Currently, approximately 70 million adults having T2D. Globally,

Currently, the prevalence of type 2 diabetes (T2D) in
India is estimated at 10.4%, with approximately 70 million adults having T2D.
Globally, India ranks second after China in the number of adults with T2D.1
The prevalence of T2D has more than doubled in the last two decades, reaching
epidemic proportions. Moreover, the prevalence of prediabetes in India is
higher than that of T2D at approximately more than 77 million.2
Prediabetes is not only a strong risk factor for future development of diabetes,
but also for microvascular complications and cardiovascular disease.3
In addition, microvascular complications of diabetes could manifest during the
prediabetes stage.4

Diabetic peripheral neuropathy (DPN) is among the most
common microvascular complications of diabetes and is associated with increased
morbidity, economic burden, and impaired quality of life.5 Distal
symmetrical polyneuropathy (DSPN), the most common presentation of DPN,
involves the somatic and autonomic nerve fibers. Its somatic component may be
manifested by pain, paresthesia, cramps, or muscle weakness, predominantly in
the lower limbs. Debilitating neuropathic pain frequently occurs in patients
with DSPN.6, 7 Patients with DSPN may barely recognize its
progression. Foot ulceration and amputation are the two major complications of
DSPN. In India, the traditional risk factors like glycemic control and the
duration of diabetes are compounded by the practice of bare foot walking, nutritional
deficiencies, poor foot hygiene, and improper foot wear.8 The absence
of symptoms in the early stages, lack of reliable diagnostic techniques,
regular screening programs, and poor awareness all contribute to delayed
diagnosis.8, 9  

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!

order now


DPN affects more than 50% of patients with
long-standing T2D, and it may be a presenting feature of diabetes in elderly patients.10
Several recent studies have consistently reported the occurrence of DPN in participants
with impaired glucose tolerance (IGT) and prediabetes.11-13 Early
neuropathy associated with prediabetes is the focus of current research as it
may be the most responsive to novel therapies targeting different
pathophysiological pathways of DPN. Early diagnosis is also important for
optimizing glycemic control, patient education on foot care practices, and
implementing preventive measures. Moreover, screening strategies for early
detection of neuropathy and foot care education have been shown to reduce the
incidence of foot ulceration and amputation. 14, 15


Data on the prevalence of DPN in prediabetes among
Indians are sparse. Given the burden of prediabetes and the potential
complications associated with DPN, having an estimate of the prevalence of DPN
in prediabetes and understanding the factors influencing its occurrence are
important. Hence, the objective of the present study is to estimate the
prevalence of DPN in prediabetes among Indians and to identify the main
determinants of DPN.



Participants and Methods

2. 1 Study design

The present cross-sectional study was conducted in an
outpatient setting at the Vydehi Institute of Medical Sciences and Research
Centre, Bangalore, India between February 2016 and November 2017. Informed
consent was obtained from the participants, and the study design was approved
by the Vydehi Institutional Ethics Committee. Consecutive participants aged
> 18 or < 65 years with prediabetes were recruited for the study (n = 414). Prediabetes was defined according to the criteria of the American Diabetes Association with a fasting plasma glucose (FPG) of 100–125 mg/dL or a 2-hour oral glucose tolerance test (OGTT) PG of 140–200 mg/dL or hemoglobin A1c (HbA1c) of 5.7%–6.4%. Both known and newly diagnosed cases of prediabetes were recruited for the study. Previously diagnosed cases of prediabetes that did not fulfil the diagnostic criteria for prediabetes at the time of recruitment were excluded from the study. Participants with chronic alcohol consumption, an active foot ulcer, and secondary causes of DPN such as rheumatological conditions, alcoholic polyneuropathy, untreated hypothyroidism, and hereditary neuropathy were excluded. A detailed clinical history was taken, and demographic information (age, sex, and ethnicity), life-style factors (smoking), and family history of diabetes were collected using standardized self-report questionnaires. Cigarette smoking status was assessed per the National Health Interview Survey criteria and included both former and current smokers.16 Participants were questioned for the presence of unsteady gait, paresthesia, burning sensation, aching pain or tenderness in the legs or feet, and numbness and weakness of the lower extremities. A detailed clinical and neurological examination was performed in all the participants. Anthropometric measurements including weight, height, and body mass index (BMI; kg/m2) were recorded in all the participants. Height and weight were taken in duplicate according to standardized procedures, and the averages of these measurements were used in the analyses. Blood pressure was recorded in the right arm to the nearest 2 mm Hg with a clock model aneroid blood pressure apparatus (Diamond, Pune, India) after a 5-min rest with the patient in a sitting position. 2.1.1.   Neurological examinations A detailed neurological examination was performed according to standardized procedures and included assessment of pin-prick, temperature, vibration sensation, and Achilles reflex, each of which were tested twice on each subject.17 The Diabetic Neuropathy Symptom Score (DNS), Modified Neuropathy Disability Score (NDS), and vibration perception threshold (VPT) using biothesiometry were used to screen for DPN. DNS: The 4-item DNS score is a validated and easy-to-perform symptom score for the diagnosis of DPN.18, 19 The maximum score for DNS is 4 points, and a score of ? 1 suggests an abnormality. NDS: The modified NDS, as described by Young et al., is a validated test for the detection of DPN.20 The minimum acceptable criteria for a diagnosis of peripheral neuropathy using NDS are moderate signs with or without symptoms (NDS ? 6) or moderate symptoms with at least mild signs of neuropathy (NDS ? 3).20 VPT: The VPT was assessed using a biothesiometer (Dhansai Lab, Mumbai, India) at 6 different body sites including the great toe, first metatarsal, third metatarsal, fifth metatarsal, medial arch, and heel in a graduated manner from 0 volts upwards. Patients were asked to give a verbal response once they could feel the vibration. Three cycles of readings were recorded at each site, and the mean was calculated. A mean value of > 15
volts was considered abnormal. 21

DPN was defined as any of the following: (i) modified
NDS ? 6, (ii) NDS ? 3 or < 6 with a DNS score of ? 1, and (iii) VPT > 15.

2.1.2.   Biochemical

was carried out in the morning (7:00 A.M. to 11:00 A.M.) after a 10-hour
overnight fast. Participants were asked to avoid heavy physical activity on the
day before examination and to refrain from smoking before and during the test.
Fasting venous blood glucose was sampled, and 75-g anhydrous glucose was then given,
and second sample was drawn two hours after ingestion. Fasting samples for
glycated hemoglobin, lipids, serum thyroid-stimulating hormone (TSH), and
vitamin B12 were also collected and analyzed using a fully automated Beckman
Coulter DXC 860i Auto Analyzer (Beckman Coulter, California, USA).


2.2. Statistical analyses

All statistical analyses were performed using SPSS
version 23.0. Data are presented as mean ± SD for continuous variables and as percentages
for categorical variables. Between-group comparisons were performed using the
student’s t-test for continuous data and the chi-squared test for categorical
data. Pearson’s or Spearman’s correlation coefficient was computed to evaluate the
relationship between the variables. Univariate and multivariate logistic
regression analyses were performed to determine the relationships between the
presence of DPN and various demographic/lifestyle factors (namely, age, sex,
BMI, and smoking habits) and biochemical parameters (namely, FPG, HbA1c,
hemoglobin, serum TSH, vitamin B12, and lipid components). Unadjusted and
adjusted odds ratios (ORs) and 95% confidence intervals were estimated via logistic
regression analyses. Statistical significance was set at P < 0.05.           3.           Results The participants' mean age was 45.3 ± 11.1 years, and the male-to-female ratio was 0.95:1. The mean duration of prediabetes was 0.65 ± 0.78 years, and the mean BMI was 26.17 ± 4.4 kg/m2. The mean FPG, 2-hr OGTT PG, and HbA1c was 105.4 ± 11.2 mg/dl, 158.1 ± 27.48, and 5.9 ± 0.4%. Geographically, the study group predominantly comprised participants from eastern (54.8% of participants) and southern India (41.3%). Prevalence of DPN: Overall, 38 patients were detected to have DPN, rendering a prevalence of 9.2%. A total of 1.7% of patients had NDS ? 6. Meanwhile, 4.8% of patients had an NDS ? 3 and < 6 with a DNS score of ? 1. The prevalence rates of DPN based on the NDS and biothesiometry were 6.5% and 5.1%, respectively (Table 1). A significant correlation was observed between NDS and VPT values (r = 0.54, P = 0.01). Patients in the DPN (n = 38, 9.2%) group were significantly older and had a greater duration of prediabetes than those in the non-DPN group (n = 376, 90.8%). The HbA1c value was also significantly higher in the DPN group than in the non-DPN group (6.1% vs 5.9%, P = 0.01) (Table 2). Factors associated with DPN: Univariate analysis revealed age, duration of prediabetes, HbA1c, hypertension, and smoking as significant predictors of DPN. In the multivariate logistic regression model after adjustment for the confounding factors, only age (OR: 1.11; 95% CI: 1.06–1.15, P = < 0.001), smoking (OR: 3.01; 95% CI: 1.01–9.20, P = 0.04), and hypertension (OR: 3.34; 95% CI: 1.43–7.77, P = 0.005) were independently associated with DPN (Table 3).     4.           Discussion Our study reports on the prevalence of and factors associated with DPN in patients with prediabetes. To our knowledge, this is the first major report on the prevalence of DPN in prediabetes among Indians. The results of our study indicate old age, smoking, and hypertension as the major predictors of DPN. The findings of our study are in line with the observations noted in previous studies. Dyck et al. reported a prevalence of 12.6% for neuropathy diagnosed based on abnormal nerve conduction studies (NCS).11 Zeigler et al. reported a 13% prevalence of neuropathy, defined as Michigan Neuropathy Screening Instrument score of > 2, in patients with prediabetes.12
Another study reported a 15.6% prevalence of neuropathy using abnormal
vibratory perception and thermal discrimination thresholds as the diagnostic
criteria.22 However, a low rate of neuropathy has also been reported
in a few studies.23, 24 Differences in the diagnostic criteria,
screening techniques, participant characteristics, genetic and ethnic factors,
and subjective nature of screening tests could explain the variation in the frequency
of DPN noted among different studies. In general,
studies employing NCS have reported a higher prevalence than other diagnostic

Biothesiometry is a commonly used screening technique
for DPN in epidemiological studies because of its ease, high specificity, capability
to predict risk of foot ulceration, and low cost.25, 26 However, it
has a low sensitivity because it detects only large-fiber dysfunction, whereas
small-fiber neuropathy is typically more common in early DPN.27
Hence, a combination of a validated screening examination score such as NDS
with VPT can yield a higher sensitivity for detecting DPN than biothesiometry
alone, as the results of our study indicate. Although NCS is still considered
to be the gold standard for the diagnosis of DPN, it is difficult to employ for
large-scale epidemiological purposes, and small-fiber neuropathy might be
missed by NCS.28, 29 A combination of ankle reflex and vibration
sense has been shown to have a high sensitivity in the diagnosis of DPN.30
In addition, several studies have shown the capability of NDS to accurately
diagnose patients with DPN.31, 32 Hence, we believe that the
indicators of the neuropathy employed in our study are valid.

We found that age, smoking, and hypertension are
independent and significant factors correlated with DPN. This is in accordance
to findings from previous studies. In a previous study, age was independently
associated with DPN among participants with prediabetes, diabetes, and
normoglycemia.24 Hypertension and smoking were independent risk factors
for the development of neuropathy in patients without neuropathy at baseline in
the EuroDIAb study.33 Factors other than hyperglycemia could also be
involved in the pathogenesis of neuropathy in prediabetes.34
Evidence points to the involvement of components of the metabolic syndrome,
specifically obesity, hypertension, and dyslipidemia in the pathogenesis.
Oxidative stress, endothelial perturbation, and elevated inflammatory markers
frequently associated with metabolic syndrome are thought to contribute to
neuropathy.34-36 Similarly, oxidative low-density lipoprotein particles
have been shown to induce direct toxicity to the neuronal cells. 37

DPN is a major contributory factor to increased
morbidity and lower-limb complications associated with T2D.38-41 In
addition, individuals with impaired glucose metabolism who have neuropathy are
nearly four times more likely to have retinopathy and two times more likely to
have albuminuria.42 Autonomic neuropathy in prediabetes has been
linked with increased risk of cardiovascular mortality.43, 44 Hence,
the early diagnosis of DPN in the prediabetes stage play an important role in preventing
complications such as foot ulceration/amputation and in initiating intervention
strategies directed toward better glycemic control, cardiovascular protection,
and patient education.

The strengths of our study are the large sample size,
use of the OGTT for the accurate diagnosis of IGT, and use of a combination of
a validated examination score and VPT for the diagnosis of DPN. However, our
study also has several limitations. First, it is a cross-sectional study
conducted in a tertiary care center. Population-based epidemiological studies
are required to confirm our findings. Second, NCS was not performed in the
patients to confirm the diagnosis of DPN. However, we believe the results would
not be much different if NCS had been performed.


summary, DPN occurs at a high frequency in patients with prediabetes,
underscoring the need to screen for complications in this patient population.
Screening for DPN using simple bedside examination and point-of-care
instruments is a cost-effective strategy toward early detection and
intervention as a means to reduce the incidence of peripheral neuropathy and
its complications.