Handbook of Clinical Neurology, Vol.

126 (3rd series)

Diabetes and the Nervous System
D.W. Zochodne and R.A. Malik, Editors
© 2014 Elsevier B.V. All rights reserved

Chapter 1

Epidemiology of polyneuropathy in diabetes and prediabetes

DAN ZIEGLER1*, NIKOLAOS PAPANAS2, AARON I. VINIK3, AND JONATHAN E. SHAW4
1
Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research;
Department of Endocrinology and Diabetology, University Hospital, Dü sseldorf, Germany
2
Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
3
Diabetes Center for Endocrine and Metabolic Disorders and Neuroendocrine Unit, Eastern Virginia Medical School, Norfolk,
VA, USA
4
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia

INTRODUCTION ulceration, amputations and impaired quality of life,

The epidemiology of a disease primarily describes the
frequency with which it occurs, and determines the risk
factors associated with it. The former informs the clini-
cian about the likelihood that the patient in front of him
or her has the condition, and the public health authorities
about the potential overall burden relating to the condi-
tion. The latter sheds light on etiologic processes,
although the associations described by epidemiologic
studies cannot alone be taken as proof of causality.
In order to understand the epidemiology of a disease
properly, it is crucial to have well validated diagnostic
tests that can be used by a variety of investigators asses-
sing different populations in a similar manner. Further-
more, it is important that the populations studied are
representative of the total population being considered,
and have not been subjected to significant selection
biases. However, the study of the epidemiology of dia-
betic distal symmetric sensorimotor polyneuropathy
has been beset by numerous problems relating both to
diagnostic tests and to population selection.
Clinical impact of diabetic distal symmetric
sensorimotor polyneuropathy
Diabetic distal symmetric sensorimotor polyneuropathy
(DSPN) represents a major health problem as it may pre-
sent with excruciating neuropathic pain and is responsi-
ble for substantial morbidity, resulting from foot
as well as being associated with increased mortality
(Abbott et al., 1998; Forsblom et al., 1998; Galer et al.,
2000). Neuropathic pain can cause considerable interfer-
ence with sleep, daily activities, and enjoyment of life.
The neurologic impairment caused by DSPN may lead
to functional limitations of walking ability (Resnick
et al., 2000). Older patients with DSPN perform worse
on tests of walking speed, static and dynamic balance,
and coordination than those without DSPN (Resnick
et al., 2002; Strotmeyer et al., 2008; Strotmeyer et al.,
2009). In women above 85 years, diabetes still contrib-
utes to large fiber peripheral nerve dysfunction which
is markedly accelerated by age, but no synergistic effect
of age and diabetes was observed (Resnick et al., 2001).
There is accumulating evidence suggesting that not
only surrogate markers of microangiopathy such as
albuminuria but also markers used for DSPN such as
nerve conduction velocity (NCV) and vibration percep-
tion threshold (VPT) predict mortality in diabetic
patients (Forsblom et al., 1998; Coppini et al., 2000). Ele-
vated VPT also predicts the development of neuropathic
foot ulceration, one of the most common causes for hos-
pital admission and lower limb amputations among dia-
betic patients (Abbott et al., 1998). Two recent studies
underline the major impact of DSPN on morbidity and
mortality. In the DIAD study (Young et al., 2009), both
sensory deficits and neuropathic pain were independent
predictors of cardiac death or nonfatal myocardial
infarction. Self-reported history of neuropathy was a

*Correspondence to: Professor Dan Ziegler, MD, FRCPE, Institute for Clinical Diabetology, German Diabetes Center at Heinrich
Heine University, Leibniz Center for Diabetes Research, Auf’m Hennekamp 65, 40225, Dü sseldorf, Germany. Tel: +49-211-33820,
Fax: +49-211-3382244, E-mail: dan.ziegler@ddz.uni-duesseldorf.de
4 D. ZIEGLER ET AL.
significant predictor for increased mortality in type 2
diabetic subjects allocated to a very intensive diabetes
therapy aimed at HbA1c < 6.0% in the ACCORD trial
(Calles-Escandón et al., 2010).
TESTING FOR PERIPHERAL
NEUROPATHY
DSPN is a symmetric, length-dependent sensorimotor
polyneuropathy attributable to metabolic and microves-
sel alterations as a result of chronic hyperglycemia expo- lights the difficulties of comparing studies with differ-
sure and associated cardiovascular risk factors (Tesfaye
et al., 2010). DSPN is a complex disorder, in which the
disease process may affect different sets of nerve fibers
to different degrees in different individuals. Thus, one
individual may have an abnormality of large fiber sen-
sory function, which could be detected by measuring
the vibration perception threshold (VPT), while another
may have a predominantly small fiber neuropathy that
can only be detected by measuring the thermal percep-
tion threshold (TPT). This feature of neuropathy can
be problematic in selecting a single test with which to
screen a population. The issue of measurement of neu-
rologic function is further complicated by the nature of
the tests. Many are psychophysical tests, in which the
subject is required to interpret the nature of an external VPT are both likely to be older and have poorer glycemic
stimulus (usually applied to the foot). This subjectivity
can lead to relatively poor reproducibility of tests such
as VPT, in which the subject has to differentiate light
touch from vibratory sensation.
This lack of certainty over the value of individual
tests for the assessment of diabetic neuropathy has led
to recommendations that several different tests should
be performed, and that diabetic neuropathy should only
be diagnosed when more than one is abnormal (Consensus
Statement, 1988). While this may make the diagnostic
process more rigorous in any individual or in an individ-
ual study, it can make comparisons between studies
more difficult. Such recommendations have been only
patchily adopted, and where they have been put into
practice, the selection of tests has not been uniform.
Thus, we are faced with having to compare the preva-
lence when neuropathy is determined by a single test
with a prevalence when neuropathy is diagnosed when
any two out of perhaps three to five tests are abnormal.
Increasing the number of tests that are performed will
automatically increase the number of individuals in
whom an abnormality is found, while requiring that
more than one abnormality is present will then tend to
decrease the prevalence. The overall effect is thus com-
plex. The impact of varying the diagnostic testing proce-
dure is exemplified by the Diabetes Control and
Complications Trial (DCCT) data, where the prevalence
of DSPN at baseline in the standard therapy cohort
varied from 0.3% (abnormalities of reflexes, sensory
examination and neuropathic symptoms) to 21.8%
(abnormal nerve conduction in at least two nerves)
(Diabetes Control and Complications Trial Group,
1995). Confirmed clinical neuropathy (abnormal history
or examination, confirmed by abnormal nerve conduc-
tion or autonomic function) was the gold standard for
the study, and was found in 2.1% of this cohort. This
73-fold difference in the prevalence of DSPN, between
the two extremes, but within a single population, high-
ing diagnostic criteria.
The influence of test selection on the understanding
of etiologic factors associated with neuropathy is likely
to be considerably smaller than that on prevalence. As
long as each diagnostic process is indeed measuring
some aspect (or aspects) of neuropathy, it is likely that
those who are rated as having neuropathy are genuinely
more severely affected than those who are not so rated.
Thus, associations with factors such as age or glycemic
control may be easier to compare across different stud-
ies than are prevalences, which are highly dependent not
only on the test (or tests) selected, but also on the diag-
nostic threshold that is used. For example, the groups
selected either by absent ankle reflexes or by elevated
control than the groups who are normal on these respec-
tive tests. However, unless loss of ankle reflexes repre-
sents the same degree of neuropathy as does an
abnormal VPT (according to the threshold selected; see
below), the prevalences generated from the same popu-
lation by these two tests could be quite different.
Even when the same test has been used, the methods
and the selection of thresholds have not been uniform.
VPT is widely used, but some studies use age-related
thresholds (based on UK normative data) (Delcourt
et al., 1998), while others have ignored age and used a
single cut-off (Nelson et al., 1988). Locally derived nor-
mal ranges have been increasingly applied, although in
one study these were derived separately for different
age groups (Shaw et al., 1998), while another compared
all diabetic subjects to a young nondiabetic population
(Herman et al., 1998).
It is obvious from the discussion above that there is a
long way to go in finding a definition of neuropathy that
can be widely used, although it is clearly needed for
accurate epidemiologic study. This definition needs to
be appropriate for the clinical forms that the disease
may take (e.g., small fiber or large fiber involvement),
related to hard end points, such as foot ulceration,
agreed upon widely, and useful for a range of both clin-
ical and research purposes. Multiple testing of different
neurologic functions, although recommended as the
gold standard (Consensus Statement, 1988), can be
 EPIDEMIOLOGY OF POLYNEUROPATHY IN DIABETES AND PREDIABETES
difficult and expensive, especially in large field studies.
Furthermore, recent data suggest complex patterns of
sensation in DSPN with decreased VPT (hypoesthesia)
and heat stimulus-induced hyperesthesia (low thresh-
olds), both being characteristic of mild DSPN as they cor-
relate with neuropathic symptoms and deficits, whereas
panmodality hypoesthesia is typical for severe DSPN
(Dyck et al., 2000). The only studies that relate measures
of neurologic function (in a prospective manner) with
subsequent foot ulceration and amputation have used
simple quantitative sensory tests, such as VPT or mono-
filament sensitivity (Rith-Najarian et al., 1992; Young
et al., 1994).
PAINFUL NEUROPATHY
Pain is a subjective symptom of major clinical impor-
tance as it is often this complaint that motivates patients
to seek health care. Pain associated with diabetic neurop-
athy exerts a substantial impact on the quality of life,
particularly by causing considerable interference in sleep
and enjoyment of life (Galer et al., 2000). However, in
one UK survey only 65% of diabetic patients received
treatment for their neuropathic pain, although 96%
had reported the pain to their physician (Daousi et al.,
2006). While 77% of the patients reported persistent pain
over 5 years, 23% were pain free over at least 1 year
(Daousi et al., 2006). Thus, neuropathic pain persists
in the majority of diabetic patients over periods of
several years.
Chronic painful DSPN is present in 13–26% of dia-
betic patients (Daousi et al., 2006; Davies et al., 2006;
Ziegler et al, 2009a, b) (Table 1.1). In the general popu-
lation (region of Augsburg, southern Germany), the
prevalence of painful DSPN was 13.3% in the diabetic
subjects compared with 1.2% in those with normal glu-
cose tolerance (NGT) (Ziegler et al., 2009a). Among sur-
vivors of myocardial infarction (MI) from the Augsburg
MI Registry, the prevalence of painful DSPN was 21.0%
in the diabetic subjects and 3.7% in those with NGT
(Ziegler et al., 2009b). Thus, prediabetic and diabetic
subjects with macrovascular disease appear to be prone
to neuropathic pain. The most important risk factors for
painful DSPN in these surveys were age, obesity, and low
physical activity, while the predominant comorbidity was
peripheral arterial disease, highlighting the paramount
role of various cardiovascular risk factors and diseases
in prevalent DSPN.
Painful DSPN is characterized by persistent or epi-
sodic pain that typically may worsen at night and
improve during walking, and is localized predominantly
in the feet. The pain often has a burning thermal quality
but there may also be a deep-seated aching or superim-
posed lancinating stabs. In a clinical survey including 105
5
patients with painful DSPN, the following locations of
pain were most frequent: 96% feet, 69% balls of feet,
67% toes, 54% dorsum of foot, 39% hands, 37% plantar
aspect of foot, 37% calves, and 32% heels. The pain was
most often described by the patients as “burning/hot”,
“electric”, “sharp”, “achy”, and “tingling”, and was
worse at nighttime and when tired or stressed (Galer
et al., 2000). The average pain intensity was moderate,
approximately 5.75/10 on a 0–10 scale, with the “least”
and “most” pain 3.6 and 6.9/10, respectively. Evoked
pain such as allodynia (pain due to a stimulus which does
not normally cause pain, e.g., stroking) or hyperalgesia
(increased sensitivity to a painful stimulus) may also
be features. The symptoms may be accompanied by sen-
sory loss, but patients with severe pain may have few
clinical signs. Pain may persist over many years
(Boulton et al., 1983), causing considerable disability
and impaired quality of life in some patients (Galer
et al., 2000), whereas it remits partially or completely
in others (Young et al., 1988a; Benbow et al., 1994),
despite further deterioration in small fiber function
(Benbow et al., 1994). Pain remission tends to be associ-
ated with sudden metabolic change, short duration of
pain or diabetes, preceding weight loss, and less severe
sensory loss (Young et al., 1988a; Benbow et al., 1994).
POPULATION SELECTION
The second important obstacle in determining the prev-
alence of neuropathy is the selection of people who are
going to be tested. Hospital clinic based studies will usu-
ally bias towards those with more serious problems, and
are likely to overestimate the prevalence of neuropathy
in the general diabetic population. Nevertheless, the
value of hospital-based prevalence studies should not
be underestimated. While they do not directly address
the issue of what the general risk of having neuropathy
is in a person with diabetes, they precisely answer the
question of how common neuropathy is among hospital
clinic patients. This in itself may be a very important and
valuable issue. The problem, however, is that one
hospital-based population may not be the same as
another – an issue that can be partially overcome with
multicentre studies (Young et al., 1993). Another prob-
lem is that temporal trends in referral patterns from pri-
mary care can make today’s hospital population quite
different to tomorrow’s.
Using registers of people with diabetes that are
derived from primary care will overcome the hospital-
based biases, and not surprisingly have reported lower
prevalences (Walters et al., 1992). However, this selec-
tion methodology remains dependent on the proportion
of people with diabetes who are actually diagnosed.
Since approximately 50% of all of those with diabetes
Table 1.1
Prevalence of distal symmetric polyneuropathy (DSPN) and painful DSPN in subjects with established diabetes

Population selection

Primary care or
Hospital-based population screening

Study site Neuropathy diagnosis Type 1 (%) Type 2 (%) Type 1 (%) Type 2 (%)

Australia (Knuiman et al., 1986) Reduced pin-prick 8 17

USA (Fujimoto et al., 1987) NCV 46
USA (Maser et al., 1989) Symptoms, signs 34
USA (Franklin et al., 1990) Signs 26
USA (Dyck et al., 1993) Symptoms, signs, QST, NCV, 54 45
HRV (deep breathing)
USA (Harris et al., 1993) Symptoms 30 38
USA (Adler et al., 1997) Monofilament 50
Tanzania (Wikblad et al., 1997) Symptoms and signs 28
Egypt (Herman et al., 1998) VPTa 22
Mauritius (Shaw et al., 1998) VPTb 13
Saudi Arabia (Nielsen, 1998) Absent pin-prick or vibration 26
Europe (Tesfaye et al., 1996) Symptoms, signs, VPTc, AFTs 28
Netherlands (Verhoeven et al., 1991) Symptoms 18
Netherlands (de Neeling et al., 1996) Absent VPT (big toe) 50
Germany (Mü ller et al., 1993) VPT 25 27
*D, A, CH (Ziegler et al.,1993) Symptoms and signs 17 35
Italy (Veglio and Sivieri, 1993) Symptoms and signs 28
Italy (Fedele et al., 1997) Signs 32
Italy (Beghi and Monticelli, 1997) Symptoms and signs 19
UK (Walters et al., 1992) Symptoms and signs 13 17
UK (Young et al., 1993) Symptoms, signs 23 32
UK (Kumar et al., 1994) Signs 42
Spain (Cabezas-Cerrato, 1998) Symptoms and signs 13 24
France (Delcourt et al.,1998) VPTc 20
Sweden (Nielsen, 1998) Absent pin prick or vibration 19
Denmark (Olsen et al., 2000) VPT 63
Portugal (Barbosa et al., 2001) Signs, symptoms 32
India (Ashok et al., 2002) VPT 19
Malaysia (Mimi et al., 2003) NSS, NDS 51
Iran (Janghorbani et al., 2006) Symptoms, signs, NCV 75
Bahrain (Al-Mahroos and Al-Roomi, 2007) VPT 37
India (Pradeepa et al., 2008) VPT 26
Germany (Ziegler et al., 2008) Signs: MSNI > 2 28
Sweden (Kärvestedt et al., 2009) VPT, monofilament 34
Taiwan (Hsu et al., 2009) NCV 29
China (Liu et al., 2010) VPT (TF), monofilament 18
UK (Daousi et al., 2004) Painful DSPNd 16
UK (Davies et al., 2006) Painful DSPNe 26
Germany (Ziegler et al., 2009a) Painful DSPNf 13
Germany (Ziegler et al., 2009b) Painful DSPNf 21

Data shown are %; AFTs, autonomic function tests; HRV, heart rate variability; NCV, nerve conduction velocity; QST, quantitative sensory testing;
VPT, vibration perception threshold; TF, tuning fork; MNSI, Michigan Neuropathy Screening Instrument.
*D, Germany; A, Austria; CH, Switzerland.
a
Compared to locally derived values for healthy young adults.
b
Compared to locally derived age-specific normal values.
c
Adjusted for age, sex and height.
d
VPT, NSS, NDS, Pain Symptom Score.
e
Toronto Clinical Scoring System (TCSS), Neuropathic Pain Scale (NPS).
f
MNSI > 2 and pain in the feet.
 EPIDEMIOLOGY OF POLYNEUROPATHY IN DIABETES AND PREDIABETES
are undiagnosed (Harris, 1995), this method also has
flaws. Population-based epidemiologic surveys in which
a high proportion of a representative sample of the gen-
eral population is directly tested for diabetes (by blood
glucose testing), and then those found to have diabetes
(previously diagnosed and newly diagnosed) are
screened for neuropathy, represent an alternative
approach. This should be a more reliable and reproduc-
ible way of determining the prevalence of diabetic
neuropathy.
One drawback of this approach is that the group with
“newly diagnosed” diabetes (i.e., diagnosed as part of
the study by blood glucose testing) is usually identified
by an abnormal glucose value measured on a single day.
Since the diagnosis of diabetes requires verification of
this on another day (American Diabetes Association,
1997), it is likely that the group identified includes a num- are assessed for DSPN, the prevalence has been rela-
ber of individuals who would have a nondiabetic glucose
value on repeat testing, and therefore do not actually
have diabetes. Assuming that these people do not have
diabetic neuropathy (since they do not have diabetes),
their inclusion would dilute the sample and lead to an
underestimate of the prevalence of neuropathy in the
newly diagnosed group. Nevertheless, neuropathy prev-
alence estimates derived from population-based samples
that include all of those people who have diabetes (both
diagnosed and undiagnosed) should be the most accu-
rate and reproducible approach.
PREVALENCE IN DIABETES
Taking into account the issues discussed above, it is dif-
ficult to determine with any precision the prevalence of
diabetic neuropathy. Table 1.1 shows the prevalence of
DSPN in type 1 and type 2 diabetic subjects from
hospital-based surveys and those carried out in primary
care settings or by population screening (Knuiman et al.,
1986; Fujimoto et al., 1987; Lehtinen et al., 1989, 1993;
Maser et al., 1989; Ratzmann et al., 1991; Verhoeven
et al., 1991; Walters et al., 1992; Dyck et al., 1993;
Harris et al., 1993; Mü ller et al., 1993; Veglio and
Sivieri, 1993; Young et al., 1993; Ziegler et al., 1993,
2008; Franklin et al., 1994; Kumar et al., 1994;
Partanen et al., 1995; de Neeling et al., 1996; Tesfaye
et al., 1996; Adler et al., 1997; Beghi and Monticelli,
1997; Fedele et al., 1997; Wikblad et al., 1997; Cabezas-
Cerrato, 1998; Delcourt et al., 1998; Herman et al.,
1998; Nielsen, 1998; Shaw et al., 1998; Olsen et al.,
2000; Barbosa et al., 2001; Ashok et al., 2002; Mimi
et al., 2003; Janghorbani et al., 2006; Al-Mahroos and
Al-Roomi, 2007; Pradeepa et al., 2008; Hsu et al.,
2009; Kärvestedt et al., 2009; Liu et al., 2010). Although
the ranges of the percentages of patients with DSPN
within the four population selections are rather high,
7
surprisingly, a median prevalence is almost identical
for three of the four populations: hospital-based type 1
(median [range]): 17% (13–23%), type 2: 28% (18–75%);
primary care/population screening type 1: 29%
(8–63%), type 2: 28% (13–51%). In type 2 diabetic
patients, the median prevalence is 28% for both settings.
It is possible that the lower median prevalence observed
in the hospital based type 1 diabetic populations is due to
the fact that only three studies were considered. Studies
that included NCV measures to diagnose DSPN have
reported considerably higher median prevalence rates
of 46% (29–75%) due to increased sensitivity
(Fujimoto et al., 1987; Dyck et al., 1993; Janghorbani
et al., 2006; Hsu et al., 2009).
When general populations are screened by glucose
tolerance testing, and those identified as having diabetes
tively low (Table 1.2). In a study from the Indian Ocean
island of Mauritius (in which 70% of the population orig-
inates from India) the data showed a very low prevalence
of DSPN in type 2 diabetes (Shaw et al., 1998). The over-
all prevalence in the total diabetic population was 8.3%,
i.e., 12.7% in subjects with known diabetes and just 3.6%
among those with newly diagnosed diabetes. Consistent
with the low neuropathy prevalence was a low prevalence
of lower limb amputation – a finding that has been
reported elsewhere for people who originate from the
Indian subcontinent (Gujral et al., 1993). Neuropathy
was based on VPT measurements, using locally derived
age-specific normal ranges. In a similar study from
Egypt (Herman et al., 1998), 14% of the newly diagnosed
diabetic population were found to have DSPN. However,
the reference range used for VPT in that study related to
healthy adults under the age of 45, and therefore prob-
ably did not account for the normal age-related rise in
VPT. Thus, since the majority of those with diabetes were
over the age of 45, DSPN prevalence in that study may be
an overestimate. In two Native American populations
which are regularly screened for diabetes with glucose
tolerance testing the prevalence of DSPN in the whole
diabetic population was 19% (Nelson et al., 1988; Rith-
Najarian et al., 1992).
It can be seen from Tables 1.1 and 1.2 that diagnostic
methodology is far from uniform. Indeed, there are
hardly any two studies that have used identical methods.
Nevertheless, a pattern can be discerned in these studies.
The median prevalence of DSPN is 28–29% in
community-based type 1 and type 2 diabetic populations
and in hospital-based type 2 diabetic populations,
whereas it is lower (17%) in hospital-based type 1 diabetic
subjects, for which only three studies were included.
Among the complete diabetic population, including both
diagnosed and undiagnosed diabetes, the prevalence of
DSPN is probably less than 20%. The median prevalence
8 D. ZIEGLER ET AL.
Table 1.2
Prevalence of distal symmetric polyneuropathy in subjects with newly diagnosed diabetes
Study
Egypt (Herman et al., 1998)
Mauritius (Shaw et al., 1998)
Finland (Lehtinen et al., 1989, 1993; Partanen et al., 1995)
Germany (Ratzmann et al., 1991)
Netherlands (de Neeling et al., 1996)
Hong Kong (Wang et al., 1998)
USA (Nelson et al., 1988)
USA (Rith-Najarian et al., 1992)
China (Liu et al., 2010)
Data shown are %. OGTT, oral glucose tolerance test; TF, tuning fork; NCV, nerve conduction velocity;VPT, vibration perception threshold; TPT,
thermal perception threshold.
a
Compared to locally derived values for healthy young adults.
b
Compared to locally derived age-specific normal values.
c
These figures relate to the total diabetic population including both diagnosed and undiagnosed diabetes.
of painful neuropathy in community-based type 2 dia-
betic populations is 18.5% (13–26%) (Daousi et al.,
2006; Davies et al., 2006; Ziegler et al., 2009a, b).
PREVALENCE IN PREDIABETES
Although the development of diabetic polyneuropathy is
typically insidious over several years, it may occasionally
be the presenting feature in type 2 diabetic patients
(Watkins, 1990). It is a matter of discussion whether this
“early” nerve alteration has developed during a period of
unrecognized diabetes or evolves gradually during a
state of prediabetes, i.e., impaired fasting glucose
(IFG) and/or impaired glucose tolerance (IGT) prior to
the transition to overt diabetes. In this context, it is
unclear whether there is a glycemic threshold beyond
which nerve dysfunction develops. If prediabetes consti-
tutes such a threshold which needs to be passed, subjects
with IGT should not have a degree of neuropathy higher
than nondiabetic subjects (Eriksson et al., 1994).
Impaired fasting glucose or impaired glucose
tolerance to diagnose prediabetes?
According to the American Diabetes Association (ADA),
prediabetes includes IFG and IGT (Expert Committee on
the Diagnosis and Classification of Diabetes Mellitus,
2003). The former is defined as fasting plasma glucose
concentrations between 5.6 and 6.9 mmol/L and the latter
as plasma glucose concentrations between 7.8 and
Population selection
Clinically OGTT
Neuropathy diagnosis diagnosed (%) screening (%)
VPTa 14
VPTb 4
Symptoms and NCV 8
Symptoms and signs 6
VPT (big toe/malleolus 39/7
Ankle/knee reflexes 29/3
VPT 13
VPT > 20 V 19c
Monofilament 19c
TPT (TF), monofilament 6
11.0 mmol/L at 2 h following glucose administration dur-
ing an oral glucose tolerance test (OGTT) (Expert
Committee on the Diagnosis and Classification of
Diabetes Mellitus, 2003). Initially, a threshold of
6.1 mmol/L was used for the diagnosis of IFG, but this
has now been replaced by the lower threshold
(5.6 mmol/L), which is more sensitive (Expert
Committee on the Diagnosis and Classification of
Diabetes Mellitus, 2003). This threshold alteration has
been debated (Borch-Johnsen et al., 2004; Tai et al.,
2004), but the new cut-off value is now increasingly used
to assess glucose metabolism in patients with neuropathy.
In general, IGT is considered a more reliable predictor
of cardiovascular morbidity and mortality than IFG in
clinically overt diabetes mellitus (DECODE Study
Group, 2001; Qiao et al., 2002; Hyvärinen et al., 2009;
Ning et al., 2010). In terms of microvascular disease,
analysis of receiver operating curves revealed that
increased risk of diabetic retinopathy was associated
with fasting plasma glucose concentrations within a nar-
row range (6.0–6.4 mmol/L), and that hyperglycemia
exceeding 6.5 mmol/L would be indicative of higher risk.
Using glucose concentrations at 2 hours, however, a
wider range ensued (9.8–10.6 mmol/L) and no threshold
could be unequivocally associated with a higher risk of
retinopathy (Colagiuri, 2011). A study demonstrated that
individuals with fasting plasma glucose in excess
of
7.0 mmol/L exhibited higher sensory thresholds
for perception of vibration, warm and cold than those
 EPIDEMIOLOGY OF POLYNEUROPATHY IN DIABETES AND PREDIABETES
with lower fasting glucose and concomitant 2 h glucose
levels
11.1 mol/L (Sosenko et al., 2004). Consequently,
the fasting plasma glucose threshold of 7.0 mmol/L
might be inappropriately high to screen for effective
avoidance of complications. Conversely, the upper 2 h
glucose concentration threshold might be able to detect
a substantially higher number of subjects earlier in
the natural course of type 2 diabetes mellitus, before
the complications would start to develop (Sosenko
et al., 2004).
It has been suggested that a practical distinction
between subjects with normoglycemia and those with
adverse glucose metabolism (IFG and/or IGT) would
suffice to assess the association between prediabetes
and neuropathy (Novella et al., 2001; Dyck et al.,
2007). The majority of studies, however, have focused
on IGT rather than IFG (Franklin et al., 1990; Novella
et al., 2001; Singleton et al., 2001a; Sumner et al.,
2003; Smith and Singleton, 2004). Clinic-based
(Singleton et al., 2001b; Smith and Singleton, 2004;
Hoffman-Snyder et al., 2006) and population-based
(Ziegler et al., 2008, 2009a, b) work has demonstrated
that peripheral neuropathy and neuropathic pain occur
more frequently in subjects with IGT than in those with
IFG. In addition, the OGTT is more accurate in the diag-
nosis of adverse glucose metabolism than measurement
of fasting plasma glucose (Hoffman-Snyder et al.,
2006), although many groups have used the cut-off
value of glucose 6.1 mmol/L and not the revised thresh-
old of 5.6 mmol/L (Expert Committee on the Diagnosis
and Classification of Diabetes Mellitus, 2003).
The concept of a relationship between neuropathy
and IGT prompted two studies: the Impaired Glucose
Tolerance Neuropathy Study (Smith et al., 2006;
Singleton et al., 2007) and the Rochester Diabetic
Neuropathy Study of patients with Impaired Glucose
Metabolism (Dyck et al., 2007). The former followed
up 71 patients with IGT and neuropathy for a period
of up to 3 years to document early evidence of neurop-
athy and the potential favorable effect of lifestyle inter-
vention. The latter was designed to follow about 300
individuals with IGT and 300 matched controls from
the general population of Olmsted County, MN, USA,
for a minimum of 10 years to ascertain the gradual devel-
opment of neuropathy (Dyck et al., 2012).
Several studies have addressed the question whether
prediabetes is linked with neuropathy of unknown cause
(Table 1.3) (Franklin et al., 1990; Harris et al., 1998; Novella
et al., 2001; Singleton et al., 2001a, b; Sumner et al., 2003;
Hughes et al. 2004; Smith and Singleton, 2004; Hoffman-
Snyder et al., 2006). In these works, neuropathy was either
generally described as peripheral (Sumner et al., 2003) or
specified as chronic distal symmetric, predominantly sen-
sory polyneuropathy (Novella et al., 2001), painful
9
(Singleton et al., 2001a, b) or axonal (chronic idiopathic
axonal neuropathy, in which nerve conduction studies
revealed mainly axonal loss, without demyeliniation)
(Hughes et al. 2004; Smith and Singleton, 2004;
Hoffman-Snyder et al., 2006). In general, a higher fre-
quency of prediabetes was found among patients with
neuropathy than among historical healthy controls
(Franklin et al., 1990; Novella et al., 2001; Singleton
et al., 2001a, b; Sumner et al., 2003; Smith and
Singleton, 2004; Hoffman-Snyder et al., 2006). By con-
trast, Hughes et al. (2004) reported negative findings.
They compared 50 consecutive patients with axonal neu-
ropathy and 50 healthy controls from the same geographic
area. Prediabetes (IFG and IGT) was diagnosed in
14 (28.6%) of 49 patients, as compared with six (12.2%)
of 49 controls. Frequency of prediabetes was 45.5%
among patients with painful neuropathy versus 14.8%
among those with painless neuropathy. After adjusting
for age and sex, the differences between patients and con-
trols were insignificant (Hughes et al., 2004).
Taken together, the abovementioned studies suggest
that prediabetes is common among patients with neurop-
athy. This relationship notwithstanding, caution is
needed in its interpretation. In the majority of studies
(Franklin et al., 1990; Novella et al., 2001; Singleton
et al., 2001a, b; Sumner et al., 2003; Smith and
Singleton, 2004; Hoffman-Snyder et al., 2006), high fre-
quencies of prediabetes were derived by comparison with
controls from population-based studies with extremely
wide age ranges (20–74 years) that had been carried
out some years previously (Harris et al., 1998). It should
not escape our notice that Hughes et al. (2004) actually
recruited matched controls, and their findings did not
confirm those of studies using historical controls.
Regrettably, the numbers of patients and controls were
small, especially in the subgroup analyses of painful
and painless neuropathy and, therefore, the study may
have been underpowered. The small patient series is a lim-
itation of all studies on patients with neuropathy. Evalu-
ation of glucose metabolism, especially by OGTT, was
not carried out in all patients and, therefore, most com-
parisons have relied on subgroup analyses. Another
important drawback of these clinic-based studies is selec-
tion bias due to inclusion of patients referred to very spe-
cialized centers (Franklin et al., 1990; Novella et al., 2001;
Singleton et al., 2001a, b; Sumner et al., 2003; Hughes
et al., 2004; Smith and Singleton, 2004; Hoffman-
Snyder et al., 2006; Nebuchennykh et al., 2008).
Neuropathy in people with prediabetes
Population studies have been conducted to investigate
the presence of neuropathy in prediabetes (Table 1.4)
(Fujimoto et al., 1987; Franklin et al., 1990; Eriksson
10 D. ZIEGLER ET AL.
Table 1.3
Studies of prediabetes in patients with neuropathy

Patients (n, %)

Study Patients (n) Type of neuropathy IFG IGT Interpretation

Novella et al., 2001 48 Idiopathic sensory 18 (64.3) 13 (27.1) More frequent IGT vs.
neuropathy symptomatic NHANES 3 (15.3%),
more frequent IGR vs.
asymptomatic (30.0%)*
Singleton et al., 2001a 89 Idiopathic painful 0 15 (24.6) More frequent IGT vs.
neuropathy NHANES 3 (15.3%)
Sumner et al., 2003 73 Idiopathic neuropathy 0 26 (35.6) More frequent IGT vs.
NHANES 3 (15.3%)
Smith and Singleton, 87 CIAP 2 (2.3) 39 (44.8) More frequent IGT vs.
2004 NHANES 3 (15.3%)
Singleton et al., 2001b 107 Idiopathic painful NA 36 (33.6) More frequent IGT vs.
neuropathy NHANES 3 (15.3%)
Hoffman-Snyder 100 CIAP NA 38 (38.0) More frequent IGT vs.
et al., 2006 NHANES 3 (15.3%)
Hughes et al., 2004 49 patients/ CIAP CIAP 2 (4.1)/ CIAP 12 (24.5)/ IFG/IGT associated with
49 matched control 1 control 5 CIAP but not
healthy (2.0) (10.2) significant after
controls adjustment for age
and sex
Nebuchennykh et al., 70 Idiopathic sensory 3 (4.3) 9 (12.8) p ¼ NS vs. normoglycemic
2008 neuropathy subjects (50.0%)
p ¼ NS vs. normoglycemic
subjects (42.6%)

CIAP, chronic idiopathic axonal neuropathy; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; NHANES, National Health and
Nutrition Examination Survey; IENFD, intraepidermal nerve fiber density; IGR, impaired glucose regulation; NA, not applicable; NCS, nerve
conduction studies; NS, not significant; vs., versus.
(Adapted with permission from Papanas et al., 2011, ©Nature Publishing Group.)

et al., 1994; Barr et al., 2006; Grandinetti and Chow,
2007; Isak et al., 2008; Ziegler et al., 2008, 2009a, b;
Dyck et al., 2012). Neuropathy, neuropathic pain,
impaired nerve conduction, reduced sweat secretion,
and diminished sympathetic skin response have been
demonstrated in subjects with IGT. The population-
based KORA (Co-operative Research in the Region of
Augsburg) studies (Ziegler et al., 2008, 2009a, b)
explored the association between IGT and neuropathy
in the general population. A score of 2 in the validated
Michigan Neuropathy Screening Instrument (Feldman
et al., 1994; Moghtaderi et al., 2006) was employed for
the diagnosis of DSPN. Prevalence of DSPN was 28%
among patients with diabetes mellitus, 13% among those
with IGT, 11.3% among those with IFG, and 7.4% among
those with normoglycemia (Ziegler et al., 2008). The
strengths of these studies include the large, real-world
population-based cohort, the separate evaluation of neu-
ropathy and neuropathic pain and the use of a validated
screening tool for the diagnosis of neuropathy. These
observations support the earlier ones from the Hoorn
study (de Neeling et al., 1996), in which prevalence of
large fiber dysfunction was highest among people with
diabetes mellitus, followed by IGT and normoglycemia,
while the thermal discrimination threshold (a measure of
small fiber function) also decreased with increasing fast-
ing and postload insulin levels.
Some studies of DSPN in prediabetes did not find an
increased prevalence (Fujimoto et al., 1987; Barr et al.,
2006; Grandinetti and Chow, 2007; Isak et al., 2008;
Dyck et al., 2012), but they had various important limi-
tations. Indeed, the frequency of neuropathy in the
populations examined was very low (Shaw et al., 1998;
Isak et al., 2008). Moreover, VPT was used to evaluate
neuropathy severity but this test is insensitive to small-
fiber function (Shaw et al., 1998). Thirdly, some subjects
came from ethnic groups differing from those included
in the majority of studies (Fujimoto et al., 1987; Shaw
et al., 1998). Fourthly, some were not specifically
designed to assess neuropathy in prediabetes (Shaw
 EPIDEMIOLOGY OF POLYNEUROPATHY IN DIABETES AND PREDIABETES 11
Table 1.4
Population studies of peripheral neuropathy in diabetes and prediabetes

Findings

Study Parameter IGT/IFG Normoglycemic Statistics

Franklin et al., 1990 DSPN 11.2% IGT 3.9% OR for IGT vs. NGT 3.5
(95% CI 1.5–7.9)
Ziegler et al., 2008 DSPN 13.0% IGT 7.4% p ¼ NS for IGT vs. IFG, IGT
11.3% IFG vs. NGT or IFG vs. NGT
Ziegler et al., 2009a Painful DSPN 8.7% IGT 1.2% p ¼ NS IGT vs. IFG, IGT vs.
4.2% IFG NGT or IFG vs. NGT
Ziegler et al., 2009b Painful DSPN 14.8% IGT 3.7% p ¼ NS IGT vs. IFG, IGT vs.
5.7% IFG NGT or IFG vs. NGT
de Neeling et al., 1996 VPTF, AR, 16.2%, 15.6%, median 10.5%, VPTF p ¼ NS;
VPT (mm), TPT ( C) 8.5 (range 4.0–17.6), 6%, p <0.05 for IGT vs. NGT;
median 0.3 (range median 7.6 VPT p ¼ NS;
0.2–0.7) (range 3.8–19.7), TPT p ¼ NS
median 0.4
(range 0.2–0.7)
Grandinetti et al., 2007 Sweat volume Mean 3.18 Mean 4.65 p < 0.001
Isak et al., 2008 USCV (m/s), Mean 51.4  5.8, Mean 57.5  5.4, USCV p < 0.05; PDML
PDML (ms), mean 2.2  0.2, mean 2.0  0.2, p ¼ NS; SSRA p ¼ 0.013
SSRA (mV) median 1.1  0.9 median 1.9  1.3
Fujimoto et al., 1987 NCS 2.9% 5.1% p ¼ NS for IGT vs. NGT
Shaw et al., 1998 VPT (V) Median 11.5 (range Median 11.5 p ¼ NS for IGT vs. NGT
9–14) (range 10–14)
Barr et al., 2006 DSPN IGT + IFG overall
score 6.1, NDS 3.9
Eriksson et al., 1994 SSCV (m/s), Median 47.0 (range Median 45.0
PMCV (m/s) 43.0–49.5), median (range 42.0–48.0),
45.5 (range median 44.8
43.0–48.0) (range 43.0–47.0)

AR, bilateral absence of ankle reflexes; CI, confidence interval; DSPN, distal symmetric sensorimotor polyneuropathy; IFG, impaired fasting glu-
cose; IGT, impaired glucose tolerance; NCS, nerve conduction study; NDS, Neuropathy Disability Score; NGT, normoglycemia; NS, not signif-
icant; NSS, Neuropathy Symptom Score; OR, odds ratio; PDML, peroneal nerve distal motor latency; PMCV, peroneal motor nerve conduction
velocity; PPS: Pressure Perception Score; SSCV, sural nerve sensory conduction velocity; SSRA, amplitude of sympathetic skin response left leg;
TPT, thermal perception threshold; TSV, total sweat volume; USCV, ulnar sensory nerve conduction velocity; VPT, vibration perception threshold;
VPTF, bilateral absence of vibration perception at the hallux by tuning fork.
(Adapted with permission from Papanas et al., 2011, ©Nature Publishing Group.)

et al., 1998) or lacked of a control group for comparison
(Barr et al., 2006).
In the prospective Olmsted County Impaired Glucose
(OC IG) Survey, Dyck et al. (2012) studied DSPN and
atypical DPN (small fiber sensory or autonomic neurop-
athies) in subjects with IG (IFG: FPG
100–125 mg/dL or
IGT: PG 140–199 mg/dL 2 h after 75 g OGTT; n ¼ 174),
non-IG (n ¼ 150) and new diabetes (n ¼ 218). Numbers
(%) with DSPN + atypical DPN in non-IG, IG and new
diabetes were: 3 (2%), 3 (1.7%), and 17 (7.8%) with neu-
ropathy narrowly defined and 10 (12.7%), 22 (12.6%), and
38 (17.4%) defined broadly. In neither case (narrow or
broad) was DPN more frequent in IG than non-IG, sug-
gesting that IG was not associated with increased
prevalence of either DSPN or atypical DPN. However,
in that report both IFG and IGT as well as DSPN and
atypical DPN were not considered separately.
Eriksson et al. (1994) followed up men with IGT of
12–15 years duration, those who previously had IGT
for 12–15 years and had progressed to diabetes mellitus,
men with diabetes mellitus of 12–15 years duration and
normoglycemic controls. The authors aimed to ascertain
whether long-term glucose intolerance was connected
with the development and deterioration of neuropathy.
There was no difference in peripheral nerve function
between men with current IGT and controls. By contrast,
patients with diabetes mellitus exhibited lower nerve
conduction velocity than those with IGT and controls.
12 D. ZIEGLER ET AL.
It was concluded that diabetes mellitus, but not IGT, is
associated with peripheral nerve dysfunction. It should
not escape our notice, however, that this study investi-
gated the effect of long-term IGT on peripheral nerve
function but not the prevalence of neuropathy in IGT
(Eriksson et al., 1994).
INCIDENCE AND NATURAL HISTORY
OF DIABETIC POLYNEUROPATHY
Most of the data describing the frequency of diabetic
neuropathy relate to prevalence. The long-term natural
history and progression of diabetic neuropathy has been
difficult to study due to the following problems: (1) var- US veterans reported neuropathy (monofilament insen-
ious nerve fiber populations might be affected at differ- sitivity) developing in 20% of subjects over approxi-
ent rates; (2) expected changes may take place over
several years; (3) minor changes may not be detected
due to a low reproducibility of some methods; (4) mea-
sures of nerve function such as nerve conduction veloc-
ity (NCV) may deteriorate with age in nondiabetic
subjects; (5) glycemic control or risk factor profile
may change and nerve dysfunction may be reversible
over time. It has been emphasized that inception cohorts
followed from the diagnosis onward are needed to deter-
mine the impact of diabetic neuropathy, because preva-
lence rates consider only the surviving cases and
therefore might underestimate the true risk of acquiring
the disease (Melton and Dyck, 1987).
A long-term clinic-based study carried out in a large
group of type 1 and type 2 diabetic patients designed to
investigate the relationship between the duration and
degree of hyperglycemia and the prevalence of clinically
overt neuropathy from the onset of diabetes, was per-
formed by Pirart (1978) over a period of 25 years. He
defined neuropathy as a loss of Achilles and/or patellar
reflexes combined with a reduced vibration sensation or
presence of “a more dramatic polyneuropathy or mono-
or multi-neuropathy”. The prevalence of neuropathy
increased from about 8% among the 1900 patients eval-
uated at the time of diagnosis to about 50% among 100
patients reassessed after a follow-up of 25 years. The
incidence of neuropathy increased from three cases
per 100 unaffected patients per year to about 19 cases
per 100 patients after 25 years. However, Pirart’s study
had several drawbacks: it was not population-based, no
standardized diagnostic measures were employed, the
various forms of neuropathy were not differentiated,
control subjects were not assessed, and the types of dia- 1970s compared to those diagnosed earlier, suggesting
betes were not evaluated separately.
In a study focusing on 133 Finnish patients with newly improving (Pambianco et al., 2006).
diagnosed (following clinical presentation) type 2 diabe-
tes, the 10 year incidence of DSPN among those who
were free of neuropathy at baseline was 17–20% depend-
ing on whether electrophysiologic or clinical parameters
were used (Partanen et al., 1995). This gives an annual
incidence of approximately 2%. Hypoinsulinemia pre-
dicted the development of DSPN.
Over the first 12 years of the UKPDS (which similarly
studied people newly presenting with type 2 diabetes),
neuropathy (as judged by a VPT > 25 V) developed in
approximately 20% of subjects irrespective of treatment
arm, giving an annual incidence of just under 2%
(UK Prospective Diabetes Study Group, 1998a). In the
American San Luis Valley study (Sands et al., 1997),
DSPN was determined by a combination of symptoms
and clinical signs. Over nearly 5 years, its average annual
incidence was 6.1% (6.1 per 100 person-years). A study of
mately 2.5 years (Adler et al., 1997). The higher
incidence in the last two studies was probably due to
the fact they only included people with established dia-
betes who, due to their longer disease duration, would
have had a higher baseline risk than the subjects with
newly diagnosed diabetes who were included in the other
two studies.
In the Rochester Diabetic Neuropathy Study (RDNS)
after 2 years, the Neuropathy Impairment Score (NIS)
was unchanged in 81%, worse in 10% and better in 9%
of the patients, and the Neuropathy Symptom Score
(NSS) was unchanged in 92%, worse or better in 4%
of the patients, respectively. The most prominent mono-
tone (consistent) worsening over 2 years was found for a
composite score combining neuropathic deficits and
quantitative measures of DSPN (NIS[lower limbs] + 7
tests) which worsened on average by 0.34 points per year
in the entire cohort and by 0.85 points per year in patients
with DSPN (Dyck et al., 1997).
The Epidemiology of Diabetes Complications (EDC)
study reported on a 6-year follow-up of 453 type 1 dia-
betic patients who were free of DSPN at baseline, 15%
of whom developed DSPN in 6 years, giving an incidence
rate of 2.8 per 100 person-years and a cumulative prob-
ability of 0.29 (Forrest et al., 1997). DSPN was defined as
the presence of
2 of the following: symptoms, sensory
and/or motor signs, and/or absent (or present only with
reinforcement) tendon reflexes. The 12 year incidence of
DSPN per 100 person-years in the EDC study was 1.2 (CI:
0.98–1.5) in patients with a diabetes duration < 20 years
and 3.83 (2.64–5.37) in those with 20–30 years. There was
a decline in DSPN incidence in patients diagnosed in the
that the natural history of DSPN in type 1 diabetes is
In the DCCT, which included groups of highly
selected individuals with type 1 diabetes, polyneuropathy
(abnormal history or examination, confirmed by abnor-
mal nerve conduction or autonomic function) developed
 EPIDEMIOLOGY OF POLYNEUROPATHY IN DIABETES AND PREDIABETES
in 9.6% of those on standard treatment, and in 2.8% of
those in the intensively treated group, over 5 years
(Diabetes Control and Complications Trial Group,
1995). After 13–14 years of EDIC, the cumulative inci-
dence of confirmed clinical neuropathy was 25% of
the intensively treated versus 35% of those with prior
standard treatment (p < 0.05) (Albers et al., 2010). Com-
paring this to the data for type 2 diabetes, it appears that
the incidence of neuropathy in type 1 diabetes (using the
data from the group with prior standard treatment –
approximately 2% per year) is similar to that in newly
diagnosed type 2 diabetes, but less than that in previously
diagnosed type 2 diabetes. However, age is an important
factor in diabetic neuropathy (see below), and the consid-
erably younger age of the subjects in the DCCT probably
accounts for the differences seen. Indeed, after correc-
tion for age, the prevalence of neuropathy does not dif-
fer between type 1 and type 2 diabetes (Walters et al.,
1992; Young et al., 1994).
In the EURODIAB Prospective Complications Study
including 986 type 1 diabetic subjects without DSPN at
baseline, the cumulative prevalence after an average
follow-up of 7.3 years was 25% (Tesfaye et al.,
1996, 2005).
Several clinic-based prospective studies examined the
relationship between the natural history of abnormalities
in nerve function tests and the degree of long-term gly-
cemic control. Hillson et al. (1984) followed 71 patients
who showed a slight deterioration in mean pedal VPT
during the first 5 years after diagnosis of type 2 diabetes,
which correlated significantly with increased mean fast-
ing blood glucose. A more pronounced deterioration in
sensory nerve function as assessed by thermal, vibration,
and pressure perception thresholds has been observed
over 1–3.5 years and 2 years in newly diagnosed and
longer-term type 2 diabetic patients, respectively
(Sosenko et al., 1993; Wang et al., 1998). There was a cor-
relation between the changes in the various sensory
thresholds (Sosenko et al., 1993), suggesting that small
and large nerve fiber dysfunction may develop in paral-
lel in type 2 diabetic patients.
Young et al. (1986, 1988a) studied 75 type 1 diabetic
patients aged 16–19 years over an average of 2.4 years,
70 of whom were reassessed again after 6 years. During
the first study period the deterioration in motor and sen-
sory NCV was associated with poor glycemic control, but
no patient had symptoms and only seven had minor signs
of neuropathy (Young et al., 1986a). After 5 years,
16 patients had symptoms, 12 had “major signs”,
15 had “minor signs”, and 27 showed no symptoms of
neuropathy. Initially, HbA1c was significantly higher in
patients who developed symptoms or major signs com-
pared with those showing minor signs or no symptoms.
In addition, peroneal MNCV deteriorated in the
13
symptomatic but not in the asymptomatic group
(Young et al., 1988b). On the other hand, it has been dem-
onstrated that neuropathic pain may improve and resolve
completely within 3–4 years of follow-up despite persis-
tent poor glycemic control, but thermal perception
thresholds continue to deteriorate (Benbow et al.,
1994). Thus, small fiber function tests do not seem to
predict the evolution of painful symptoms.
Regarding the magnitude of changes in the quantita-
tive measures of DSPN, we have shown that over 24 years
from the diagnosis of type 1 diabetes the decline in pero-
neal MNCV and sural SNCV in well controlled patients
(mean HbA1c: 6.5  0.1%) was 0.1 and 0.2 m/s/year,
respectively, comparable to a nondiabetic control group
(Ziegler and Roden, 2010). In contrast, poorly controlled
patients (mean HbA1c: 8.3  0.2%) showed correspond-
ing losses of 0.4 and 0.5 m/s/year, respectively. After
24 years, none of the well controlled patients, but
12 (57%) of those who were poorly controlled, developed
clinical polyneuropathy confirmed by NCV. Thus, near
normoglycemia maintained from the diagnosis of type
1 diabetes over the next 24 years effectively prevented
the development of confirmed DSPN, a threefold faster
annual hyperglycemia-induced decline in NCV, whereas
poor glycemic control constituted the paramount per-
missive factor contributing to the evolution and progres-
sion of DSPN (Ziegler and Roden, 2010). Macleod et al.
(1991) estimated the annual rate of change for the vibra-
tion perception threshold (VPT) on the great toe to be 0.4
volts in healthy subjects and 2.5 volts in those with dia-
betic neuropathy.
In a mixed cohort of type 1 and type 2 diabetic subjects
followed over 9–16 years (mean 10 years), peroneal
MNCV was progressively reduced with increasing dura-
tion of diabetes but it stabilized once it reached a
“plateau” between 36 and 38 m/s (Negrin and Zara, 1995).
ETIOLOGIC FACTORS RELATED
TO DIABETIC NEUROPATHY
While debate continues about the precise pathophysio-
logic changes that finally result in diabetic neuropathy,
there is a degree of agreement over the risk factors that
are associated with its development. The risk factors and
risk indicators for, and their relative degree of associa-
tion with DSPN are listed in Table 1.5.
Hyperglycemia
The central role of hyperglycemia has been demon-
strated in a range of studies. Mean HbA1c was approx-
imately 1% higher in men with newly diagnosed type 2
diabetes who went on to develop DSPN 10 years later
than in those who did not (Partanen et al., 1995). The risk
of developing DSPN (as measured by the odds ratio) has
14 D. ZIEGLER ET AL.
Table 1.5 the chronic diabetic complications (Knuiman et al.,
Risk factors and comorbidities of diabetic polyneuropathy 1986; Kumar et al., 1994). Thus, only a minority of the
patients enrolled in these studies had symptomatic DSPN
Type 1 diabetes Type 2 diabetes at entry.
Studies in type 1 diabetic patients show that intensive
Age + + diabetes therapy retards but does not completely prevent
Sex – – the development of DSPN. The DCCT (Diabetes Control
Height + (+) and Complications Trial Group, 1995) demonstrated that
Weight – ++ intensive glycemic control led to a 64% reduction in the
Hyperglycemia ++ ++
5 year risk of developing DSPN in patients with type 1
Hypoinsulinemia NA +
diabetes. In the similar but smaller Stockholm Diabetes
Duration of diabetes ++ ++
Smoking + (+) Intervention Study, symptoms of DSPN developed in
Alcohol (+) (+) only 14% of those who were intensively treated, com-
Hyperlipidemia (+) (+) pared to 32% in the conventional arm (Reichard
Hypertension ++ (+) et al., 1996).
Nephropathy ++ + In the DCCT/EDIC cohort, the benefits of former
Retinopathy ++ + intensive insulin treatment persisted for 13–14 years
CAN ++ ++ after DCCT closeout and provide evidence of a durable
CVD + ++ effect of prior intensive treatment on polyneuropathy
PAD (+) ++ and cardiac autonomic neuropathy (“hyperglycemic
Depression + +
memory”) (Fujimoto et al., 1987; Maser et al., 1989),
Association strong ++, moderate +, controversial: (+), not found;
despite subsequent deterioration of glycemic control,
CVD, cardiovascular disease; PAD, peripheral arterial disease; similar to the findings described for diabetic retinopathy
CAN, cardiovascular autonomic neuropathy; NA, not applicable. and nephropathy.
In contrast, in type 2 diabetic patients, who represent
been calculated to rise by approximately 10–15% for the vast majority of people with diabetes, the results were
every 1 mmol/L rise in fasting plasma glucose or every largely negative. In the large UKPDS study, there was no
1% rise in HbA1c (Adler et al., 1997; Herman et al., significant impact of tight glycemic control on the devel-
1998). The importance of hyperglycemia in the develop- opment of DSPN over the first 12 years (UK Prospective
ment of neuropathy has of course been confirmed in Diabetes Study Group, 1998a). The UKPDS showed a
interventional studies. lower rate of impaired VPT (VPT > 25 V) after 15 years
In the Rochester Diabetic Neuropathy Study (RDNS) for intensive therapy (IT) versus conventional therapy
mean HbA1, diabetic retinopathy severity level, and (CT) (31 versus 52%). However, the only additional time
mean ln(24 h proteinuria  duration of diabetes) were point at which VPT reached a significant difference
the main covariates for severity of DSPN at the 7 year between IT and CT was the 9 year follow-up, whereas
follow-up (Dyck et al., 1999). the rates after 3, 6, and 12 years did not differ between
Thus, the etiologic link between hyperglycemia and the groups. Likewise, the rates of absent knee and
DSPN seems sound, but while it is clear that glucose low- ankle reflexes did not differ between the groups
ering protects against the development of neuropathy in (UK Prospective Diabetes Study Group, 1998a). Among
type 1 diabetes, the case is not yet proven in type 2 the overweight subjects, whose intensive therapy was pri-
diabetes. marily metformin, there was no impact of intensive ther-
apy at all on DSPN (UK Prospective Diabetes Study
Group, 1998b).
ROLE OF INTENSIVE DIABETES THERAPY IN PREVENTION
In the ADVANCE study including 11 140 patients with
AND PROGRESSION OF DIABETIC NEUROPATHY
type 2 diabetes randomly assigned to either standard glu-
Several long-term prospective studies that assessed the cose control or intensive glucose control, the relative risk
effects intensive diabetes therapy on the prevention reduction (95% CI) for new or worsening neuropathy for
and progression of chronic diabetic complications have intensive versus standard glucose control after a median
been published. The large randomized trials such as of 5 years of follow-up was,4 (10 to 2), without a sig-
the Diabetes Control and Complications Trial (DCCT) nificant difference between the groups (ADVANCE
and UK Prospective Diabetes Study (UKPDS) were Collaborative Group, 2008). Likewise, in the VADT
not designed to evaluate the effects of intensive diabetes study including 1791 military veterans (mean age,
therapy on DSPN, but rather to study the influence of 60.4 years) who had a suboptimal response to therapy
such treatment on the development and progression of for type 2 diabetes, after a median follow-up of 5.6 years
 EPIDEMIOLOGY OF POLYNEUROPATHY IN DIABETES AND PREDIABETES
no differences between the two groups on intensive or
standard glucose control were observed for DSPN or
microvascular complications (Duckworth et al., 2009).
In the ACCORD trial (Ismail-Beigi et al., 2010), intensive
therapy aimed at HbA1c < 6.0% was stopped before
study end because of higher mortality in that group,
and patients were transitioned to standard therapy after
3.7 years on average. At transition, loss of sensation to
light touch was significantly improved on intensive ver-
sus standard diabetes therapy. At study end after 5 years,
MNSI score > 2, loss of sensation to vibration and light
touch were significantly improved on intensive versus
standard diabetes therapy. However, due to the prema-
ture study termination and the aggressive HbA1c goal,
the neuropathy outcome in the ACCORD trial is difficult
to interpret. In addition, the trial was complicated by a
lipid lowering arm using fibric acid derivatives and a
blood pressure lowering arm, making it difficult to
ascribe the differences between ACCORD, VADT and
ADVANCE as being due to glycemic lowering.
In the Steno 2 Study (Gaede et al., 2008), intensified
multifactorial risk intervention including intensive dia-
betes treatment, angiotensin-converting enzyme (ACE)
inhibitors, antioxidants, statins, aspirin, and smoking
cessation in patients with microalbuminuria showed no
effect on DSPN after 7.8 (range: 6.9–8.8) years and again
at 13.3 years, after the patients were subsequently fol-
lowed observationally for a mean of 5.5 years. Regretta-
bly, the only measure of neuropathy was VPT.
However, it has to be acknowledged that, in contrast
to the DCCT, the aforementioned trials conducted in
type 2 diabetic patients have used only a few clinical
end points of DSPN rather than an array of quantitative
measures including NCV. Thus, there is no firm evidence
that intensive diabetes therapy or a target-driven intensi-
fied intervention aimed at multiple risk factors favor-
ably influences the development or progression of
DSPN in type 2 diabetic patients.
Diabetes duration
DSPN, like the other specific diabetic complications, is
rare at the outset of type 1 diabetes. It is more common
among people with established type 2 diabetes than
among those with newly diagnosed diabetes (Herman
et al., 1998; Shaw et al., 1998). This association between
disease duration and the risk of diabetes is strong, has
been confirmed in a variety of studies in both type 1
and type 2 diabetes, and remains after adjustment for
age (Tesfaye et al., 1996; Adler et al., 1997; Forrest
et al., 1997; Shaw et al., 1998). In a UK study, the prev-
alence of DSPN rose from 21% in those with a diabetes
duration of less than 5 years to 37% in people with a
duration of over 10 years (Young et al., 1994). In a
15
Spanish study, the prevalence rose from 14% at under
5 years duration to 44% at a duration of more than
30 years (Cabezas-Cerrato, 1998). Interestingly, in one
study, the association between DSPN and duration of
diabetes was not seen in those over the age of 54, but
was strong in those aged under 54 (Delcourt et al.,
1998). This, however, has not been reported elsewhere.
Age
Advancing age has been widely reported to increase the
risk of DSPN. In a large sample (6487 subjects) of UK
diabetic hospital outpatients, the prevalence of DSPN
rose from 5% in the 20–29 year age group to 44% in
the 70–79 year age group (Young et al., 1994). Among
a population-based sample from Egypt, DSPN was
detected in 8% of those aged 20–44, and in 23% of those
aged
45 years (Herman et al., 1998). In this study, the
risk of DSPN independently attributed to age approxi-
mately doubled for every 10 year increment in age.
A number of other studies have also documented age
as an independent risk factor for DSPN (Walters et al.,
1992; Franklin et al., 1994; Tesfaye et al., 1996; Adler
et al., 1997). However, the influence of age may not be
straightforward. Neurologic function, especially VPT,
deteriorates with advancing age even in the normal, non-
diabetic population (Bloom et al., 1984; Wiles et al., 1991).
While some studies have adjusted for the effects of age
on VPT, this is not universal. Furthermore, diagnostic
criteria for DSPN often include other parameters, such
as clinical signs, monofilament sensitivity and electro-
physiology, which are not adjusted for age. Interestingly,
in a study from France, where VPT was adjusted for age,
height and gender, there was no relationship between
neuropathy and age (Delcourt et al., 1998). Data from
Mauritius confirmed the increase in VPT with age in both
diabetic and nondiabetic subjects (Shaw et al., 1998). Age
was recently confirmed as a strong independent risk
indicator for DSPN and painful DSPN in the
population-based MONICA/KORA cohorts from south-
ern Germany (Ziegler et al., 2008, 2009a, b).
Height
DSPN, like other metabolic, nutritional and toxic neu-
ropathies, is a distal disease, which is first manifest in
the feet. It is therefore, clearly a length dependent pro-
cess, although the pathophysiology underpinning this
phenomenon is not understood. It seems logical, there-
fore, that height, as a surrogate measure of the length
of the longest nerves, might be associated with DSPN.
This hypothesis has been borne out in a number of dif-
ferent cross-sectional and prospective studies (Tesfaye
et al., 1996; Adler et al., 1997; Forrest et al., 1997;
Shaw et al., 1998).
16 D. ZIEGLER ET AL.
Hypoinsulinemia
Partanen et al. (1995) have suggested a link between
hypoinsulinemia and DSPN, which they believed resulted
from the possible beneficial effects of insulin and
C-peptide on neuronal metabolism and function (Ido
et al., 1997). They found that baseline fasting and 2 hour
insulin levels were lower in newly diagnosed Finnish
male subjects with type 2 diabetes who developed DSPN
10 years later, compared to those who remained free of
DSPN. In the San Luis Valley Study (Sands et al., 1997),
these findings were also evident (using C-peptide), but
this univariate association disappeared when diabetes
duration was taken into account. Data from Mauritius
(Shaw et al., 1998) also suggested a similar association
with hypoinsulinemia, but perhaps because of the low
prevalence of DSPN in that study, the association was
not apparent in all analyses.
Diabetes duration almost certainly has an important
confounding effect on the assessment of this potential
relationship, since it might be expected both to increase
the prevalence of DSPN and to reduce insulin levels. It is
difficult to account for duration in type 2 diabetes, as the
date of disease onset is not usually known (only the date
of clinical presentation). Only a study in a population in
which an accurate estimate of the time of onset of type 2
diabetes can be made will allow a better insight into the
role of hypoinsulinemia.
Cardiovascular risk factors
HYPERTENSION
Hypertension is attractive as an etiologic factor in DSPN,
as it could be viewed as lending weight to the vascular
theory of the pathophysiology of DSPN. Hypertension
has been associated with DSPN in several studies, most
notably in the data from the Pittsburgh cohort of type 1
diabetes (Forrest et al., 1997). In this study, hypertension
was the single strongest predictor of DSPN, and was
associated with an approximately fourfold risk of devel-
oping DSPN over 6 years. In the EURODIAB Prospec-
tive Complications Study systolic blood pressure was
shown to be one of the predictors of the development
of DSPN after adjustment for age, duration of diabetes,
and HbA1c (Tesfaye et al., 2005). Reports in type 2 dia-
betes, however, have been conflicting (Franklin et al.,
1994; Partanen et al., 1995; Savage et al., 1996; Adler
et al., 1997), but mainly have not confirmed this associ-
ation. In a small interventional study (including subjects
with both type 1 and type 2 diabetes), treatment with the
ACE inhibitor trandolapril reduced progression of elec-
trophysiologic parameters of DSPN, and also lowered
systolic blood pressure (Malik et al., 1998). However,
the UKPDS reported that intensive blood pressure
lowering, with a variety of agents, had no effect in ame-
liorating the progression to DSPN (UK Prospective Dia-
betes Study Group, 1998c).
LIPIDS
A high total cholesterol (Herman et al., 1998) and ele-
vated triglycerides (Tesfaye et al., 1996) have been
reported as independent risk factors for DSPN (after
adjustment for HbA1c, age and other potential con-
founders). Elevated LDL was also found to predict neu-
ropathy in a study of type 1 diabetes, but the association
was lost after adjustment for other risk factors (Forrest
et al., 1997). In the EURODIAB Prospective Complica-
tions Study, apart from glycemic control, incidence of
neuropathy over 7.3  0.6 (SD) years was associated with
cardiovascular risk factors including a raised triglycer-
ide level, BMI, smoking, and hypertension. Cardiovas-
cular disease at baseline was associated with double
the risk of neuropathy, independent of cardiovascular
risk factors (Tesfaye et al., 2005).
In a highly selected group of patients from two iden-
tical randomized, placebo-controlled clinical trials with
mild to moderate DSP elevated triglycerides correlated
with sural nerve myelinated fiber loss over 1 year inde-
pendent of disease duration, age, diabetes control, or
other variables. Thus, hyperlipidemia may play a role
in the progression of DSPN (Wiggin et al., 2009). In
the Fremantle Diabetes Study (Davis et al., 2008), fibrate
and statin use increased to 10.4% and 36.5%, respec-
tively, over 5 years. In time-dependent Cox proportional
hazards modeling, fibrate use (hazard ratio (HR) 0.52,
95% CI 0.27–0.98) and statin use (HR 0.65, 95% CI
0.46–0.93) were significant determinants of incident
neuropathy. However, in type 2 diabetic patients the
link between DSPN and dyslipidemia must remain tenta-
tive at this stage, as several studies have failed to
observe such a relationship (Partanen et al., 1995; Shaw
et al., 1998).
OBESITY
Weight and waist circumference were independent risk
factors for both DSPN and painful DSPN in diabetic
patients participating in the population-based MONICA/
KORA surveys from southern Germany (Ziegler et al.,
2008, 2009a, b). In the 2001–2004 National Health and
Nutrition Examination Survey (NHANES), adults
aged
40 years were evaluated for clustering of
2 car-
diometabolic characteristics, including elevated triglyc-
erides or plasma glucose, low HDL cholesterol levels,
increased waist circumference, or hypertension. Overall,
9.0% of individuals had peripheral neuropathy alone,
8.5% had peripheral artery disease (PAD) alone, and
2.4% had both DSPN and PAD. Obese subjects were
 EPIDEMIOLOGY OF POLYNEUROPATHY IN DIABETES AND PREDIABETES
more likely to have DSPN (OR 2.20, 95% CI 1.43–3.39),
PAD (OR 3.10, 95%CI 1.84–5.22), and both DSPN and
PAD (OR 6.91, 95% CI 2.64–18.06) compared with non-
obese subjects without clustering. Thus, obesity and the
presence of two or more cardiometabolic risk factors
markedly increases the likelihood of DSPN and PAD
(Ylitalo et al., 2011).
SMOKING
Cigarette smoking has been identified as an independent
risk factor for DSPN in two different studies of type 1
diabetes, in which it was associated with an approximate
doubling of the risk of DSPN (Tesfaye et al., 1996;
Forrest et al., 1997). Smoking was also found to carry
an independent risk in the San Luis Valley study of type
2 diabetes (Sands et al., 1997), but was actually associ-
ated with a protective effect in US veterans (Adler
et al., 1997), and had only a weak (and not independent)
association in the study from Mauritius (Shaw
et al., 1998).
Alcohol consumption
Alcohol consumption has been associated with DSPN on
a number of occasions (Adler et al., 1997), but it may be
difficult, at least in epidemiologic studies, to differenti-
ate between diabetic neuropathy in which alcohol is a
risk factor and alcoholic neuropathy in a person with
diabetes.
Depression
Neuropathy is a risk factor for depressive symptoms
because it generates pain and unsteadiness. Unsteadi-
ness is the symptom with the strongest association with
depression, and is linked to depressive symptoms by per-
ceptions of diminished self-worth as a result of inability
to perform social roles (Vileikyte et al., 2009).
Genetic factors
Striking ethnic and racial differences in the prevalence
of nephropathy and macroangiopathy have been
reported, but no such effects have been observed in
the population-based surveys of diabetic neuropathy
(Franklin et al., 1994; Harris et al., 1993). Although hyper-
glycemia and diabetes duration are generally accepted to
represent major contributory factors to the prevalence of
diabetic neuropathy, many diabetologists have come
across patients who do not develop neuropathy despite
long-term poor glycemic control. Whole-genome screen-
ing and candidate gene strategies can be applied to
the genetics of type 1 diabetes complications (Marre,
1999). The most significant results were obtained regard-
ing a role for polymorphisms of the renin–angiotensin
17
system in diabetic nephropathy (Marre, 1999). In diabetic
polyneuropathy, reduced Na+/K+-ATPase activity and
increased aldose reductase activity have been suggested
to play an important pathogenetic role. Na+/K+-ATPase
is encoded by various genes, of which the ATP1 A1 gene
is expressed predominantly in peripheral nerves and
erythrocytes. A case-control study found that type 1 dia-
betic patients bearing a restriction fragment length poly-
morphism (RFLP) of the ATP1 A1 gene carried a 6.5-fold
(95% CI 3.3–13) increased risk of peripheral neuropathy.
Moreover, these patients showed reduced erythrocyte
Na+/K+-ATPase activity (Vague et al., 1997). Another
case-control study showed increased susceptibility to
peripheral neuropathy in type 1 diabetic patients who
had a polymorphism at the 50 end of the aldose reductase
(ALR2) gene (Heesom et al., 1998). In contrast, a study in
Japanese type 2 diabetic patients found an association
of the ALR2 gene polymorphism in the 50 region with
retinopathy but not peripheral and autonomic neuropa-
thy or nephropathy (Ichikawa et al., 1999). In Russian
type 1 diabetic patients, Leu54Phe and Val762Ala poly-
morphisms in the poly(ADP-ribose)polymerase-1 gene
(Nikitin et al., 2008), the 262 T > C promoter of the cat-
alase gene (Chistiakov et al., 2006), and genes encoding
the enzymes Mn-superoxide dismutase (SOD) and extra-
cellular superoxide dismutase (EC-SOD) (Strokov et al.,
2003) were associated with diabetic polyneuropathy in
Russian type 1 diabetic patients, suggesting a role for
genes coding for oxidative stress.
a2B adrenergic receptor (Papanas et al., 2007) and
apolipoprotein E polymorphisms (Monastiriotis et al.,
2011) have also been associated with more severe diabetic
neuropathy. Finally, Asp299Gly and Thr399Ile geno-
types of the TLR4 gene were associated with a reduced
prevalence of diabetic neuropathy in patients with type 2
diabetes (Rudofsky et al., 2004). However, these studies
were performed in relatively small, highly selected popu-
lations. Population-based data from large cohorts are not
available. Thus, at present only a low level of evidence
for a role of these candidate genes obtained from
case-control studies is available. Only prospective con-
trolled trials using strata selected along a candidate gene
would clarify whether polymorphisms might have thera-
peutic relevance in future.
CONCLUSIONS
The study of the epidemiology of diabetic neuropathy
remains clouded by lack of agreement over diagnostic
criteria and variation in subject selection methods. It is
essential that agreement is reached over diagnosis,
although it is hard at the present time to see how this
is going to come about. One issue that may be relevant
in this context is the basis on which the diagnosis should
18 D. ZIEGLER ET AL.
be made. Is diabetic neuropathy a condition which pre-
disposes to clinical end points such as foot ulceration
and amputation, in which case quantitative sensory test-
ing should suffice, or is it a condition in which neurologic
function differs from that in a healthy population, in
which case diagnosis may require a more detailed
assessment?
The available data indicate that DSPN is present in
approximately 28% of hospital clinic patients and those
in primary care, and < 20% of the total diabetic popula-
tion, including both diagnosed and undiagnosed diabe-
tes. Between 25% and 62% of patients with idiopathic
peripheral neuropathy are reported to have prediabetes,
and among individuals with prediabetes 11–25% are
thought to have peripheral neuropathy and 13–21%
neuropathic pain.
The major confirmed risk factors for diabetic poly-
neuropathy are age, poor glycemic control, diabetes
duration, height, and cardiovascular risk factors. The
most important comorbidities are nephropathy, retinop-
athy, peripheral artery disease, cardiovascular disease,
and depression. Clinic-based data suggest that DSPN is
associated with increased mortality in diabetic patients,
but prospective population-based studies are required to
confirm these findings.
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