DIABETES/METABOLISM RESEARCH AND REVIEWS

REVIEW
Diabetes Metab Res Rev 2012; 28(Suppl 1): 814.
Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2239

ARTICLE

Advances in the epidemiology, pathogenesis and

management of diabetic peripheral neuropathy

Solomon Tesfaye*
Dinesh Selvarajah
Shefeld Teaching Hospitals,
Shefeld, UK
*Correspondence to:
Solomon Tesfaye M.D., Room Q26,
Royal Hallamshire Hospital, Glossop
Road, Shefeld S10 2JF, UK.
E-mail: solomon.tesfaye@sth.nhs.uk.

SUMMARY
Diabetic peripheral neuropathy (DPN) affects up to 50% of patients with
diabetes and is a major cause of morbidity and increased mortality. Its clinical
manifestations include painful neuropathic symptoms and insensitivity, which
increases the risk for burns, injuries and foot ulceration.
Several recent studies have implicated poor glycaemic control, duration of
diabetes, hyperlipidaemia (particularly hypertryglyceridaemia), elevated
albumin excretion rates and obesity as risk factors for the development of
DPN.
Although there is now strong evidence for the importance of nerve microvascular
disease in the pathogenesis of DPN, the risk factors for painful DPN are not
known. However, emerging evidence regarding the central correlates of painful
DPN is now afforded by brain imaging.
The diagnosis of DPN begins with a careful history of sensory and motor symptoms. The quality and severity of neuropathic pain if present should be
assessed using a suitable scale. Clinical examination should include inspection
of the feet and evaluation of reexes and sensory responses to vibration, light
touch, pinprick and the 10-g monolament.
Glycaemic control and addressing cardiovascular risk is now considered important
in the overall management of the neuropathic patient. Pharmacological treatment
of painful DPN includes tricyclic compounds, serotoninnorepinephrine reuptake
inhibitors (e.g. duloxetine), anticonvulsants (e.g. pregabalin), opiates, membrane
stabilizers, the antioxidant alpha lipoic acid and others. Over the past 7 years, new
agents with perhaps less side effect proles have immerged. Management of
patients with painful neuropathy must be tailored to individual requirements and will depend on the presence of other co-morbidities. There is
limited literature with regard to combination treatment. Copyright 2012
John Wiley & Sons, Ltd.
Keywords diabetic neuropathy; diabetic peripheral neuropathy; painful diabetic
neuropathy; pathogenesis of diabetic neuropathy; MRI

Received: 6 September 2011

Revised: 12 September 2011
Accepted: 13 October 2011

Copyright 2012 John Wiley & Sons, Ltd.

Diabetic peripheral neuropathy (DPN) is associated with considerable

morbidity, mortality and diminished quality of life [1]. Characterized by
pain, paraesthesia and sensory loss, it affects up to 50% of people with
diabetes [1]. In absolute numbers, against the estimated global prevalence
of diabetes of 472 million by 2030 [2], DPN is likely to affect as many as
236 million persons worldwide and at a tremendous cost. In the United
States alone, the total cost associated with DPN is $10.9 billion a year [3]. Thus,
from these epidemiologic data, it is clear that DPN and the associated foot
ulceration and neuropathic pain are far from rare and far from benign,
posing a major healthcare challenge to the medical profession and to
the society.

Advances in Epidemiology, Pathogenesis and Management of DPN

Clinical features of DPN

Diabetic peripheral neuropathy is the most common neuropathic syndrome seen in persons with diabetes. The
Toronto Consensus Panel on Diabetic Neuropathy recently
dened DPN as a symmetrical, length-dependent sensorimotor polyneuropathy attributable to metabolic and
microvessel alterations as a result of chronic hyperglycaemia
exposure and cardiovascular risk covariates. An abnormality
of nerve conduction tests, which is frequently subclinical,
appears to be the rst objective quantitative indication of
the condition [4]. Less common neuropathic syndromes
include cranial mononeuropathies and focal neuropathies
such as proximal motor neuropathy. DPN starts in the toes
and gradually moves proximally. Once it is well established
in the lower limbs, it affects the upper limbs, with sensory
loss following the typical glove and stocking pattern of
distribution [1]. Signicant motor decits are not common
in the early stages of DPN [1]. The patient does not typically
complain of weakness, but when symptoms are present,
they tend to be sensory in nature. Symptomatic muscle
weakness tends to develop later in the disease course.
Painful symptoms such as burning, tingling (pins and
needles or paraesthesia), shooting (like electric shock)
or lancing (stabbing) are present in around a third of patients
with DPN and around 20% of all diabetic patients [1,5].
These symptoms are generally worse at night and
disturb sleep [6]. Together with painful symptoms during
the day, this often leads to a reduction in individuals
ability to perform daily activities [6]. The burden of
painful DPN was reported to be considerable in one study,
which resulted in a persistent discomfort despite polypharmacy and high resource use, and led to limitations
in daily activities and poor satisfaction with treatments that
were often deemed to be inappropriate [7]. Chronic persistently painful DPN can be extremely distressing and might
be associated with profound depression together with anxiety [7]. Importantly, symptoms are not a reliable indicator of
the severity of the nerve damage. Some patients with severe
pain symptoms have little sensory decit, whereas others
with no painful symptoms have completely numb feet,
putting them at extremely high risk for foot ulceration.
Insensitivity, or loss of pain, can lead to foot ulceration
and a host of unintentional but serious injuries. Patients
who have lost feeling in their hands cannot sense temperature and often burn themselves while, for example,
cooking or ironing, and also have difculty handling small
objects. Those who have lost sensation in their feet often
sustain puncture wounds, friction wounds and burns that
can become infected and/or ulcerated and lead to amputation. However, with appropriate foot care, a signicant
number of ulcerations can be prevented [8].

Risk factors for DPN

Studies in patients with type 1 or type 2 diabetes have
shown that poor glycaemic control is a risk factor for
Copyright 2012 John Wiley & Sons, Ltd.

DPN, but other risk factors are involved as well. The

EURODIAB IDDM Complications Study, which involved
3250 patients with type 1 diabetes from 31 centres in 16
European countries, found that DPN was related to both
glycaemic control and duration of disease [9]. Although
the 28% baseline prevalence of DPN was signicantly
related to glycosylated haemoglobin (HbA1c) (p < 0.001),
the prevalence varied from 17 to 41% after data were
adjusted for duration of diabetes, with lower HbA1c levels
associated with lower prevalence rates and higher levels
associated with higher prevalence rates. However, even
those with good glycaemic control (HbA1c < 5.4%, equivalent to Diabetes Control and Complications Trial HbA1c
of 7%) still developed microvascular disease, suggesting
that factors other than glycaemic control and disease duration are involved [9].
Follow-up data from the EURODIAB cohort of patients
with type 1 diabetes revealed that over a 7-year period,
approximately one-quarter of type 1 diabetic patients
developed DPN; with age, duration of diabetes and poor glycaemic control being major factors [10]. The development of
DPN was also associated with potentially modiable cardiovascular risk factors, such as hypertension, hyperlipidaemia,
obesity and cigarette smoking (Figure 1) [10].
Recently, other studies have also implicated cardiovascular risk factors, such as obesity [11] and triglycerides [12]
in the pathogenesis of DPN. Moreover, Wiggin et al.
found that elevated tryglycerides correlated with
myelinated bre loss independent of disease duration,
age and diabetes control [13]. These data support
the evolving concept that hyperlipidaemia might be
instrumental in the progression of DPN.
There is also evidence that DPN is associated with
cardiovascular disease and mortality. In a study of 132
patients with type 2 diabetes, 38 died during the 9-year
follow-up period [14]. Macroangiopathy was found to be
the strongest independent risk factor for mortality,
followed in descending order by DPN, albumin excretion

Figure 1. Risk factors for incident neuropathy. The EURODIAB

Prospective Complications Study showing odds ratios for the various risk factors for diabetic peripheral neuropathy in a cohort of
1101 type 1 diabetes mellitus patients followed for 7.3  0.6
years. BMI, body mass index; CVD, cardiovascular disease
Diabetes Metab Res Rev 2012; 28(Suppl 1): 814.
DOI: 10.1002/dmrr

10

rate and HbA1c. Elevated vibration threshold has also

been found to be a risk factor for mortality in diabetic
patients [15].

Pathogenesis of DPN
Until recently, there were two schools of thought regarding
the aetiology and pathogenesis of DPN: metabolic versus
vascular. Recent studies, however, have shown that both
vascular factors and metabolic interactions are involved at
all stages of DPN [16]. Nerve bre loss is the cause of
insensitivity in DPN. As revealed by fascicular biopsy
of the sural nerve, nerve bres in patients with diabetes
but no DPN are more numerous than in those with DPN
[16]. Sural nerve biopsies also reveal microvascular
defects in the endoneurial vessels, such as gross basement
membrane thickening, endothelial cell proliferation and
hypertrophy [17] as well as reduced oxygen tension [18]
in patients with DPN compared with those who have diabetes but do not have DPN. Similarly, photography of surgically
exposed sural nerve in vivo reveals microvascular abnormalities in its epineurial arteries and veins (Figure 2) [19],
whereas uorescein angiography reveals arteriosclerosis on
the surface of the nerve and impaired blood ow [19] in
patients with DPN compared with those with diabetes but
no DPN.

Mechanisms of neuropathic pain

in diabetes
The exact pathophysiological mechanisms of neuropathic
pain in diabetes remain enigmatic although several mechanisms including neurostructural correlates for painful neuropathy have been postulated (Table 1) [20]. Other potential
mechanisms include the association of increased blood

Figure 2. Microvascular abnormalities in epineurial vessels in

diabetes and diabetes with DPN. The patient with DPN has
epineurial arterial attenuation/tortuosity and an arteriovenous
shunt leading to increased venous pressure and tortuosity
Copyright 2012 John Wiley & Sons, Ltd.

S. Tesfaye and D. Selvarajah

Table 1. Mechanisms of neuropathic pain (adapted from
Reference [20])
Peripheral mechanisms

Central mechanisms

Changes in sodium channel

distribution and expression
Changes in calcium channel
distribution and expression
Altered neuropeptide expression

Central sensitization
Ab-bre sprouting into
lamina II of the dorsal horn
Reduced inhibition via
descending pathways

Sympathetic sprouting
Peripheral sensitization
Altered peripheral blood ow
Axonal atrophy, degeneration
or regeneration
Damage to small bres
Glycaemic ux

glucose instability in the genesis of neuropathic pain [21],

an increase in peripheral nerve epineurial blood ow [22],
altered foot skin microcirculation [23], reduced intraepidermal nerve bre density in the context of early
neuropathy [24], an increase in thalamic vascularity
[25] and autonomic dysfunction [26].

Imaging studies of the central

nervous system and DPN
There is now increasing evidence that the impact of
diabetes may be at all levels of the nervous system after
all, diabetes is a metabolic disorder and brain micro/
macrovascular disease in diabetes appears to be associated
with cognitive decline and brain atrophy [27], and involvement of the central nervous system (CNS) in DPN is also
increasingly being recognized.

Spinal cord involvement in DPN

Involvement of the spinal cord has been reported in postmortem studies. However, many of these studies did not
examine patients with DPN specically and were conducted at a time when diabetes treatments were less than
optimal and other neurological diseases of the cord (e.g.
syphilis) were more prevalent [28]. The possibility of
spinal cord involvement in DPN came to light when it
was observed that electrical spinal cord stimulation,
which can alleviate neuropathic pain, was ineffective in
subjects with severe loss of vibration and joint position
sense [29]. Using a non-invasive magnetic resonance
(MR) imaging technique, Eaton et al. reported a signicantly lower cord area in the cervical and upper thoracic
regions in subjects with established DPN compared with
healthy nondiabetic control subjects [30]. Diabetic subjects with no DPN had intermediate cord area measurements between nondiabetic controls and established
DPN [30]. To conrm these ndings and examine if these
changes occur early in the natural history of DPN, a larger,
adequately powered study was conducted. In this study,
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Advances in Epidemiology, Pathogenesis and Management of DPN

subjects with type 1 diabetes were subdivided into three

subgroups (no DPN, subclinical DPN and established
DPN), and spinal cord area measurements were performed at the C2/C3 level [31]. The study revealed that
there was a signicant shrinkage of the spinal cord even
in subject with early subclinical DPN. Signicant correlations were also found between cord area and neurophysiological parameters of DPN severity. Thus, this study
showed that the neuropathic process in diabetes is not
conned to the peripheral nerve and appears to involve
the spinal cord. Of concern is that this occurs early in
the neuropathic process [31].

Brain MR spectroscopy in DPN

Our ndings of involvement of the spinal cord in DPN
made us question whether the brain too may be involved.
Ascending sensory pathways of the spinal cord terminate
within the ventroposterior lateral (VPL) thalamic subnucleus before high-order sensory projections are sent to
the cortex [32]. The thalamus plays an important modulatory role of sensory information that is presented to the
cortex [33]. We used proton MR spectroscopy (H-MRS),
a non-invasive MR technique that can provide metabolic
information from different body tissues, to investigate if
thalamic neuronal function is affected in DPN. H-MRS
produces spectra that contain several resonances or
peaks. In brain parenchyma, the three major peaks
detected are due to N-acetyl groups, total creatine and
choline-containing compounds [28]. Immunohistochemical studies have suggested that N-acetyl aspartate
(NAA), the major constituent of the N-acetyl group resonance at long echo time (TE), is localized exclusively in
neurons and their processes throughout the CNS [28].
Thus, NAA resonance on H-MRS can provide a useful
marker for brain neuronal and axonal integrity in vivo.
In a preliminary study, subjects with type 1 diabetes (no
DPN and established DPN) and age-matched and sexmatched nondiabetic healthy controls underwent H-MRS
of the thalamus. The study showed a signicantly lower
long TE (135 ms) thalamic NAA/choline ratio in the group
of patients with DPN compared with patients with no DPN
and healthy volunteer controls [34]. The data also demonstrated signicant correlations between short TE
(20 ms) signal from NAA and neurophysiological markers
(overall neuropathy composite score and individual nerve
function tests) of DPN severity [34]. These ndings may
reect thalamic neuronal dysfunction in DPN, implicating
the brain in the neuropathic process.
However, the mechanism of thalamic involvement is
unclear. One possible explanation for thalamic neuronal
dysfunction in DPN may be that loss of afferent input, as a
result of peripheral nerve damage. Correlations observed
between NAA acquired at short TE, duration of diabetes
and severity of neuropathy are supportive of this suggestion.
It may also be equally likely that the observed changes in the
thalamus may be occurring concomitantly to the changes
seen in the peripheral nervous system. Further studies
Copyright 2012 John Wiley & Sons, Ltd.

utilizing these techniques on a much larger numbers of

subjects including a subgroup of patients with painful
DPN are now clearly necessary.

MR perfusion imaging in DPN

Although the pathogenesis of thalamic involvement on
H-MRS in DPN is unknown [34], it is likely that both
vascular and metabolic etiological factors that have
been postulated in the pathogenesis of DPN and other
microvascular complications of diabetes (retinopathy
and nephropathy) may be involved. A further MR perfusion imaging study at 1.5 T was undertaken involving
subjects with type 1 diabetes (no DPN, painful DPN
and painless DPN) and a group of nondiabetic healthy
volunteers. Exogenous perfusion contrast (intravenous
bolus of gadolinium chelate) was used to examine the
microvascular perfusion characteristics of both the thalamus and caudate nucleus (control region). Established
markers of cerebral microvascular perfusion used as
study endpoints were relative cerebral blood volume
(rCBV), ow and bolus transit time. Figure 3 shows the
composite mean relative concentration-time prole in
the thalamus for the four groups. Group comparisons
showed that painless DPN had lower thalamic rCBV
compared with healthy volunteers and no DPN, whereas
painful DPN had higher thalamic rCBV (p = 0.04, Chi
squared = 8.3) [34]. Hence, painful DPN is accompanied by increased thalamic vascularity, whereas painless
DPN is associated with greater thalamic microvascular
impairment. Similar changes were not demonstrated in
the caudate nucleus, which was a control area (not
involved in somatosensory perception) [25]. Similar
thalamic microvascular abnormalities have been demonstrated in other chronic pain states and may thus be
important in the pathogenesis of painful DPN.
However, what is causing thalamic hyperperfusion is
unclear; possible reasons include impaired autoregulation
40
No DPN

35

HV

30

Painless DN

25

Painful DPN

20
15
10
5
0
0

10

20

30

40

50

60

70

80

90 100 110 120 130

Figure 3. Composite concentration-time proles of the bolus passage of exogenous contrast agent (gadolinium-diethylenetriamine
pentaacetic acid) through the thalamus in each subgroup. DPN,
diabetic peripheral neuropathy; HV, healthy volunteer. Adapted
from Reference [28]
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because of C-bre-mediated/endothelial dysfunction or

aberrant spontaneous thalamic activity. A recent study in
the streptozotocin diabetic rat model of neuropathic pain,
thalamic VPL neurons were found be hyperexcitable, with
increased responses to phasic brush, press and pinch
stimuli applied to identied peripheral receptive eld
[35]. VPL neurons from diabetic rats also displayed
enhanced spontaneous activity, independent of ascending
afferent barrage and enlarged receptive elds. The
authors suggested that thalamic neurons act as central
generators or ampliers of pain in diabetes, and this could
be associated with increased thalamic vascularity [36].

Functional MR imaging and painful DPN

Functional MR imaging (fMRI) is one scientic development that has led to recent advances in our understanding
of the function of the human brain [37]. The technique
relies on mapping localized changes in magnetic susceptibility that occurs following the hemodynamic response to
neuronal activity. Small susceptibility changes (which
depend on alteration of the localized ratio of oxyhaemoglobin
to deoxyhaemoglobin, hence the acronym BOLD or bloodoxygen-level-dependent fMRI) lead to small signal changes
on susceptibility-weighted imaging at high-temporal
resolution [28]. These are detected because of small
differences in contrast to noise, following multiple dataaveraging strategies and statistical analysis. Brain areas
whose signal signatures signicantly correlate with the
stimulus are those that are dened as being active during
a task or presentation of a stimulus. Studies using fMRI have
investigated changes in brain activity in response to various
experimental stimuli inducing pain. The results suggested
that multiple cortical and subcortical regions are activated
during painful coetaneous heat stimulation in healthy subjects. Activation in the insula, anterior cingulated cortex
(ACC), prefrontal cortex (PFC), thalamus, primary and secondary somatosensory cortices (S1 and S2) and the basal
ganglia is seen across the groups [38]. This led to the characterization of a network of brain areas that consistently activate in response to pain, forming a pain matrix[39]. These
regions are primarily responsible for discriminating location
and intensity of painful stimuli together with affective pain
processing [28]. Thus, pain is no longer a purely subjective
phenomenon fMRI studies are now trying to establish objective radiological correlates to the pain experience in different chronic pain contexts. The majority of studies to date,
however, have been performed mainly in healthy volunteers
following acute pain stimulation, and changes in the brain
associated with chronic pain have been less thoroughly investigated [28].
It is important that the pain matrix should be viewed as
a exible, integrative entity in pain perception, which may
be modulated by other aspects of the pain experience,
including context, mood and attention [40]. Many of the
previous fMRI studies have tended to group different
aetiologies of neuropathic pain together, and hence, the
exact pathophysiological CNS mechanisms of painful
Copyright 2012 John Wiley & Sons, Ltd.

S. Tesfaye and D. Selvarajah

DPN remain unknown. Furthermore, given the unique

pathophysiology of diabetes, involving both metabolic
and vascular abnormalities, it is likely that different
pathophysiological mechanisms may be involved.
Utilizing fMRI, Wilkinson et al. performed a preliminary
study comprising type 1 diabetic subjects (no DPN, painful
DPN and painless DPN) to test the feasibility of monitoring
the brains response to the presentation of heat pain in the
context of DPN [41]. The results show that subjects with
no DPN had greater BOLD response than those with painless
DPN. Subjects with painful DPN showed signicantly
greater response than those with painless DPN. The primary
somatosensory cortex, lateral frontal and cerebellar regions
demonstrated greatest involvement. This may be explained
by the reduced ascending nociceptive input as a result of
neuropathy. However, subjects with painful and painless
DPN had comparable neuropathy impairment scores based
on detailed neurophysiological assessments. We also found
signicant negative correlation between BOLD fMRI
response and overall neuropathy score in both the thalamus
and left parietal lobe. One component of neuropathic pain is
allodynia, which is pain elicited by normally nonpainful
stimuli, and is frequently associated with spontaneous pain
in subjects with diabetes. Schweinhardt et al. found that
the magnitude of activation in the caudal anterior insula
correlates with the perceived intensity of allodynic pain
across subjects, independent of the level of ongoing
pain [42].
In a preliminary analysis of an ongoing fMRI study, we
have looked at the BOLD response of subjects with painless DPN, painful DPN and healthy volunteers in response
to heat pain [43]. We demonstrated that nociceptive heat
stimulation applied to both foot and thigh regions elicited
signicant increase in neuronal activation within the pain
matrix in all the groups except in painless DPN during foot
stimulation. This is not unexpected because these latter
subjects were insensate at this stimulation site. Subsequent group level comparisons revealed that subjects with
painful DPN displayed signicantly greater neuronal
activation within the pain matrix, particularly in the PFC
and ACC during foot pain stimulation compared with
painless DPN [43]. This pattern of increased activation
persisted in painful DPN when compared with healthy
volunteers, with increased activation mainly in the PFC
and ACC [43]. Finally, a greater understanding of these
central processes afforded by imaging is likely to lead to
the development of robust, objective radiological correlates to the subjective pain experience and the targeting
of specic pain networks/pathways to develop more
effective and novel treatments with less side effects.

Treatment of painful DPN

The current approach to management of painful DPN
centres around achieving and maintaining near-normal
glycaemia (HbA1c) as an initial step. However, many
patients with diabetes, particularly those with type 2
diabetes, nd this difcult. The assessment and
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Advances in Epidemiology, Pathogenesis and Management of DPN

pharmacological treatment of painful DPN has been

reviewed recently, and the reader is advised to read this
consensus report [20]. On the basis of the clinical trial evidence for the various pharmacological agents (efcacy
and safety) for painful DPN, the Toronto Consensus Panel
on Diabetic Neuropathy recommended that a tricyclic antidepressant (TCA), a serotoninnorepinephrine reuptake
inhibitor (SNRI) or an a-2-d agonist should be considered
for rst line treatments. On the basis of trial data, duloxetine would be the preferred SNRI and pregabalin would
be the preferred a-2-d agonist. If pain is inadequately controlled, depending upon contraindications, these rst line
agents can be combined, although this is not backed by
trial evidence [20]. If pain is still inadequately controlled,
opioids such as tramadol and oxycodone might be added
in a combination treatment [20].
Initial selection of rst line treatment will be inuenced
by the assessment of contraindications, consideration of
co-morbidities and cost; for example, in diabetic patients
with a history of heart disease, elderly patients on other
concomitant medications such as diuretics and antihypertensives, patients with co-morbid orthostatic hypotension
and others, TCA have relative contraindications. In
patients with liver disease, duloxetine should not be
prescribed, and in those with oedema, pregabalin or
gabapentin should be avoided [20].

Pathogenetic treatments
Apart from glycaemic control, there has been little
advance in the development compounds that can halt the
neuropathic process. Although several disease-modifying
agents are under investigation, only the antioxidant a-lipoic
acid is supported by a meta-analysis and is marketed in
certain countries [44].

Conclusions
Diabetic peripheral neuropathy is common, affecting up to
50% of patients with diabetes. In addition, it accounts for
considerable morbidity, mortality and reduced quality of
life. Glycaemic control is the central component of
treatment, but it is difcult to achieve for many patients.
Because cardiovascular risk factors play a major role in
diabetes and the pathogenesis of DPN, they should be
controlled as well.
Painful DPN is difcult to treat. On the basis of the trial
evidence, rst line therapies include a TCA, the SNRI
duloxetine and the anticonvulsant pregabalin. Combination therapy might be useful for those with more severe
pain, but there is paucity of studies and further research
is required. Studies are also required on direct head-tohead comparative trials and long-term efcacy of drugs,
as most trials have lasted less than 6 months.
Imaging evidence that the CNS is involved in DPN
should open new avenues of investigation. Key target
areas generating or modulating pain in painful DPN
including peripheral small bres with modulation at the
level of the spinal cord, the thalamus and the other pain
matrix areas in the brain require further studies to
develop more effective treatments. The association of
painful DPN with autonomic neuropathy also merits
further investigation. Finally, as available therapies for
pain and nerve impairment are less than satisfactory,
rational therapies that address the underlying pathogenesis
need to be developed.

Conict of Interest
Both S. Tesfaye and D. Selvarajah have received honoraria
from Eli Lilly and Company. S. Tesfaye has also received
honoraria from Pzer.

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DOI: 10.1002/dmrr