Abstract: Aims This study investigated the Methods Cross-sectional analysis

Abstract:

Aims

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This
study investigated the 

Methods

Cross-sectional
analysis on 414 consecutive individuals with prediabetes aged between 18 and 65?years.  Diabetic peripheral neuropathy (DPN) was
evaluated with Diabetic neuropathy symptom score (DNS), modified neuropathy
disability score (NDS) and vibration perception threshold (VPT) using
biothesiometry. DPN was defined as either a modified NDS score ? 6, or NDS (? 3
and < 6) with a DNS score ? 1 or VPT > 15.  Logistic regression analyses with estimation
of Odd’s ratios were performed to determine the relationships between the
presence of DPN and various demographic/ lifestyle factors, and biochemical
parameters.

 

Results:
We observed a prevalence of 9.2% for DPN in individuals with prediabetes. Prevalence rates based on abnormal
examination score (NDS) and VPT were 6.5% and 5.1% respectively. Age, duration
of prediabetes and glycated haemoglobin were significantly greater in patients
with DPN group (n=38) as compared with those in the non-DPN group (n =
376).  In multivariate regression
analysis, age (OR 1.11, P< 0.001), smoking (OR 3.01, P = 0.04) and hypertension (OR 3.34, P = 0.005) were independent factors associated with DPN.    Conclusions: Our study documents the prevalence of DPN in subjects with prediabetes. The study findings reiterate the need for early detection and intervention to prevent the progression and complications of DPN.               Introduction India is home to about 70 million adults with T2D with an estimated prevalence of 10.4%. Globally, India ranks second after China in the number of adults with T2D. (1)  Prevalence of T2d has more than doubled in the last two decades reaching epidemic proportions. The prevalence of prediabetes is higher than that of T2D in India and is estimated to be 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 stage of prediabetes.(4) Diabetic peripheral neuropathy represents one of the most common microvascular complications of diabetes and is associated with increased morbidity, economic burden and impaired quality of life. (5) Distal symmetrical polyneuropathy, the most common presentation of DPN involves somatic and autonomic nerve fibres. Its somatic component may be manifested by pain, paraesthesia, cramps or muscle weakness, predominantly in the lower limbs. Debilitating neuropathic pain is a frequent occurrence in patients with DSPN. (6, 7) Foot ulceration and amputation are two major complications of DSPN and its progression may be barely recognized by the patient. In India the traditional risk factors are compounded by common practice of bare foot walking, nutritional deficiencies, poor foot hygiene and improper foot wear.(8) Absence of symptoms in early stages, lack of reliable diagnostic techniques, regular screening programs and poor awareness, all contribute to delayed diagnosis.(8, 9)     DPN affects more than 50% of patients with long-standing T2D and it may be a presenting feature of diabetes in older patients. (10) Several recent studies have consistently reported the occurrence of DPN in subjects with 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 demonstrated to reduce the incidence of foot ulceration and amputation (14, 15).   Sparse data exist on the prevalence of DPN in prediabetes among Indians. Given the burden of prediabetes and the potential complications associated with DPN, it is important to have an estimate of DPN in prediabetes and understand the factors influencing its occurrence. 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.     Materials and methods 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 was approved by the Vydehi Institutional Ethics Committee, Bangalore, India. Consecutive participants aged > 18 or < 65 years meeting the inclusion criteria were recruited for the study. A total of 414 consecutive participants with prediabetes were recruited. Prediabetes was defined according to the criteria of the American Diabetes Association with a FPG of 100–125 mg/dL or 2-hour OGTT PG of 140– 200 mg/dL or haemoglobin A1c (HbA1c) of 5.7% to 6.4%. Both known cases of prediabetes and newly diagnosed cases of prediabetes were recruited for the study. Previously diagnosed cases of prediabetes that didn't fulfil the diagnostic criteria for prediabetes at the time of recruitment were excluded from the study. Subjects 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 information on the demographics (age, sex, ethnicity), life-style factors (smoking), and family history of diabetes were collected in standardized questionnaires by self-report. 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 unsteadiness in walking, paraesthesia, burning sensation, aching pain or tenderness in legs or feet, numbness and weakness of 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 sitting position 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. Neurological examinations: A detailed neurological examination was performed and included assessment of pin-prick, temperature, vibration sensation and Achilles reflex, each of which were tested two times on each subject, according to standardized procedures.(17) 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 mean was calculated. A mean value of > 15 volts was considered abnormal (21).

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

Biochemical
investigations: Oral glucose tolerance
test (OGTT) 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 given and second sample drawn two hours after ingestion.  Fasting samples for glycated haemoglobin,
lipids, serum TSH and vitamin B12 were also collected and analysed using a
fully automated Beckman Coulter DXC 860i auto analyser (Beckman Coulter, California,
USA).

 

 

 

 

 

 

 

 

 

 

 

 

 

Statistical analyses:

All
statistical analyses were performed with SPSS version 23.0. Data are presented
as mean ± SD for continuous variables, and percentages for categorical
variables. Between-group comparisons were performed with the student t test for
continuous data, and the chi-squared test for categorical data. Pearson’s or
Spearman’s correlation coefficient was computed to test the relationship
between the variables. Univariate and multivariate logistic regression analyses
were performed to determine the relationships between the presence of diabetic
peripheral neuropathy and various demographic/lifestyle factors (age, sex, body
mass index BMI and smoking habits), and biochemical parameters (FPG, HbA1c,
haemoglobin, serum TSH, vitamin B12, and lipid components). Unadjusted and
adjusted Odds ratios (ORs) and 95% confidence intervals were estimated by
logistic regression analyses. Statistical significance was set at P < 0.05.                                       Results: The mean age of the study group 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 mean body mass index was 26.17 ± 4.4 kg/m2. The mean FPG was 105.4 ± 11.2 mg/dl, mean 2 Hr OGTT was 158.1 ± 27.48 and HbA1c was 5.9 ± 0.4%. Geographic representation comprised of subjects predominantly 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%. NDS ? 6 was present in 1.7% of patients. NDS (? 3 and < 6) with a DNS score ? 1 was present in 4.8% of patients. Prevalence rates based on the examination score (NDS) and biothesiometry were 6.5% and 5.1% respectively. Table 1 Significant correlation was observed between NDS and VPT values. (r=0.54, p=0.01) Patients with DPN group were significantly older and had a greater duration of prediabetes as compared with those in the non-DPN group (n = 376, 90.8%). HbA1c value was also significantly higher in DPN group as compared with non-DPN group (6.1 vs 5.9, P =0.01). Table 2 Factors associated with DPN: The univariate regression 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                             Discussion: Our study reports on the prevalence and factors associated with neuropathy 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 older 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 NCS. (11) In a study done by Zeigler et al the prevalence of neuropathy defined as MNSI score of > 2 was found to be 13% in patients with
prediabetes.(12) Another study reported a prevalence of 15.6% of neuropathy
utilising abnormal vibratory perception and thermal discrimination thresholds
as the diagnostic criteria (22). However, a lower 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
frequency of DPN noted among different studies. In
general, studies employing NCS have reported a higher prevalence than other
modalities of diagnosis.

Biothesiometry
is a commonly used screening technique for DPN employed in epidemiological
studies because of its ease, high specificity, ability to predict risk of foot
ulceration and low cost.(25, 26) However, it has a lower 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 like NDS with VPT could yield a higher sensitivity
for the detection of DPN when compared to biothesiometry alone, as the results
of our study indicate. Although NCS is still considered to be the gold standard
for 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, ability of NDS to accurately diagnose patients with DPN has been
demonstrated in several studies.(31, 32) Hence we believe the results of our
study are valid indicator of the neuropathy in the target population with
prediabetes.

Age,
smoking and hypertension were identified as independent and significant
correlates of DPN in our study. 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 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)  Likewise oxidative LDL particles has 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
stage of prediabetes could play an important role in prevention of complications
like foot ulceration/ amputation and also for initiating intervention
strategies directed towards better glycaemic control, cardiovascular protection
and patient education.

Strengths
of our study are the large sample size, use of the OGTT for the accurate
diagnosis of IGT, and using a combination of a validated examination score and
VPT for the diagnosis of DPN. Our study has several limitations. Firstly, it is
a cross-sectional study conducted in a tertiary care centre. Population-based
epidemiological studies are required to confirm these findings. Secondly, NCS
was not performed in the patients to confirm the diagnosis of DPN. We believe
the results wouldn’t be much different if the NCS had been performed in all the
patients.

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

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