain in diabetes has distinct presentations as
burning, sharp, aching, electric, and evoked pains [37].
However, patients may also describe symptoms of numbness,
tingling, and pins and needles, irrespective of the presence of
pain. Neuropathic pain may also induce various degrees of
physical disability, depression, anxiety, insomnia, and a
poorer quality of life than patients with painless-DPN, partic-
ularly with moderate to severe neuropathic pain [23••,27••,
38]. Despite these profound differences in a patient’sclinical
presentation, there are few distinct differences in the neuro-
logical examination between painless- and painful-DPN. The
majority of patients with painful-DPN demonstrate sensory
loss on clinical examination but a small proportion of patients
with painful-DPN have evidence of “gain of function”signs
such as allodynia and hyperalgesia [23••]. There is controver-
sy regarding whether the severity of neuropathic impairment
is greater in painful-DPN. Several studies have reported a
correlation between neuropathy severity and the presence
and/or severity of neuropathic pain in DPN [8,11,15,23••,
39–41] whereas other studies have not [18•,28••]. Although
the weight of evidence seems to suggest that an increasing
severity of DPN may increase the risk of developing painful
neuropathic symptoms, severe DPN and painare not mutually
exclusive, and there may have been a selection bias in
recruiting painful-DPN patients from tertiary referral centers.
Cardiovascular Autonomic Neuropathy
Both autonomic neuropathy and painful-DPN involve small
fibers, and a potential relationship was therefore investigated.
In a small study, we demonstrated greater changes in heart rate
variability studies, as measures of cardiovascular autonomic
neuropathy (CAN) in subjects with painful- compared with
painless-DPN [42], while other small studies reported that
painful DPN was more likely to be associated with the ab-
sence of a nocturnal fall in blood pressure (“non-dipping”)
[43], or with reduced Valsalva ratio [40]. However, these are
in contrast with other studies that have not found any differ-
ences in measures of CAN between painful and painless-DPN
[39,44,45].
Central
mechanisms
Vascular alteraons
(ACC/Thalamus)
Corcal reorganisaon Reduced inhibion of
descending pathways
A-β fibre sproung into
lamina II of dorsal horn
Central sensisaon
Peripheral
mechanisms
Glycaemic flux
Altered peripheral
blood flow
Peripheral sensisaon
Small fibre alteraons
Change in ion channel
distribuon and expression
Axonal atrophy,
degeneraon or
regeneraon
Genotype
e.g. VGSC
Obesity
Glycaemic
burden
Risk factors Mechanisms of pain generaon Clinical phenotype
Neuropathic
pain
Degeneraon/
regeneraon
Spinal cord
Vascular abnormalies
abnormal
neuropepde/ion
channel expression
Neurotransmier
imbalance
Abnormal funconal
connecvity
Female
gender
Ascending pathways
Descending pathways
NGF excess
Impaired spinal
inhibitory funcon
Inflammaon
Fig. 1 An overview of the current postulated pathogenesis of painful-
DSPN. The risk factors for the generation of neuropathic pain in DSPN
may include glycemic burden (duration of diabetes), obesity, female
gender, and genetic variants of voltage-gated sodium channels (VGSC).
Both the central and peripheral mechanisms have been postulated in the
pathogenesis of painful-DSPN. ACC, anterior cingulate cortex. (Adapted
from: Sloan G, et al. Diabetes Res Clin Pract. 2018; 144: 177–91, with
permission from Elsevier) [17]
Curr Diab Rep (2019) 19: 32 Page 3 of 13 32
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Diagnostic Methods of Painful-DPN
Conventional neurophysiological testing methods, which
measure large fiber function, such as nerve conduction studies
(NCS), cannot detect pure small fiber neuropathy (SFN) [46].
However, QST and more recent advances in diagnostic tech-
niques, e.g., skin biopsy with intraepidermal nerve fiber den-
sity (IENFD) quantitation, corneal confocal microscopy
(CCM), and laser Doppler imaging flare (LDI Flare) have
allowed the reliable diagnosis of SFN [5•,46]. Because of
their role in physiological nociception, studies have explored
whether damage or alterations in SF may relate to neuropathic
pain in DPN.
Skin Biopsy
Immunostaining of skin biopsy samples with protein gene
product 9.5 and quantitation of IENFD is a reliable means of
diagnosing SFN [46]. However, IENFD is unable to distinguish
between individuals with or without neuropathic pain [23••,
27••,28••,47••,48,49]. Other studies have been performed
to determine whether morphological and functional markers
of the epidermal innervation revealed differentiating features.
Intraepidermal nerve fiber (IENF) regeneration, by measuring
the ratio of growth associated protein-43 (GAP-43) to nerve
fibers, has been shown to be enhanced in painful-compared
with painless-DPN [49,50•,51]. However, Scheytt et al. found
no relationship between pain and GAP-43 reactivity in subjects
with peripheral neuropathies of varying etiologies [52]. There
are contradictory findings in studies investigating other IENF
markers to differentiate painful- from painless-DPN including
IENF length [50•,53] and axonal swellings, which are mea-
sures of axonal degeneration [49,54]. Levels within the skin of
the neurotrophin nerve growth factor (NGF) were increased in
patients with DPN and sensory symptoms, including pain, com-
paredtopainless-DPN[55]. NGF has recently been shown to
sensitize nociceptors in human skin and it has been hypothe-
sized that the remaining IENF in painful-DPN may be exposed
to excessive levels of NGF (“over-trophing”) resulting in hy-
persensitivity and neuropathic pain [19,55–58].
Corneal Confocal Microscopy
Confocal corneal microscopy (CCM) can rapidly, non-
invasively, and accurately image corneal nerves and is a re-
cently developed diagnostic test for DPN [59–61]. Studies of
CCM have explored the role of corneal innervation and neu-
ropathic pain in DM [53,62•,63]. Quattrini et al. reported
reduced corneal nerve fiber length with unaltered other
CCM measures [53], whereas Marshall et al. found unaltered
corneal nerve fiber length but reduced corneal nerve fiber
density [62•]. Recently, Kalteniece et al. [63] described signif-
icantly lower corneal inferior whorl length, and average and
total nerve length in painful- compared to painless-DPN.
Changes within this region have been suggested to be indica-
tive of early neuropathic damage. However, there were con-
founding factors, which could account for these group differ-
ences. Therefore, the association of CCM abnormalities to
neuropathic pain in DPN is thus far inconclusive.
Evoked Responses
Non-invasive tests have been developed to investigate the
peripheral function of SF to diagnose SFN. Such tests can
measure evoked potentials in response to stimuli that activate
the nociceptive pathway, for example contact heat-evoked po-
tentials (CHEPS) [64]. CHEPs correlates with other measures
of SFN including IENFD and leg skin flare responses [65,66].
One small study found a relationship between enhanced brain
CHEP amplitudes in subjects with painful-DPN; this result
was most marked in those with thermal hyperalgesia and me-
chanical allodynia [67].
Quantitative Sensory Testing
QST is a psychophysical measure of the perception of differ-
ent external stimuli of controlled intensity to assess a range of
sensory modalities [68,69]. Some studies with a relatively
small sample size suggested that conventional QST measures
of SF function may be statistically different between painful-
and painless-DPN [41,44,70,71]. More recent studies have
employed the German Research Network on Neuropathic
Pain (DFNS) QST protocol to quantify sensory loss, for small
and large fiber function, and sensory gain abnormalities [72,
73••]. Three recent large cross-sectional cohort studies have
applied this protocol to patients with painful- and painless-
polyneuropathies with different etiologies [48] and painful-
and painless-DPN [23••,27••]. In two studies of painful-
DPN, DFNS QST revealed more severe loss of function in
those with neuropathic pain, particularly patients with
moderate/severe pain [23••,27••]. Thermal hyposensitivity
was more severe in painful-DPN whereas mechanical stimuli
showed fewer differences compared with painless-DPN. Gain
of function abnormalities and preserved SF function with
hyperalgesia were both rare. However, Üçeyler et al. studied
patients with painful- and painless-polyneuropathies of differ-
ent etiologies and found that patients with neuropathic pain
demonstrated elevated mechanical pain and detection thresh-
old, and lower mechanical pain sensitivity with no difference
in SF deficits [48]. This perhaps indicates there may be a
unique somatosensory phenotype associated with painful-
DPN characterized by more severe SF dysfunction with ther-
mal hyposensitivity [23••,27••]. However, SF changes are
common and can occur in early DPN without pain [74–76];
therefore, these findings alone are unable to completely ex-
plain why some patients develop neuropathic pain and others
32 Page 4 of 13 Curr Diab Rep (2019) 19: 32
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do not. Perhaps, other investigations into small fiber function
and structure, such as skin biopsy studies, may shed further
light onto this paradox.
Pathogenesis of Painful-DPN
Microvascular Blood Flow
Consistent with vascular risk factors increasing the risk of
DPN [4•], both structural and functional microvascular abnor-
malities of the vasa-nervorum have been shown to be involved
in the pathogenesis of DPN [77–79]. Patients with treatment
induced neuropathy of diabetes who had extremely severe
neuropathic pain have proliferating blood vessels on the
epineurial surface bearing striking similarities to those found
in proliferative diabetic retinopathy [80]. It is well recognized
that very rapid improvement in glucose control can cause
proliferative retinopathy mediated by retinal ischemia and a
similar process appears to take place in the peripheral nerve.
Furthermore, several studies have shown that regulation of
peripheral blood flow is altered in patients with painful- com-
pared with painless-DPN [81–84]. Our group demonstrated
elevated sural nerve epineurial oxygen saturation and faster
blood flow in patients with painful- compared to painless-
DPN, perhaps secondary to arteriovenous shunting [82].
Other studies have examined the role of skin microvascular
vasodilator and vasoconstrictor responses in subjects with
DPN, with contradictory findings [71,85–87].
Studies measuring serum markers of angiogenesis (vascu-
lar endothelial growth factor, VEGF) and endothelial dysfunc-
tion (soluble intercellular adhesion molecule –1, sICAM-1)
have found them to be elevated in painful-DPN [86,88•]and
symptomatic DPN respectively [89]. Furthermore, punch skin
biopsy studies have also indicated that skin microcirculation
may be involved in the pathogenesis of painful-DPN. One
study demonstrated evidence of hypoxia, by immunostaining
with hypoxia inducible factor 1α(HIF-1 α), to be related to
pain intensity in subjects with DPN [90]. Recently, our group
has also found dermal von Willebrand factor (vWF) immuno-
reactivity, as a blood vessel marker, to be significantly elevat-
ed in subjects with painful-DPN, in comparison to subjects
with painless-DPN, patients with DM without DPN and
healthy volunteers [56]. Moreover, small studies have demon-
strated that pain improves with topical application of vasodi-
lator treatments [91,92], perhaps indicating that local blood
flow dysregulation could be a viable target for the manage-
ment of pain in DPN.
Hyperglycemia and Downstream Effects
Hyperglycemia mediated metabolic pathways have long been
associated in the pathogenesis of DPN, but their role in those
with neuropathic pain is less clearly defined. Studies using
DM rodent models have found neuropathic pain behaviors
to be related to numerous metabolic pathways including the
polyol pathway, protein kinase C activity, and increased ad-
vanced glycation end-products (AGEs) [93]. However, there
is limited evidence to support glycemic control or lifestyle
modifications in improving painful neuropathic symptoms
[3•]. Moreover, the evidence to support pathogenic treatments
for neuropathic pain in DPN has generally been disappointing
and only a few pharmacotherapeutic agents are available in
select countries [50•].
Methylglyoxal is a highly reactive dicarbonyl compound
and is a precursor to the formation of (AGEs). The formation
of AGEs has downstream deleterious effects on peripheral
nerves and Schwann cells including inflammation and oxida-
tive stress [94]. Methylglyoxal has been suggested to be an
important factor in the development of DM and incident DPN
[20•,95]. In rodent models of painful-DPN, methylglyoxal
has been shown to induce hyperalgesia via activation of the
voltage-gated sodium channel Nav 1.8 and transient receptor
potential channel ankyrin-1 [96,97]. Similarly, in a small
number of patients with DM (n= 30), serum methylglyoxal
levels were found to be elevated in painful-DPN [96]. In con-
trast to these findings, a larger study (n=882) reported
methylglyoxal levels to be unrelated to painful-DPN [98].
Although the role of hyperglycemia mediated pathways in
generating neuropathic pain is uncertain, pathogenically ori-
ented treatments, particularly anti-oxidants, have been dem-
onstrated to improve pain in some pre-clinical and clinical
trials [99,100].
Vitamin D
Although vitamin D is most commonly recognized for its role
in calcium metabolism and bone health, vitamin D is involved
in many disparate physiological processes [101]. Deficiency
of vitamin D has been shown to be predictive of numerous
chronic diseases including DM, DPN, and chronic pain
[101–104]. Pre-clinical studies indicate that vitamin D appears
to play a critical role in nerve function in health and may play
a role in neuropathic pain syndromes [105–109]. Our group
recently found vitamin D levels to be significantly lower in
patients with painful- compared to painless-DPN, with a sig-
nificant correlation between serum 25-hydroxyvitamin D lev-
el and pain scores on the Doleur Neuropathique 4 neuropathic
pain screening tool [110•]. The study was cross-sectional, and
therefore cannot establish a causal relationship, but it does
suggest a possible mechanistic link between vitamin D and
painful-DPN. Indeed, three non-randomized clinical trials
have demonstrated an improvement in painful neuropathic
symptoms with vitamin D therapy but, further, larger, ade-
quately powered RCTs are necessary to investigate this further
[111–113].
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Inflammation
Inflammation has been postulated to play a major part in DM
and DPN [114]. Low grade inflammation has been suggested
as a link between obesity and T2DM, via inflammation in-
duced insulin resistance [114]. Inflammatory chemokine and
cytokine production has been reported to be induced by sev-
eral metabolic pathways implicated in the pathogenesis of
DPN [115,116•]. Multiple studies have demonstrated higher
systemic acute-phase proteins, cytokines, and chemokines in
DPN [88•,117•], recently reviewed by Bönhof et al. [118•].
Furthermore, rodent models of neuropathic pain associated
with the metabolic syndrome and T2DM demonstrate elevat-
ed pro-inflammatory mediator expression in the serum [119]
and the dorsal root ganglia [119,120].Theoutcomesofstud-
ies examining the association of inflammatory biomarkers and
painful-DPN have been variable. Numerous inflammatory
markers have been associated with painful-DPN: C-reactive
protein (CRP) [86], tumor necrosis factor-α(TNF-α)[121],
inducible nitric oxide synthase [121], and interleukin 6 [117•].
Additionally, inflammatory mediators have been shown to
differentiate between painful- from painless-neuropathies of
various etiologies, including elevated serum IL-2, TNF-α,
and reduced anti-inflammatory IL-10 [122]; IL-6 and IL-10
sural nerve biopsy expression [123]; and TNF-αin human
Schwann cells [124].
The Central Nervous System
Technological advances in imaging modalities have enabled
detailed in vivo investigation of the nervous system in DM.
Key differences have been identified within the CNS in pain-
ful-DPN, using a variety of different techniques, especially
advanced MR imaging modalities.
Spinal Cord Changes in Painful-DPN
We have identified a reduction in the cross-sectional
area of the spinal cord in subjects with DPN in com-
parisontopatientwithDMwithoutDPN,healthycon-
trols, and disease control subjects with hereditary senso-
ry motor neuropathy type 1A [125]. However, structural
differences in the spinal cord area have not been found
between subjects with painless- and painful-DPN [125].
Recent studies have indicated that spinal disinhibition,
measured using the rate dependent depression (RDD) of
the Hoffman reflex (H-reflex), may be a potential bio-
marker of spinally mediated pain to differentiate painful-
from painless-DPN [126]. The RDD has been demon-
stratedtoassessγ-aminobutyric acid (GABA) type A
receptor-mediated spinal inhibitory function in neuro-
pathic pain models of DM rats [127]. Impaired RDD
was found in DM rat models of T1DM and T2DM with
neuropathic pain phenotypes [62•]. Also, the RDD in
groups of healthy controls and T1DM subjects with
painful- and painless-DPN was evaluated and it was
significantly impaired in those with painful-DPN.
Patients with greater RDD attenuation had higher pain
scores but no difference in measures of large or small
fiber dysfunction, perhaps suggesting spinal inhibitory
dysfunction may occur independent of PNS alterations
in painful-DPN.
Advanced MRI Studies of the Brain
Functional MRI (fMRI) measures the activity of brain regions
by detecting changes in the oxygenation of hemoglobin, the
blood oxygen level dependent signal (BOLD). The neurolog-
ical signature of physical pain has been identified by fMRI
and includes activation of the venterolateral thalamus, dorsal
posterior insula, and somatosensory cortex, as well as brain
regions related to emotional pain processing, including the
anterior insula and anterior cingulate cortex (ACC)
[128–130].
The Thalamus
The thalamus receives somatosensory signals from the spinal
cord where they are processed, modulated, and transmitted to
higher brain centers. A variety of brain alterations have been
demonstrated in DPN and painful-DPN using advanced im-
aging techniques that examine brain neurochemistry, micro-
vascular blood flow, and functional changes. MR spectrosco-
py (MRS) enables the measurement of selected metabolites
within the brain [131]. Our group has used MRS to show
neuronal dysfunction within the thalamus, by reduced N-
acetyl aspartate (NAA) to choline ratio as a neuronal marker,
in subjects with painless-DPN [132]. Furthermore, DM ani-
mal models of painful-DPN have shown that the thalamus
may be responsible for central amplification of somatosensory
signals [133,134]. Similarly, thalamic dysfunction appears to
play a key role in human painful-DPN. We have recently
shown preserved thalamic NAA and the GABA levels within
the thalamus in patients with painful-DPN, whereas these
levels were reduced in patients with painless-DPN [135,
136]. These findings suggest that neurochemical measures of
the thalamic neuronal function and neurotransmitters may be
essential for pain signal transmission and/or amplification in
painful-DPN.
Recently, we performed a study administering exoge-
nous perfusion contrast to subjects with painful- and
painless-DSPN to compare the thalamic microvascular
perfusion at rest [137•]. Subjects with DPN both dem-
onstrated delayed bolus arrival time to the thalamus, but
subjects with neuropathic pain had a significantly taller
peak concentration, a higher mean cerebral blood
32 Page 6 of 13 Curr Diab Rep (2019) 19: 32
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volume, and the longest blood transit time compared to
painless-DPN. Therefore, microvascular vasodilation
within the thalamus may induce hyperperfusion which
could be related to elevated thalamic neuronal activity.
Finally, fMRI study of the brain has indicated there may
be disruption in thalamocortical connectivity in painful-
DPN. Cauda et al. measured resting state fMRI to de-
termine temporal correlations of brain activity in a small
number of subjects with painful-DPN and healthy con-
trol patients [138]. Compared with the control group,
there was reduced synchrony between the somatosenso-
ry cortex and thalamic nuclei in painful-DPN patients.
Descending Inhibition
It is well recognized that the midbrain and medullary
brain regions can exert bidirectional control over
nociception [139]. The periaqueductal gray (PAG) and
rostroventromedial medulla (RVM) are key sites for the
control of descending pain modulation, disruption of
which in rodent models of painful-DPN has been shown
to lead to enhancement of descending pain facilitation
[140,141]. In human studies, our group performed MR-
dynamic susceptibility contrast imaging at rest and un-
der experimental pain, by applying heat pain to the lat-
eral thigh where participants did not experience neurop-
athy [142]. During experimental pain, the time to peak
concentration of contrast reduced in healthy volunteers
but significantly increased in subjects with painful-DPN
in the bilateral sensory cortices and thalami, perhaps
indicating an underlying impairment in descending inhi-
bition. Segerdahl et al. interrogated the ventrolateral
PAG (vlPA G) using res ting st ate fMR I and art eri al spin
labelling to determine cerebral blood flow at rest and
during heat stimulation to the foot [143•]. The painful-
DPN group demonstrated altered vlPAG functional con-
nectivity, which correlated to their pain intensity and the
cerebral blood flow changes induced by experimental
thermal stimulation. These studies indicate that abnor-
malities within the descending pain modulatory system
may result not only in reduced inhibition of pain but
increased amplification of pain signals in painful-DPN.
Higher Brain Centers
The higher brain centers are involved in the localization
of pain (e.g., somatosensory cortex) as well as the be-
havioral, cognitive, and emotional response to painful
stimuli (e.g., ACC, amygdala, insular cortex). Using a
technique known as voxel-based morphometry, we cal-
culated the brain volumes in subjects with DPN and
identified total brain volume reduction which was local-
ized to the somatosensory regions [144,145].
Furthermore, our group has performed the largest cohort
study of brain volume changes in DPN and painful-
DPN to date [146]. In painful-DPN, cortical atrophy is
localized within the somatomotor cortex and insula. We
have also demonstrated abnormal cortical interactions
within the somatomotor network at rest which correlated
with measures of pain and behavior in subjects with
painful-DPN [147]. A recent study performed single-
photon emission computed tomography to assess cere-
bral blood flow (CBF) in 24 subjects with painful- and
20 painless-DPN [148]. The painful-DPN group demon-
strated increased CBF within the right ACC and left
nucleus accuumbens. However, the painless-DPN group
demonstrated more severe neurophysiological neuropath-
ic impairment which may be a potential confounding
factor. Furthermore, application of thermal heat stimuli
resulted in altered BOLD fMRI responses in painful-
compared with painless-DPN, seen in two studies [149,
150]. A pilot study within our group found greater
BOLD response within the primary somatosensory cor-
tex, lateral frontal, and cerebellar regions [149].
Whereas Tseng et al. demonstrated augmented responses
in multiple limbic and striatal structures (i.e., ACC, su-
perior frontal gyrus, medial thalamus, anterior insular
cortex, lentiform nucleus, and premotor area) with the
BOLD signal in the ACC and lentiform nucleus corre-
lating with pain rating to thermal stimulation [150]. It is
currently unknown whether the CNS changes described
in these studies are a response to peripheral nervous
system afferent inputs or a primary mechanism respon-
sible for the maintenance of neuropathic pain.
Conclusions
Painful-DPN is a major cause of morbidity in patients
with DM. Unfortunately, our understanding of why pa-
tients with DPN develop neuropathic pain remains inad-
equate (Fig. 1.). We have summarized the current evi-
dence of the differences between painful- and painless-
DPN (see Table 1.). However, there are limitations in
many of the studies including small sample sizes, inap-
propriate definition of neuropathic pain and DPN, and
measurement of multiple variables, leading to a risk of
false positives. More recently, large, well-characterized
cross-sectional cohort studies have given valid insights
into the risk factors and somatosensory profiles of
painful-DPN [23••,27••,28••]. Unfortunately, longitudi-
nal studies which prospectively identify definitive differ-
ences in painful-DPN have not yet been performed, and
would be logistically challenging and costly to perform.
These limitations notwithstanding, painful-DPN seems
to be associated with female gender, increased small
Curr Diab Rep (2019) 19: 32 Page 7 of 13 32
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Table 1 Recently reported differences between painful- and painless-diabetic peripheral neuropathy
Contributing factor Difference associated with painful-DPN References
Risk factors Female gender [21••,26,27••,28••]
Nephropathy [26,27••]
Na
v
1.7 mutations [35•]
Small nerve fiber alterations Hyposensitivity phenotype [23••,27••]
Epidermal nerve fiber regeneration [49,50•,51]
Microvascular alterations Elevated immunostaining for blood vessels [56]
Vitamin D Reduced 25-hydroxyvitamin D levels [110•]
Inflammatory biomarkers C-reactive protein, tumor necrosis factor-α, inducible nitric oxide synthase and interleukin 6. [86,117•,121]
Central nervous system
Spinal cord Impaired spinal inhibitory function [62•]
Thalamus Preserved thalamic NAA and GABA neurochemistry [135,136]
Thalamic hyperperfusion [137•]
Altered somatosensory cortex and thalamic functional connectivity [138]
Descending modulatory pain centers Descending pain facilitation [142,143•]
Higher brain centers Somatomotor cortex and insula cortical atrophy [146]
Abnormal cerebral blood flow at rest and in response to heat pain [142,148]
Altered functional connectivity in higher brain centers at rest and experimental pain conditions [147,149,150]
DPN diabetic distal symmetrical polyneuropathy, NAA N-acetyl aspartate, GABA γ-aminobutyric acid, BOLD
32 Page 8 of 13 Curr Diab Rep (2019) 19: 32
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fiber injury and/or function, and peripheral/central vas-
cular alterations. The role of autonomic dysfunction, vi-
tamin D, inflammatory mediators, genetic factors, and
methylglyoxal needs further clarification. Studies of the
CNS demonstrate clear differences in painful- compared
with painless-DPN. The spinal, somatomotor, limbic,
thalamic, and ascending and descending modulatory sys-
tems demonstrate alterations using numerous testing
techniques. However, what remains unclear is the causal
relationship between painful-DPN and CNS changes.
Further studies are necessary to determine whether these
findings are the primary cause of neuropathic pain or
adaptive to neuropathic afferent impulses. Irrespective
of this, advanced MR imaging modalities have the po-
tential for acting as biomarkers for monitoring therapeu-
tic responses to treatments [151••].
Compliance with Ethical Standards
Conflict of Interest Pallai Shillo, Gordon Sloan, Marni Greig, Leanne
Hunt, Dinesh Selvarajah, Jackie Elliott, Rajiv Gandhi, and Iain D.
Wilkinson declare that they have no conflict of interest.
Solomon Tesfaye reports grants from Impeto Medical; personal fees
from Neurometrix, Pfizer, Miro, Worwag Pharma, Mundipharma, Merck,
and Mitsubishi Pharma; and personal fees and other from Novo Nordisk.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appro-
priate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
References
Papers of particular interest, published recently, have been
highlighted as:
•Of importance
•• Of major importance
1. International Diabetes Federation. International diabetes federa-
tion: IDF Atlas. Brussels: Belgium; 2017. Available from: http://
diabetesatlas.org/resources/2017-atlas.html. Accessed 29 April
2019.
2. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM,
et al. The prevalence by staged severity of various types of diabetic
neuropathy, retinopathy, and nephropathy in a population-based
cohort: the Rochester Diabetic Neuropathy Study. Neurology.
1993;43:817–24.
3.•Pop-Busui R, Boulton AJM, Feldman EJ, Bril V, Freeman R,
Malik RA, et al. Diabetic neuropathy: a position statement by
the American Diabetes Association. Diabetes Care. 2017;40:
136–54 Recent position statement of Diabetic Neuropathy by
the American Diabetes Association.
4.•Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-
Tirgoviste C, et al. Vascular risk factors and diabetic neuropathy.
N Engl J Med. 2005;352:341–50 Prospective epidemiological
study showing that, apart from glycemic control, incident neu-
ropathy is associated with modifiable cardiovascular risk
factors.
5.•Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M,
Kempler P, et al. Diabetic neuropathies: update on definitions,
diagnostic criteria, estimation of severity, and treatments.
Diabetes Care. 2010;33:2285–93 Review by international panel
of experts making recommendations in the clinical practice
and research for DPN.
6. Sadosky A, Mardekian J, Parsons B, Hopps M, Bienen EJ,
Markman J. Healthcare utilization and costs in diabetes relative
to the clinical spectrum of painful diabetic peripheral neuropathy.
J Diabetes Complicat. 2015;29:212–7.
7. Narres M, Kvitkina T, Claessen H, Droste S, Schuster B, Morbach
S, et al. Incidence of lower extremity amputations in diabetic com-
pared with the non-diabetic population: a systematic review. PLoS
One. 2017;12:e0182081. https://doi.org/10.1371/journal.pone.
0182081.
8. Daousi C, MacFarlane IA, Woodward A, Nurmikko TJ, Bundred
PE, Benbow SJ. Chronic painful peripheral neuropathy in an ur-
ban community: a controlled comparison of people with and with-
out diabetes. Diabet Med. 2004;21:976–82.
9. Van Acker K, Bouhassira D, De Bacquer D, Weiss S, Matthys K,
Raemen H, et al. Prevalence and impact on quality of life of
peripheral neuropathy with or without neuropathic pain in type 1
and type 2 diabetic patients attending hospital outpatients clinics.
Diabetes Metab. 2009;35:206–13.
10. Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A,
KORA Study Group. Neuropathic pain in diabetes, prediabetes
and normal glucose tolerance: the MONICA/KORA Augsburg
surveys S2 and S3. Pain Med. 2009;10:393–400.
11. Abbott CA, Malik RA, van Ross ER, Kulkarni J, Boulton AJ.
Prevalence and characteristics of painful diabetic neuropathy in a
large community-based diabetic population in the U.K. Diabetes
Care. 2011;34:2220–4.
12.•Alleman CJ, Westerhout KY, Hensen M, Chambers C, Stoker M,
Long S, et al. Humanistic and economic burden of painful diabetic
peripheral neuropathy in Europe: a review of the literature.
Diabetes Res Clin Pract. 2015;109:215–25 Review article of
the epidemiology, humanistic burden and increasing
healthcare costs associated with painful-DPN.
13. Binns-Hall O, Selvarajah D, Sanger D, Walker J, Scott A, Tesfaye
S. One-stop microvascular screening service: an effective model
for the early detection of diabetic peripheral neuropathy and the
high-risk foot. Diabet Med. 2018;35:887–94.
14. Taylor-Stokes G, Pike J, Sadosky A, Chandran A, Toelle T.
Association of patient-rated severity with other outcomes in pa-
tients with painful diabetic peripheral neuropathy. Diabetes Metab
Syndr Obes. 2011;4:401–8.
15. Lauria G, Lombardi R. Small fiber neuropathy: is skin biopsy the
holy grail? Curr Diab Rep. 2012;12:384–92.16.
16. Jensen TS, Backonja MM, Hernández Jiménez S, Tesfaye S,
Valensi P, Ziegler D. New perspectives on the management of
diabetic peripheral neuropathic pain. Diab Vasc Dis Res. 2006;3:
108–19.
17. Sloan G, Shillo P, Selvarajah D, Wu J, Wilkinson ID, Tracey I,
et al. A new look at painful diabetic neuropathy. Diabetes Res Clin
Pract. 2018;144:177–91.
18.•Andersen ST, Witte DR, Dalsgaard EM, Andersen H, Nawroth P,
Fleming T, et al. Riskfactors for incident diabetic polyneuropathy
in a cohort with screen-detected type 2 diabetes followed for 13
Curr Diab Rep (2019) 19: 32 Page 9 of 13 32
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

years: ADDITION-Denmark. Diabetes Care. 2018;41:1068–75
Recent prospective study finding that cardiovascular risk fac-
tors are associated with incident DPN in T2DM.
19. Pop-Busui R, Lu J, Brooks MM, Albert S, Althouse AD,
Escobedo J, et al. Impact of glycemic control strategies on the
progression of diabetic peripheral neuropathy in the bypass angio-
plasty revascularization investigation 2 diabetes (BARI 2D) co-
hort. Diabetes Care. 2013;36:3208–15.
20. Callaghan BC, Gao LL, Li Y, Zhou X, Reynolds E, Banerjee M,
et al. Diabetes and obesity are the main metabolic drives of pe-
ripheral neuropathy. Ann Clin Transl Neurol. 2018;5:397–40521.
21.•• HébertHL, Veluchamy A, Torrance N, Smith BH. Risk factors for
neuropathic pain in diabetes mellitus. Pain. 2017;158:560–8
Recent review of the risk factors for painful-DPN.
22. Elliott J. Female sex: an independent risk factor for the develop-
ment of painful neuropathy? Diabetes. 2006;55(Supp 1) Abstract,
number 794-P
23.•• Themistocleous AC, Ramirez JD, Shillo PR, Lees JG, Selvarajah
D, Orengo C, et al. The pain in neuropathy study (PiNS): a cross-
sectional observational study determiningthe somatosensory phe-
notype of painful and painless diabetic neuropathy. Pain.
2016;157:1132–45 Detailed cross-sectional study showing that
the hyposensitivity sensory phenotype and increased severity
of neuropathy are associated with painful-DPN.
24. Algeffari MA. Painful diabetic peripheral neuropathy among
Saudi diabetic patients is common but under-recognized: multi-
center cross-sectional study at primary health care setting. J
Family Community Med. 2018;25:43–7.
25. Ziegler D, Landgraf R, Lobmann R, Reiners K, Rett K, Schnell O,
et al. Painful and painless neuropathies are distinct and largely
undiagnosed entities in subjects participating in an educational
initiative (PROTECT study). Diabetes Res Clin Pract. 2018;139:
147–54.
26. Pai YW, Lin CH, Lee IT, Chang MH, et al. Prevalence and bio-
chemical risk factors of diabetic peripheral neuropathy with or
without neuropathic pain in Taiwanese adults with type 2 diabetes
mellitus. Diabetol Metab Syndr. 2018;12:11–6.
27.•• Raputova J, Srotova I, Vlckova E, SommerC, Üçeyler N, Birklein
F, et al. Sensory phenotype and risk factors for painful diabetic
neuropathy: a cross-sectional observational study. Pain.2017;158:
2340–53 Another detailed cross-sectional study finding
painful-DPN is associated with severity of neuropathy and
thermal hyposensitivity.
28.•• Truini A, Spallone V, Morganti R, Tamburin S, Zenette G,
Schenone A,et al. A cross-sectional study investigating frequency
and features of definitely diagnosed diabetic painful
polyneuropathy. Pain. 2018;159:2658–66 Large cross-sectional
epidemiological study identifying female gender as the only
risk factor associated with painful-DPN.
29. Abraham A, Barnett C, Katzberg HD, Lovblom LE, Perkins BA,
Bril V. Sex differences in neuropathic pain intensity in diabetes. J
Neurol Sci. 2018;388:103–6.
30. Sorge RE, Strath LJ. Sex differences in pain responses. Curr Opin
Physiol. 2018;6:75–81.
31. Prabodha LBL, Sirisena ND, Dissanayake VHW. Susceptible and
prognostic genetic factors associated with diabetic peripheral neu-
ropathy: a comprehensive literature review. Int J Endocrinol.
2018;2018:8641942–9. https://doi.org/10.1155/2018/8641942.
32. Meng W, Deshmukh HA, Donnelly LA, Torrance N, Colhoun
HM, Palmer CN, et al. A genome-wide association study provides
evidence of sex-specific involvement of Chr1p35.1 (ZSCAN20-
TLR12P) and Chr8p23.1 (HMGB1P46) with diabetic neuropathic
pain. EBioMedicine. 2015;2:1386–93.
33. Meng W, Deshmukh HA, van Zuydam NR, Liu Y, Donnelly LA,
Zhou K, et al. A genome-wide association study suggests an
association of Chr8p21.3 (GFRA2) with diabetic neuropathic
pain. Eur J Pain. 2015;19:392–9.
34. Li QS, Cheng P, Favis R, Wickenden A, Romano G, Wang H.
SCN9Avariants may be implicated in neuropathic pain associated
with diabetic peripheral neuropathy and pain severity. Clin J Pain.
2015;31:976–82.
35.•Blesneac I, Themistocleous AC, Fratter C, Conrad LJ, Ramirez
JD, Cox JJ, et al. Rare Nav1.7 variants associated with painful
diabetic peripheral neuropathy. Pain. 2017;159:469–80 Study
showing that rare sodium channel genetic variants contribute
to neuropathic pain in some patients with DPN.
36. Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS,
et al. Gain of function Naν1.7 mutations in idiopathic small fiber
neuropathy. Ann Neurol. 2012;71:26–39.
37. Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy:
epidemiology, pain description, and quality of life. Diabetes Res
Clin Pract. 2000;47:123–8.
38. Gore M, Brandenburg NA, Dukes E, Hoffman DL, Tai KS, Stacey
B. Pain severity in diabetic peripheral neuropathy is associated
with patient functioning, symptom levels of anxiety and depres-
sion, and sleep. J Pain Symptom Manag. 2005;30:374–85.
39. Veves A, Young MJ, Manes C, Boulton AJ. Differences in periph-
eral and autonomic nerve function measurements in painful and
painless neuropathy. A clinical study. Diabetes Care. 1994;17:
1200–2.
40. Spallone V, Morganti R, D’Amato C, Cacciotti L, Fedele T,
Maiello MR, et al. Clinical correlates of painful diabetic neurop-
athy and relationship of neuropathic pain with sensorimotor and
autonomic nerve function. Eur J Pain. 2011;15:153–60.
41. Sorensen L, Molyneaux L, Yue DK. The level of small nerve fiber
dysfunction dose not predict pain in diabetic neuropathy: a study
using quantitative sensory testing. Clin J Pain. 2006;22:261–5.
42. Gandhi RA, Marques JL, Selvarajah D, Emery CJ, Tesfaye S.
Painful diabetic neuropathy is associated with greater autonomic
dysfunction than painless diabetic neuropathy. Diabetes Care.
2010;33:1585–90.
43. D’Amato C, Morganti R, Di Gennaro F, Marfia GA, Spallone V. A
novel association between nondipping and painful diabetic
polyneuropathy. Diabetes Care. 2014;37:2640–2.
44. Young RJ, Zhou TQ, Rodriguez E, Prescott RJ, Ewing DJ, Clarke
BF. Variable relationship between peripheral somatic and auto-
nomic neuropathy in patients with different syndromes of diabetic
polyneuropathy. Diabetes. 1986;35:192–7.45.
45. Krämer HH, Rolke R, Bickel A, Birklein F. Thermal thresholds
predict painfulness of diabetic neuropathies. Diabetes Care.
2004;27:2386–91.
46. Terkelsen AJ, Karlsson P, Lauria G, Freeman R, Finnerup NB,
Jensen TS. The diagnostic challenge of small fibre neuropathy:
clinical presentations, evaluations, and causes. Lancet Neurol.
2017;16:934–44.
47.•• Smith SM, Dworkin RH, Turk DC, Baron R, Polydefkis M,
Tracey I, et al. The potential role of sensory testing, skin biopsy,
and functional brain imaging as biomarkers in chronic pain clin-
ical trials: IMMPACT Considerations. J Pain. 2017;18:757–77
Review of the role of sensory testing, skin biopsy and brain
imaging as diagnostic, prognostic, predictive and pharmaco-
dynamic biomarkers in analgesic treatment trials.
48. Üçeyler N, Vollert J, Broll B, Riediger N, Langjahr M, Saffer N,
et al. Sensory profiles and skin innervation of patients with painful
and painless neuropathies. Pain. 2018;159:1867–76.
49. Cheng HT, Dauch JR, Porzio MT, Yanik BM, Hsieh W, Smith
AG, et al. Increased axonal regeneration and swellings in
intraepidermal nerve fibers characterize painful phenotypes of di-
abetic neuropathy. J Pain. 2013;14:941–7.
50.•Bönhof GJ, Strom A, Püttgen S, Ringel B, Brüggemann J, Bódis
K, et al. Patterns of cutaneous nerve fibre loss and regeneration in
32 Page 10 of 13 Curr Diab Rep (2019) 19: 32
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

type 2 diabetes with painful and painless polyneuropathy.
Diabetologia. 2017;60:2495–503 Study demonstrating mea-
sures of cutaneous nerve fibre regeneration are enhanced in
painful-DPN.
51. Galosi E, La Cesa S, Di Stefano G, Karlsson P, Fasolino A, Leone
C, et al. A pain in the skin. Regenerating nerve sprouts are dis-
tinctly associated with ongoing burning pain in patients with dia-
betes. Eur J Pain. 2018;22:1727–34.
52. Scheytt S, Riediger N, Braunsdorf S, Sommer C, Üçeyler N.
Increased gene expression of growth associated protein-43 in skin
of patients with early-stage peripheral neuropathies. J Neurol Sci.
2015;355:131–7.
53. Quattrini C, Tavakoli M, Jeziorska M, Kallinikos P, Tesfaye S,
Finnigan J, et al. Surrogate markers of small fiber damage in
human diabetic neuropathy. Diabetes. 2007;56:2148–54.
54. Cheung A, Podgomy P, Martinez JA, Chan C, Toth C. Epidermal
axonal swellings in painful and painless diabetic peripheral neu-
ropathy. Muscle Nerve. 2015;51:505–13.
55. Anand P, Terenghi G, Warner G, Kopelman P, Williams-Chestnut
RE, Sinicropi DV. The role of endogenous nerve growth factor in
human diabetic neuropathy. Nat Med. 1996;2:703–7.
56. Shillo P, Selvarajah D, Greig M, Wilkinson I, Yiangou Y,
Donatien P, et al. Nerve and vascular biomarkers in skin biopsies
differentiate painful from painless advanced diabetic peripheral
neuropathy. Diabet Med. 2017;34(Supp 1):31–3.
57. Anand P, Bley K. Topical capsaicin for pain management: therapeu-
tic potential and mechanism of action of the new high-concentration
capsaicin 8% patch. Br J Anaesth. 2011;107:490–502.
58. Obreja O, Rukwied R, Nagler L, Schmidt M, Schmelz M, Namer
B. Nerve growth factor locally sensitizes nociceptors in human
skin. Pain. 2018;159:416–26.
59. Alam U, Jeziorska M, Petropoulos IN, Asghar O, Fadavi H,
Ponirakis G, et al. Diagnostic utility of corneal confocal micros-
copy and intra-epidermal nerve fibre density in diabetic neuropa-
thy. PLoS One. 2017;12:e0180175. https://doi.org/10.1371/
journal.pone.0180175.
60. Malik RA, Kallinikos P, Abbott CA, van Schie CH, Morgan P,
Efron N, et al. Corneal confocal microscopy: a non-invasive sur-
rogate of nerve fibre damage and repair in diabetic patients.
Diabetologia. 2003;46:683–8.
61. Jiang MS, Yuan Y, Gu ZX, Zhuang SL. Corneal confocal micros-
copy for assessment of diabetic peripheral neuropathy: a meta-
analysis. Br J Opthalmol. 2016;100:9–14.
62.•Marshall AG, Lee-Kubli C, Azmi S, Zhang M, Ferdousi M,
Mixcoatl-Zecuatl T, et al. Spinal disinhibition in experimental
and clinical painful diabetic neuropathy. Diabetes. 2017;66:
1380–90 Experimental and clinical study showing spinal in-
hibitory dysfunction may contribute to the pathogenesis of
painful-DPN.
63. Kalteniece A, Ferdousi M, Petropoulos I, Azmi S, Adam S, Fadavi
H, et al. Greater corneal nerve loss at the inferior whorl is related to
the presence of diabetic neuropathy and painful diabetic neuropa-
thy. Sci Rep. 2018;8:3283. https://doi.org/10.1038/s41598-018-
21643-z.
64. Gasparotti R, Padua L, Briani C, Lauria G. New technologies for
the assessment of neuropathies. Nat Rev Neurol. 2017;13:203–16.
65. Atherton DD, Facer P, Roberts KM, Misra VP, Chizh BA, Bountra
C, et al. Use of the novel Contact Heat Evoked Potential
Stimulator (CHEPS) for the assessment of small fibre neuropathy:
correlations with skin flare responses and intra-epidermal nerve
fibre counts. BMC Neurol. 2007;7:21. https://doi.org/10.1186/
1471-2377-7-21.
66. Casanova-Molla J, Grau-Junyent JM, Morales M, Valls-Solé J. On
the relationship between nociceptive evoked potentials and
intraepidermal nerve fiber density in painful sensory
polyneuropathies. Pain. 2011;152:410–8.
67. Chao CC, Tseng MT, Lin YJ, Yang WS, Hsieh SC, Lin YH, et al.
Pathophysiology of neuropathic pain in type 2 diabetes: skin de-
nervation and contact heat-evoked potentials. Hum Brain Mapp.
2013;34:2733–46.
68. Hansson P, Backonja M, Bouhassira D. Usefulness and limitations
of quantitative sensory testing: clinical and researchapplication in
neuropathic pain states. Pain. 2007;129:256–9.
69. Cruccu G, Sommer C, Anand P, Attal N, Baron R, Garcia-Larrea
L, et al. EFNS guidelines on neuropathic pain assessment: revised
2009. Eur J Neurol. 2010;17:1010–8.
70. Tsigos C, White A, Young RJ. Discrimination between painful and
painless diabetic neuropathy based on testing of large somatic nerve
and sympathetic nerve function. Diabet Med. 1992;9:359–65.
71. Krishnan ST, Quattrini C, Jeziorska M, Malik RA, Rayman G.
Abnormal LDIflare but normal quantitative sensory testing and
dermal nerve fiber density in patients with painful diabetic neu-
ropathy. Diabetes Care. 2009;32:451–5.
72. Rolke R, Magerl W, Campbell KA, Schalber C, Caspari S,
Birklein F, et al. Quantitative sensory testing: a comprehensive
protocol for clinical trials. Eur J Pain. 2006;10:77–88.
73.•• Rolke R, Baron R, Maier C, Tölle TR, Treede RD, Beyer A, et al.
Quantitative sensory testing in the German Research Network on
Neuropathic Pain (DFNS): standardized protocol and reference
values. Pain. 2006;123:231–43 QST protocol for the character-
ization the somatosensory phenotype of patients with neuro-
pathic pain.
74. Umapathi T, Tan WL, Loke SC, Soon PC, Tavintharan S, Chan
YH. Intraepidermal nerve fiber density as a marker of early dia-
betic neuropathy. Muscle Nerve. 2007;35:591–8.
75. Løseth S, Stålberg E, Jorde R,Mellgren SI. Early diabetic neurop-
athy: thermal thresholds and intraepidermal nerve fibre density in
patients with normal nerve conduction studies. J Neurol.
2008;255:1197–202.
76. Ragé M, Van Acker N, Knaapen MW, Timmers M, Streffer J,
Hermans MP, et al. Asymptomatic small fiber neuropathy in dia-
betes mellitus: investigations with intraepidermal nerve fiber den-
sity, quantitative sensory testing and laser-evoked potentials. J
Neurol. 2011;258:1852–64.
77. Cameron NE, Eaton SE, Cotter MA, Tesfaye S. Vascular factors
and metabolic interactions in the pathogenesis of diabetic neurop-
athy. Diabetologia. 2001;44:1973–88.
78. Tesfaye S, Harris ND, Wilson RM, Ward JD. Exercise-induced
conduction velocity increment: a marker of impaired peripheral
nerve blood flow in diabetic neuropathy. Diabetologia. 1992;35:
155–9.
79. Tesfaye S, Harris N, Jakubowski JJ, Mody C, Wilson RM,
Rennie IG, et al. Impaired blood flow and arterio-venous
shunting in human diabetic neuropathy: a novel technique
of nerve photography and fluorescein angiography.
Diabetologia. 1993;36:1266–74.
80. Tesfaye S, Malik R, Harris N, Jakubowski JJ, Mody C, Rennie IG,
et al. Arterio-venous shunting and proliferating new vessels in
acute painful neuropathy of rapid glycaemic control (insulin neu-
ritis). Diabetologia. 1996;39:329–35.
81. Archer AG, Roberts VC, Watkins PJ. Blood flow patterns in pain-
ful diabetic neuropathy. Diabetologia. 1984;27:563–7.
82. Eaton SE, Harris ND, Ibrahim S, Patel KA, Selmi F, Radatz M,
et al. Increased sural nerve epineurial blood flow in human sub-
jects with painful diabetic neuropathy. Diabetologia. 2003;46:
934–9.
83. Tsigos C, Reed P, Weinkove C, White A, Young RJ. Plasma nor-
epinephrine in sensory diabetic polyneuropathy. Diabetes Care.
1993;16:722–7.
84. Tack CJ, van Gurp PJ, Holmes C, Goldstein DS. Local sympa-
thetic denervation in painful diabetic neuropathy. Diabetes.
2002;51:3545–53.
Curr Diab Rep (2019) 19: 32 Page 11 of 13 32
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

85. Quattrini C, Harris ND, Malik RA, Tesfaye S. Impaired skin mi-
crovascular reactivity in painful diabetic neuropathy. Diabetes
Care. 2007;30:655–9.
86. Doupis J, Lyons TE, Wu S, Gnardellis C, Dinh T, Veves A.
Microvascular reactivity and inflammatory cytokines in painful
and painless peripheral diabetic neuropathy. J Clin Endocrinol
Metab. 2009;94:2157–63.
87. Vas PR, Sharma S, Rayman G. Distal sensorimotor neuropathy:
improvements in diagnosis. Rev Diabet Stud. 2015;12:29–47.
88.•Herder C, Kannenberg JM, Huth C, Carstensen-Kirbgerg M,
Rathmann W, Koening W, et al. Proinflammatory cytokines pre-
dict the incidence and progression of distal sensorimotor
polyneuropathy: KORA F4/FF4 Study. Diabetes Care. 2017;40:
569–76 Prospective study finding IL-6 and TNF -αare asso-
ciated with incident DPN.
89. Deguchi T, Hashiguchi T, Horinouchi S, Uto T, Oku H, Kimura K,
et al. Serum VEGF increases in diabetic polyneuropathy, particu-
larly in the neurologically active symptomatic stage. Diabet Med.
2009;26:247–52.
90. Quattrini C, Jeziorska M, Boulton AJ, Malik RA. Reduced vascu-
lar endothelial growth factor expression and intra-epidermal nerve
fiber loss in human diabetic neuropathy. Diabetes Care. 2008;31:
140–5.
91. Yuen KC, Baker NR, Rayman G. Treatment of chronic painful
diabetic neuropathywithisosorbide dinitrate spray: a double-blind
placebo-controlled cross-over study. Diabetes Care. 2002;25:
1699–703.
92. Rayman G, Baker NR, Krishnan ST. Glyceryl trinitrate patches as
an alternative to isosorbide dinitrate spray in the treatment of
chronic painful diabetic neuropathy. Diabetes Care. 2003;26:
2697–8.
93. Obrosova IG. Diabetic painful and insensate neuropathy: patho-
genesis and potential treatments. Neurotherapeutics. 2009;6(4):
638–47.
94. Dewanjee S, Das S, Das AK, Bhattacharjee N, Dihingia A, Dua TK.
Molecular mechanism of diabetic neuropathy and its
pharmacotherapeutic targets. Eur J Pharmacol. 2018;833:472–523.
95. Shamsaldeen YA, Mackenzie LS, Lione LA, Benham CD.
Methylglyoxal, a metabolite increased in diabetes is associated
with insulin resistance, vascular dysfunction and neuropathies.
Curr Drug Metab. 2016;17:359–67.
96. Huang Q, Chen Y, Gong N, Wang YX. Methylglyoxal mediates
streptozotocin-induced diabetic neuropathic pain via activation of
the peripheral TRPA1 and Nav1.8 channels. Metabolism.
2016;65:463–74.
97. Bierhaus A, Fleming T, Stoyanov S, Leffler A, Babes A, Neacsu
C, et al. Methylglyoxal modification of Nav1.8 facilitates nocicep-
tive neuron firing and causes hyperalgesia in diabetic neuropathy.
Nat Med. 2012;18:926–33.
98. Hansen CS, Jensen TM, Jensen JS, Nawroth P, Fleming T, Witte
DR, et al. The role of serum methylglyoxal on diabetic peripheral
and cardiovascular autonomic neuropathy: the ADDITION
Denmark study. Diabetes Metab. 2015;32:778–85.
99. Zhou J, Zhou S. Inflammation: therapeutic targets for diabetic
neuropathy. Mol Neurobiol. 2014;49:536–46.
100. Çakici N, Fakkel TM, van Neck JW, Verhagen AP, Coert JH.
Systematic review of treatments for diabetic peripheral neuropa-
thy. Diabet Med. 2016;33:1466–76.
101. Holick MF, Vitamin D. Deficiency. N Engl J Med. 2007;357:266–81.
102. Powanda MC. Is there a role for vitamin D in the treatment of
chronic pain? Inflammopharmacology. 2014;22:327–32.
103. Danescu LG, Levy S, Levy J. Vitamin D and diabetes mellitus.
Endocrine. 2009;35:11–7.
104. Mathieu C. Vitamin D and diabetes: where do we stand? Diabetes
Res Clin Pract. 2015;108:201–9.
105. Fukuoka M, Sakurai K, Ohta T, Kiyoki M, Katayama I. Tacalcitol,
an active vitamin D3, induces nerve growth factor production in
human epidermal keratinocytes. Skin Pharmacol Appl Ski
Physiol. 2001;14:226–33.
106. Riaz S, Malcangio M, Miller M, Tomlinson DR. A vitamin D(3)
derivative (CB1093) induces nerve growth factor and prevents
neurotrophic deficits in streptozotocin-diabetic rats.
Diabetologia. 1999;42:1308–13.
107. Tague SE, Smith PG. Vitamin D receptor and enzyme expression
in dorsal root ganglia of adult female rats: modulation by ovarian
hormones. J Chem Neuroanat. 2011;41:1–12.
108. Tague SE, Clarke GL, Winter MK, McCarson KE, Wright DE,
Smith PG. Vitamin D deficiency promotes skeletal muscle hyper-
sensitivity and sensory hyperinnervation. J Neurosci. 2011;31:
13728–38.
109. Esteghamati A, Fotouhi A, Faghihi-Kashani S, Hafezi-Nejad N,
Heidari B, Sheikhbahaei S, et al. Non-linear contribution of serum
vitamin D to symptomatic diabetic neuropathy: a case-control
study. Diabetes Res Clin Pract. 2016;111:44–50.
110.•Shillo P, Selvarajah D, Greig M, Gandhi R, Rao G, Wilkinson ID,
et al. Reduced vitamin D levels in painful diabetic peripheral neu-
ropathy. Diabet Med. 2018;36:44–51. https://doi.org/10.1111/
dme.13798.Cross-sectional study demonstrating that
reduced serum 25-hydroxyvitamin D levels are associated
with painful-DPN.
111. Lee P, Chen R. Vitamin D as an analgesic for patients with type 2
diabetes and neuropathic pain. Arch Intern Med. 2008;168:771–2.
112. Shehab D, Al-Jarallah K, Abdella N, Mojiminiyi OA, Al
Mohamedy H. Prospective evaluation of the effect of short-term
oral vitamin d supplementation on peripheral neuropathy in type 2
diabetes mellitus. Med Princ Pract. 2015;24:250–6.
113. Basit A, Basit KA, Fawwad A, Shaheen F, Fatima N, Petropoulos
IN, et al. Vitamin D for the treatment of painful diabetic neurop-
athy. BMJ Open Diabetes Res Care. 2016;4:e000148. https://doi.
org/10.1136/bmjdrc-2015-000148.
114. Pop-Busui R, Ang L, Holmes C, Gallgher K, Feldman E.
Inflammation as a therapeutic target for diabetic neuropathies.
Curr Diab Rep. 2016;16(3):29. https://doi.org/10.1007/s11892-
016-0727-5.
115. Jin HY, Park TS. Role of inflammatory biomarkers in diabetic
peripheral neuropathy. J Diabetes Investig. 2018;9:1016–8.
116.•Feldman EL, Nave KA, Jensen TS, Bennett DL. New horizons in
diabetic neuropathy: mechanisms, bioenergetics, and pain.
Neuron. 2017;93:1296–313 Review of the recent discoveries
into the pathogenesis of DPN and painful-DPN.
117.•Herder C, Bongaerts BW, Rathmann W, Heier M, Kowall B,
Koenig W, et al. Differential association between biomarkers of
subclinical inflammation and painfulpolyneuropathy: results from
the KORA F4 study. Diabetes Care. 2015;38:91–6Study show-
ing that biomarkers of subclinical and vascular inflammation
are associated with painful-DPN.
118.•Bönhof GJ, Herder C, Strom A, Papanas N, Roden M, Ziegler D.
Emerging biomarkers, tools, and treatments for diabetic
polyneuropathy. Endocr Rev. 2018;40:153–92. https://doi.org/10.
1210/er.2018-00107.Detailed review of the biomarkers and
treatments for DPN.
119. Zhang C, Ward J, Dauch JR, Tanzi RE, Cheng HT. Cytokine-
mediated inflammation mediates painful neuropathy from meta-
bolic syndrome. PLoS One. 2018;13:e0192333. https://doi.org/10.
1371/journal.pone.0192333.
120. Cheng HT, Dauch JR, Oh SS, Hayes JM, Hong Y, Feldman EL.
p38 mediates mechanical allodynia in a mouse model of type 2
diabetes. Mol Pain. 2010;6:28. https://doi.org/10.1186/1744-
8069-6-28.
32 Page 12 of 13 Curr Diab Rep (2019) 19: 32
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

121. Purwata TE. High TNF-alpha plasma levels and macrophages
iNOS and TNF-alpha expression as risk factors for painful diabet-
ic neuropathy. J Pain Res. 2011;4:169–75.
122. Uçeyler N, Rogausch JP, Toyka KV, Sommer C. Differential ex-
pression of cytokines in painful and painless neuropathies.
Neurology. 2007;69:42–9.
123. Üçeyler N, Riediger N, Kafke W, Sommer C. Differential
gene expression of cytokines and neurotrophic factors in
nerve and skin of patients with peripheral neuropathies. J
Neurol. 2015;262:203–12.
124. Empl M, Renaud S, Erne B,Fuhr P, Straube A, Schaeren-Wiemers
N, et al. TNF-alpha expression in painful and nonpainful neurop-
athies. Neurology. 2001;56:1371–7.
125. Selvarajah D, Wilkinson ID, Emery CJ, Harris ND, Shaw PJ,
Witte DR, et al. Early involvement of the spinal cord in diabetic
peripheral neuropathy. Diabetes Care. 2006;29:2664–9.
126. Lee-Kubli C, Marshall AG, Malik RA, Calcutt NA. The H-reflex
as a biomarker for spinal disinhibition in painful diabetic neurop-
athy. Curr Diab Rep. 2018;18:1. https://doi.org/10.1007/s11892-
018-0969-5.
127. Lee-Kubli CA, Calcutt NA. Altered rate-dependent depression of
the spinal H-reflex as an indicatorof spinal disinhibition in models
of neuropathic pain. Pain. 2014;155:250–60.
128. Fomberstein K, Qadri S, Ramani R. Functional MRI and pain.
Curr Opin Anaesthesiol. 2013;26:588–93.
129. Tracey I. Imaging pain. Br J Anaesth. 2008;101:32–9.
130. Wager T, Atlas L, Lindquist M, Roy M, Woo C, Kross E. An
fMRI-based neurologic signature of physical pain. N Engl J
Med. 2013;368:1388–97.
131. Buonocore MH, Maddock RJ. Magnetic resonance spectroscopy
of the brain: a review of physical principles and technical methods.
Rev Neurosci. 2015;26:609–32.
132. Selvarajah D, Wilkinson ID, Emery CJ, Shaw PJ, Griffiths PD,
Gandhi R, et al. Thalamic neuronal dysfunction and chronic sen-
sorimotor distal symmetrical polyneuropathy in patients with type
1 diabetes mellitus. Diabetologia. 2008;51:2088–92.
133. Fischer TZ, Tan AM, Waxman SG. Thalamic neuron hyperexcit-
ability and enlarged receptive fields in the STZ model of diabetic
pain. Brain Res. 2009;1268:154–61.
134. Freeman OJ, Evans MH, Cooper GJ, Petersen RS, Gardiner NJ.
Thalamic amplification of sensory input in experimental diabetes.
Eur J Neurosci. 2016;44:1779–86.
135. Gandhi R, Selvarajah D, Wilkinson I, Emery C, Shaw PJ, Griffiths
P, et al. Preservation of thalamic neuronal function may be a pre-
requisite for pain perception in diabetic neuropathy. Diabetologia.
2006;49(Supp 1):2088–92.
136. Shillo P, Selvarajah D, Greig M, Rao D, Edden R, Wilkinson I,
et al. Painless diabetic peripheral neuropathy is characterised by
reduced thalamic gamma-aminobutyric acid (GABA). Diabet
Med. 2016;33(Supp 1):162.
137.•Selvarajah D, Wilkinson ID, Gandhi R, Griffiths PD, Tesfaye S.
Microvascular perfusion abnormalities of the thalamus in painful
but not painless diabetic polyneuropathy: a clue to the pathogen-
esis of pain in type 1 diabetes. Diabetes Care. 2011;34:718–20
Study demonstrating increased microvascular perfusion with-
in the thalamus is associated with painful-DPN.
138. Cauda F, Sacco K, D'Agata F, Duca S, Cocito D, Geminiani G, et al.
Low-frequency BOLD fluctuations demonstrate altered
thalamocortical connectivity in diabetic neuropathic pain. BMC
Neurosci. 2009;10:138. https://doi.org/10.1186/1471-2202-10-138.
139. Ossipov MH, Morimura K, Porreca F. Descending pain modula-
tion and chronification of pain. Curr Opin Support Palliat Care.
2014;8:143–51.
140. Silva M, Amorim D, Almeida A, Tavares I, Pinto-Ribeiro F,
Morgado C. Pronociceptive changes in the activity of
rostroventromedial medulla (RVM) pain modulatory cells in the
streptozotocin-diabetic rat. Brain Res Bull. 2013;96:39–44.
141. Morgado C, Terra PP, Tavares I. Neuronal hyperactivity at the
spinal cord and periaqueductal grey during painful diabetic neu-
ropathy: effects of gabapentin. Eur J Pain. 2010;14:693–9.
142. Greig M, Wilkinson ID, Shillo P, Selvarajah D, Gandhi R, Tesfaye
S. Impaired hemodynamic response to thermal pain in patients
with painful diabetic neuropathy. Diabetes. 2018;67(Supp 1):
568–P. https://doi.org/10.2337/db18-568-P.
143.•Segerdahl AR, Themistocleous AC, Fido D, Bennett DL, Tracey I.
A brain-based pain facilitation mechanism contributes to painful
diabetic polyneuropathy. Brain. 2018;141:357–64 Study finding
vlPAG altered function may contribute to neuropathic pain in
painful-DPN.
144. Ashburner J, Friston KJ. Voxel-based morphometry—the
methods. Neuroimage. 2000;11:805–21.
145. Selvarajah D, Wilkinson ID, Maxwell M, Davies J, Sankar A,
Boland E, et al. Magnetic resonance neuroimaging study of brain
structural differences in diabetic peripheral neuropathy. Diabetes
Care. 2014;37:1681–8.
146. Selvarajah D, Heiberg-Gibbons F, Wilkinson ID, Gandhi R,
Tesfaye S. A magnetic resonance imaging volumetry study of
regional brain atrophy in diabetic peripheral neuropathy.
Diabetes. 2018;67(Supp 1):550–P. https://doi.org/10.2337/db18-
550-P.
147. Selvarajah D, Awadh M, Gandhi R, Wilkinson ID, Tesfaye S.
Alterations in somatomotor network functional connectivity in
painful diabetic neuropathy—a resting state functional magnetic
resonance imaging study. Diabetes. 2018;67(Supp 1):61–OR.
https://doi.org/10.2337/db18-61-OR.
148. Watanabe K, Hirano S, Kojima K, Nagashima K, Mukai H, Sato
T, etal. Altered cerebral blood flow in the anterior cingulate cortex
is associated with neuropathic pain. J Neurol Neurosurg
Psychiatry. 2018;89:1082–7.
149. Selvarajah D, Gandhi R, Hunter M, Emery C, Griffiths P, Tesfaye
S, et al. A functional magnetic resonance imaging study demon-
strating alterations in brain responses to acute pain stimulation in
diabetic neuropathy. Diabetologia. 2007;50(Supp 1):448–S9.
150. Tseng MT, Chiang MC, Chao CC, Tseng WY, Hsieh ST. fMRI
evidence of degeneration-induced neuropathic pain in diabetes:
enhanced limbic and striatal activations. Hum Brain Mapp.
2013;34:2733–46.
151.•• Tesfaye S, Selvarajah D, Gandhi R, Greig M, Shillo P, Fang F,
et al. Diabetic peripheral neuropathy may not be as its name sug-
gests: evidence from magnetic resonance imaging. Pain.
2016;157(Supp 1):S72–80 Review of the MRI studies into pain-
ful-DPN.
Publisher’sNoteSpringer Nature remains neutral with regard to jurisdictional
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