INTRODUCTION

Diabetes mellitus (DM) is a condition that affects the body’s ability to regulate the level of glucose in the blood, resulting in consistently high blood glucose. High blood glucose levels for a period of time could cause irritation and/or damage called diabetic peripheral neuropathy (DPN)¹. DPN is the most common type of peripheral neuropathy (PN) which affects the lower extremity more than the upper extremity and decreases the patient’s quality of life². The spread of obesity has been declared a worldwide epidemic by the world health organization (WHO). In fact, a new term, global obesity, has been coined to describe the recent upsurge of overweight and obesity throughout the world's population.

According to WHO, more than one billion adults are overweight and at least 315 million are clinically obese³. A strong association exists between obesity and type ІІ diabetes. The increase in the prevalence of diabetes parallels that of obesity and some experts call this dual epidemic “diobesity”. Both obesity and type ІІ diabetes feature insulin resistance and similar atherogenic lipid profiles such as increased triglycerides and decreased high-density lipoprotein cholesterol (HDL-_C)^{4, 5}.

 Prevalence studies showed that 25-60% of type ІІ diabetes develop peripheral neuropathy^6,7. Sensorimotor PN is one of the frequent complications of diabetes mellitus⁸. The sensory impairment identified as a significantly worse proprioceptive acuity in ankle muscles compared to healthy people⁹. Impaired ankle joint proprioception has been tentatively identified as closely associated with increased standing sway¹⁰. In addition, impaired motor function of the ankle is associated with postural instability and markedly increases risk for falls¹¹.

    DPN is well documented to impair vascular reactivity at both the macrocirculation and skin microcirculation levels¹². Such impairments are associated with a reduction in endothelial nitric oxide production¹³, disturbed C-nociceptive fiber function and impaired ability of the microvasculature to respond to vasomodulators secreted by C-nociceptive fibers¹⁴.

    DPN is well documented to cause various neurophysiologic abnormalities. Latency, amplitude and nerve conduction velocity are the most common terms affected by DPN. The presence of DM causes hypoxic conduction block in the nerve fibers which resulted in a reduction in the compound muscle action potential amplitude (CMAP)^{4, 15}. Previous studies^16,18 concluded that motor conduction velocity of the peroneal nerve represents simple and reliable parameters for the evaluation of the peripheral nervous system of diabetic patients.

The purpose of this study was to evaluate the efficacy of weight reduction program on serum lipid profile and peripheral nerve function in obese patients with DPN.

PATIENTS AND METHODS

This study was conducted on 48 obese females {body mass index (BMI)¹⁹ between 30 and 39.9 kg/m²} with DPN and an age range from 36 to 45 years. The patients were selected from Neurology and Diabetes Outpatient Clinics, Kasr Al Aini University Hospitals. Peripheral neuropathy of diabetic origin was diagnosed in the presence of persistent numbness, paresthesia, loss of vibration sense, failure to elicit knee and/or ankle jerk. The diagnosis was confirmed electrophysiologically by: Electromyography (EMG) and sensorimotor nerve conduction studies (NCS).

 Inclusion criteria:

 (1) Females with known history of controlled type ІІ diabetes mellitus (with fasting capillary blood glucose concentration value around 130 mg/dl) treated by diet and/or oral hypoglycemic therapy, (2) All patients Suffered from sensory manifestation of very light intermittent feet pain, tingling, burning and pickling sensation, (3) Strength of the muscles of the lower limbs were not less than grade 3 and all patients had ability to walk household distances (at least 6m) without assistance or an assistive device, (4) No lower limb injuries affecting hips, knees or ankles in the six months before application of the study. (5) Patients had willingness to participate in the study.

    Exclusion criteria:

(1) Patients with gestational diabetes and recently diagnosed diabetes (less than one year from diagnosis). (2) History or evidence of central nervous system dysfunction. (3) Severe musculoskeletal deformity such as scoliosis.  (4) Lower extremities’ severe arthritis or pain.  (5) history of cardiovascular disease (angina, myocardial infarction with symptoms of palpitation, chest pain, nausea, vomiting, sweating, shortness of breath), (6) uncontrolled hypertension and symptomatic hypotension, (7) gastrointestinal symptoms; recurrent diarrhea, constipation, fecal incontinence, (8) autonomic bladder symptoms as retention or dribbling of urine, (9) history or evidence of planter pressure ulcers, (10) evidence of chronic diabetic complications e.g. ketoacidosis, patients on dialysis, (11) evidence of any other systemic or malignant diseases, (12) pregnancy, lactating women and severe obesity (BMI ≥40 kg/m²).

Instrumentations

Electromyography unit 12, Italy was used to confirm the diagnosis of PN by performing EMG and sensorimotor NCS and to record M-wave of extensor digitorum brevis muscle (MWEDBM) before and after the treatment program.

-Treadmill (Kistler Instrument Corporation, Amherst, NY, Type 2813M01) was used for walking training program. Time and type of exercise were adjusted from computer system attached to the treadmill.

Procedures:

    All patients signed a written informed consent and were subjected to all of the following evaluation protocol:

1-        Detailed history including: demographic (age and sex), duration of diabetes, family history of diabetes, duration of follow-up and presence of peripheral neuropathy

2-        Anthropometric characteristics of patients: height and weight

3-        Laboratory investigations to assess the diabetic state including: fasting blood sugar, glycosylated hemoglobin, urine analysis, renal and liver function tests

4-        Full neurological examinations with special emphasis on:

-    Motor examinations: inspection, muscle strength of the lower limbs, muscle tone and deep reflexes

-    Sensory examinations: superficial and deep sensation

5-        Lipid profile investigations: Baseline blood samples, obtained after an over-night fasting, for at least 12 hours, were taken and analyzed in the central laboratories of Kasr Al Aini University Hospitals. Measurements included total cholesterol, high density lipoprotein cholesterol (HDLc), low density lipoprotein cholesterol (LDLc) and triglycerides. Each of these laboratory investigations were performed at the start and at the end of the study.

6-        Electrophysiological assessment: EMG and nerve conduction studies: The modalities of electromyography and sensorimotor nerve conduction studies were done to verify the diagnosis of peripheral neuropathy using an electromyography unit 12, Italy apparatus. Nerve conduction studies were carried out for motor conduction in the left median, right ulnar, left common peroneal and the right posterior tibial nerves. Sensory conduction studies were carried out for the right ulnar and medial planter nerves. Conventional EMG examination was done for the right gluteus medius, the left quadriceps, the right tibialis anterior, the left medial head of gastrocnemius, the right extensor digitorum brevis, the left abductor digiti minimi and the extensor digitorum communis muscles.

(MWEDB recording): MWEDB was recorded while the patient relaxed supine with a small pillow was placed under his legs and head. The skin above the extensor digitorum brevis muscle (EDBM) and peroneal nerve at ankle joint was gently abraded with soft sand- paper and cleaned with alcohol swab to reduce skin resistance. Then, a surface bar recording electrode with coupling conductive gel was positioned on the belly of EDBM. The belly of the EDBM was identified by active voluntary dorsiflexion of the patient’s ankle against maximum resistance. The distance between active and reference electrodes was one inch. The surface bar stimulating electrode with coupling conductive gel was positioned on the anterior surface of the ankle in the mid position between medial and lateral malleoli.

The intensity of the stimulator was then increased gradually until maximum M-wave was obtained. Two minutes of practice run of maximum M-wave recording was carried out, followed by two minutes rest.

Treatment protocol: The patients were divided randomly into two equal groups: Both groups received their regular medication. The control group (G1) did not receive any treatment program. On the contrary, the study group (G2) received weight reduction program in the form of:

-   Diet²⁰: Diet restriction regimen provides about 1200 kcal/day. A diet with low glycemic index such as non-refined complex carbohydrates and dairy products was emphasized.

-   Treadmill training²¹: walking on treadmill for 40 minutes, three times per week for eight weeks, and included three phases:

·   Five minutes as warming up with low intensity (50-60 % of the patient’s maximal heart rate).

·   Thirty minutes as stimulus phase with speed of 60%-75% of the patient’s maximal heart rate with zero inclination.

·   Five minutes as cool down with low intensity (50-60 % of the patient’s maximal heart rate). 

Statistical analysis:

     Descriptive statistics (mean±SD) for all variables were done. Paired t-test was used for before and after treatment program comparisons within each group. Independent t-test with p<0.05 was performed for comparison between control and study groups.

RESULTS

1-       Results of lipid profile: Before the study application, there was no statistically significant difference between the control group (G1) and the study group (G2) regarding mean values of serum triglycerides and total cholesterol with P value >0.05. After intervention, a highly significant improvement was found in the study group compared to that before intervention with P=0.001 (Table1). The results also demonstrated a high statistically significant differences in the mean values of HDLc and LDLc which were improved in G2 than G1 with P=0.001 (Table2).

2-       Results of MWEDBM: Both the latency and amplitude of MWEDBM of the control group (G1) were statistically unchanged throughout the study with p=0.98 & p=0.20, respectively. On the other hand, the latency of the study group (G2) was significantly improved (p<0.001) after the weight reduction program with mean values 4.28±0.98 msec and 3.52±0.75 msec. The amplitude of the G2 was significantly higher with p=0.001(Table 3). 

Comparisons between the two groups (G1&G2) revealed statistically similar latencies and amplitude before the treatment program with p values=0.15 while there was a high statistically significant difference between both groups (P=0.001) after the treatment program (Table 4).

 Table 1. Comparisons between mean values of serum triglycerides and total cholesterol before and after treatment within the control (G1) and female patients with obesity and diabetic neuropathy group (G2)

SD Standard deviation

*significance at p<0.01

Table 2. Comparisons between mean values of serum HDLc and LDLc before and after treatment within the control (G1) and female patients with obesity and diabetic neuropathy group (G2)

HDLc high density lipoprotein cholesterol, LDLc low density lipoprotein cholesterol, SD Standard deviation

*significance at p<0.01

Table 3. Comparisons between mean values of latency and amplitude of MWEDBM before and after treatment within the control (G1) and female patients with obesity and diabetic neuropathy group (G2)

msec millisecond, mV millivolt,, SD Standard deviation

*significance at p<0.01

Table 4. Comparisons between latency and amplitude of MWEDBM mean values of the control (G1) and female patients with obesity and diabetic neuropathy group (G2) before and after treatment

msec millisecond, mV=millivolt, SD Standard deviation

*significance at p<0.01

DISCUSSION

Diabetes can be delayed or prevented with lifestyle modification (weight loss, regular moderate physical activity)²². In the context of diabetes, it is becoming increasingly clear that the epidemic of type ІІ diabetes is associated with decreasing levels of activity and an increasing prevalence of obesity²³. This study is a clinical trial to evaluate the effect of weight reduction program involving treadmill training on serum lipid profile and peripheral nerve function in obese female patients with DPN.

The results of the present study showed increase high density lipoprotein, decrease low density lipoprotein, serum cholesterol and triglyceride as well as decrease latency and increase amplitude of MWEDBM of the study group after receiving weight reduction program in comparison to the patients in the control group who received only regular medication from their physician. These improvements may be due to weight loss that leads to improvement in the glucose tolerance, insulin sensitivity and reduction in lipid levels²⁴. Previous studies^{8, 20, 24} reported that body weight loss increases insulin sensitivity and improves glucose tolerance. In addition, lifestyle modification including body weight loss and physical activity provide health benefits and functional gains²⁵.

Obesity is associated with alterations in lipoprotein profile which may increase cardiovascular disease risk even in the absence of classical metabolic risk factors. On the other hand, the female cardiovascular disease risk advantage is probably largely related to differences in traditional lipid risk factors (plasma triglyceride and HDL-cholesterol concentrations)²⁶. 

Physical activity may enhance weight loss when used along with an appropriate calorie controlled meal plan. There is positive effect of physical activity on loss of intra-abdominal fat which is associated most closely with metabolic abnormalities^{4, 8}. Thus, the importance of promoting physical activity as a vital component of the prevention of cardiovascular risk factors as well as management of type ІІ diabetes was recommended due to the consistent beneficial effect of regular physical activity training on carbohydrate metabolism and insulin sensitivity^{22, 24}. The members of USA Health and Human Services²⁷ supported the importance of physical activity in health promotion and disease prevention. The authors recommended 30 minutes of moderate physical activity on most days of the week.    

Exercise is a critical adjunct to diet and behavioral modification in a comprehensive weight-loss program. Exercise not only increases energy expenditure, but it has also been shown to diminish the loss of lean body mass and associated decline in resting metabolic rate^{4, 19}. Exercise improves the body's ability to burn fat, thus enhancing the loss of adipose tissue²⁸.

The results of the present study agree with the results of Marqueste et al. ²⁹, who reported that the increased neuromuscular activity provoked by the running exercise inhibits axon budding in the denervated muscle.  In addition, the results of previous studies proved the benefits of physical activity for the degenerated nerve, such as the increase numbers and diameters of the axons³⁰, increase muscle strength, and oxidative capacity of the muscle³¹, enhance rapid return of motor-sensory function during the initial and late phases³², thereby accelerating functional recovery and increase myelination of the fibers³³. Thus, the benefits of controlled treadmill exercise for the muscles may support its applicability, especially with regard to delaying atrophy which may be reflected directly through functional recovery following nerve regeneration²¹.

Conclusion

Weight reduction program in the form of diet control and treadmill exercises can be used as a non-pharmacological agent to improve dyslipidemia and peripheral nerve function in obese female patients with diabetic peripheral neuropathy.

[Disclosure: Authors report no conflict of interest]

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