Diabetes has a very high prevalence and a third of the diabetic population is affected with neuropathy. Moreover, one third of the patients with diabetic peripheral neuropathy (DPN) present with some kind of balance and gait disturbances. The incidence of developing diabetic peripheral neuropathy increases with the chronicity of the disease and poor glycemic control. Around 30% of people with DPN experience muscle weakness, loss of ankle reflexes, and decreased balance, coordination and gait control, thereby, limiting walking and increasing the risk of fall-related injuries. For the present article, a literature search was performed using Google Scholar, Pubmed and Cochrane data bases using the keywords. Articles were searched and reviewed using the narrative approach. This review aims to discuss the pathogenesis and factors associated with DPN, concept of balance and postural control, balance and gait impairment in DPN and exercises used to improve balance and gait parameters. In conclusion, the synthesis of the reviewed studies suggests that balance exercises are feasible and safe, and have the potential to improve balance and gait, consequently, reducing the risk of falls and fall-related injuries. Therefore, balance exercises should be used as a supportive therapy in diabetic peripheral neuropathy patients.

•    Diabetes
•    Postural control
•    Gait
•    Glycemic control

Ahmad I, Hussain E, Singla D, Verma S, Ali K (2017) Balance Training in Diabetic Peripheral Neuropathy: A Narrative Review. JSM Diabetol Manag 2(1): 1002.

Diabetes is a common metabolic disease having serious health implications and its incidence is increasing day by day. The global burden of diabetes is alarmingly high, with over 382 million diabetics in 2013 which is expected to rise up to 592 million by 2035 [1]. 60% of the world diabetic population resides in Asia [1], with Southeast Asia having around 72 million adults with diabetes in 2013 and this figure is expected to rise to 123 million by 2035 [2]. Long-term diabetes presents with various complications including retinopathy, nephropathy, neuropathy, arteriosclerosis etc. One of the many complications of diabetes mellitus is diabetic peripheral neuropathy (DPN), which is defined as “the presence of symptoms or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes [3]. It is estimated that 60% to 70% of diabetics have mild to severe forms of nervous system damage [4]. DPN is one of the serious known micro vascular complications of both type 1 and type 2 diabetes mellitus [5-7] having been diagnosed in 20-50% of the diabetic population [8-12].

The incidence of developing DPN increases with the chronicity of the disease and poor glycemic control [13,14]. Moreover, balance affliction is found in 16% diabetics [15] which may increase up to 30 to 50% with increase in the severity of the disease [16]. Peripheral neuropathies associated with diabetes are of several types. This review however, focuses on chronic sensorimotor DPN, which is most the common presentation of DPN. Peripheral neuropathies occur deceptively and start with reduced sensitivity followed by motor nerve impairment following distal to proximal pattern [17,18]. About 50% of patients may experience symptoms like burning pain, electrical or stabbing sensations, paraesthesia, hyperaesthesia, and deep aching pain [5]. Sensory disruption in diabetes leads to loss of vibration, pressure, temperature and pain (mediated by small and large afferent fibres). It also contributes to decrease in proprioception and increased reflex reaction time [19-21]. In addition, as many as 30% of people with DPN experience muscle weakness, loss of ankle reflexes, and decreased balance, coordination and gait control [4,22]. All these risk factors limit walking and other activities and increase the incidence of fallrelated injuries [20,21,23].

Previous studies have reviewed the gait characteristics in DPN [24] and the effect of various modalities to improve balance in DPN patients [25]. However, they did not take into account balance exercises as an intervention. In addition, the reviews by Liu and Frank [26] and Streckman et al. [27], present the efficacy of exercises to improve balance characteristics in older patients and patients with peripheral neuropathy respectively. This necessitates compiling the findings of studies which examine the effectiveness of balance exercises specifically in patients with DPN. Therefore, the present review aims to discuss the pathogenesis and factors associated with DPN, concept of balance and postural control, balance and gait impairment in DPN and balance exercise interventions used to improve balance and gait parameters in DPN population.

A literature search was performed using Google Scholar, PubMed and Cochrane databases. A total of 66 items showed up on PubMed and 20 on Cochrane with the term “balance training in DPN”. The search terms used were ‘Diabetes mellitus’, ‘type 2 Diabetes Mellitus’, ‘Diabetic neuropathy’, ‘Diabetic peripheral neuropathy’, ‘Glycemic control’, ‘balance’, ‘gait’, ‘falls risk’, ‘proprioception’, ‘postural control’, ‘postural stability’, ‘balance exercise’ and ‘balance training’. A broad research approach was chosen to minimize the chances of missing relevant articles. Articles that assessed variables reflecting balance & gait characteristics and the effect of balance training provided to DPN patients independently or in combination with other exercise, were included. Exercise interventions other than balance training were excluded. The studies were double checked and only full text articles were used for the review. Total 9 studies were selected to emphasize the balance and gait abnormalities in DPN patients and 11 studies were selected to demonstrate the effect of balance exercise in improving balance and gait in DPN patients (summarised in Table 1 and Table 2 respectively). These studies were reviewed in a narrative way.

DPN: Pathogenesis

DPN is said to be caused by both vascular as well as nonvascular abnormalities [28-30]. The theory although controversial, suggests that both mechanisms are a consequence of metabolic aspect (i.e. chronic hyperglycaemia). Chronic hyperglycaemia impairs micro vascular circulation by disrupting normal cellular communication and initiating signalling cascades [30-32]. The production of end products of advanced glycation signalling cascade of protein kinase C [30-32] leads to the demyelination associated with DPN [33], resulting into axonal thickening with progression to axonal loss34, basement membrane thickening, pericyte loss [35,36], loss of microfilaments (i.e. cyto skeletal filaments comprising act in and myosin) and decrease in capillary blood flow to C fibers [37] leading to decreased nerve perfusion and endoneurial hypoxia [35,36]. Furthermore, evaluation of C-nociceptive-fiber function using the nerve–axon reflex revealed that small-fibre impairment is an early event during natural history of DPN [38].These cellular-level impairments are manifested as loss of ankle reflexes, decreased position and vibratory sense, and sensory ataxia [19]. In addition, patients with DPN often demonstrate a delay in reflex responses when subjected to postural perturbations due to decrease in nerve conduction velocity, manifested as impairments in balance and thus an increased risk for falls [19].

Sensory nerve impairment

Sensory loss can be restricted to the toes; it can extend over to the feet; or spread over the lower legs or cross the knee level, totally depending on how intense the peripheral nerve lesions are. Later, it may progress to upper extremities and trunk. In most severe cases the summit of the scalp can be affected as a consequence of the involvement of the longest fibres of the trigeminal nerve [39]. In the proximal parts, superficial sensations such as pain and temperature are predominantly affected. Thermal sensibility too gets reduced either individually or along with loss of vibration sense [40]. Loss of large myelinated fibres and other proprioceptive afferent fibres causes disturbed light touch sensation, pressure sensibility, joint position sense and vibration. Disturbed joint position sense leads to increased instability of posture [41].

Motor nerve impairment

Weakness in the distal parts of the body happens late in the natural history of DPN [41]. With increased severity of DPN, a positive Romberg’s sign and ataxia may be found due to the weakness in the ankle plantar flexors and dorsiflexors [41].This instability in the muscles leads to difficulty in maintaining the balance (static as well as dynamic) and it ultimately affect the gait.

Balance is defined as the ability to maintain or return the body’s centre of gravity within the limits of stability that are determined by the base of support [42]. Postural control is the control of the body’s position in space for the purpose of balance and orientation [43]. Balance is concerned primarily with preserving, attaining, or restoring the centre of mass in relation to the limits of stability within a given base of support [44,45], and plays an important role in mobility as well as stability. Balance or postural control depends on the interactions between sensory inputs (somato sensory inputs, visual inputs and vestibular inputs) and motor response via central integrative processing systems (Figure 1). If there is any change in the sensory input it would lead to alteration in the motor response, so that appropriate responses to any external or internal perturbation can be chosen during static and dynamic positions of the body [46].

Somatosensory inputs

In the healthy, somatosensory system is comprised mainly of the proprioception and tactile sensations, where, proprioceptive sense is about joint angles, changes in the joint angles, joint position and muscle length and tension while tactile sensation is associated with sensations of touch, pressure and vibration. Each sensory stimulus makes a unique contribution to control posture.

Evidence suggests that the body’s static and dynamic positions are based on muscle proprioceptive inputs that come from foot and around the ankle joint to give continuous information to the central nervous system about the position of the body for postural regulation [47-49]. Other than this cutaneous sensation from sole of the foot has sufficient spatial relevance to induce adapted regulative posture [50]. Wang & Lin found association between increased severities of loss of plantar cutaneous sensitivity and postural sway [51]. In addition, application of sub sensory mechanical noise reduces the postural sway [52]. During upright stance position, somatosensory information from legs and feet guides both sensory feedback as well as use of experience in scaling the magnitude of the responses [53]. Reduction in the somatosensory information alters the rate as well as the magnitude of postural response [54,55].

Visual inputs

Vision has very evident role in postural control resulting from complex synergy that receives multimodal inputs. Visual inputs distinguish between translation and rotation of the head. Static visual cues may slowly control re-orientation or displacement, whereas dynamic visual cues may contribute to fast stabilization of the body [56]. Impairment of vision is strongly associated with falls in the elderly as reported in epidemiological studies [57,58].

Vestibular inputs

Vestibular information contributes to stabilization of head during various tasks for gaze control [59]. Head stabilization can optimize postural control when visual information is lacking and during complex equilibrium tasks, it provides a stable reference frame from which to generate postural responses [60]. Vestibular loss will lead to decreased trunk control but less effect would be imposed on the legs, due to legs leading inter segmental relation dynamics [61].

Motor response

Basic motor response for postural control is tone of the muscle and coordination between movement and posture. Voluntary movements show three main characteristics for postural adjustments: anticipatory movement, adaptation to condition and righting reactions to a certain task that is to be performed [62]. During movement of one segment, if the other segments are disturbed, it will produce instability; therefore stabilization of proximal segment is essential to produce precise movement of distal segments [63]. Along with this muscle weakness and muscle fatigue are also considered for postural control [20,64,65].

Central integrative system

Another aspect of postural control mechanism is the central integrative processing system, where an individual has to process the information coming from different sensory inputs for the appropriate and accurate response. If the central integrative processing is affected there is an increase in reaction time in case of presentation of conflicting sensory inputs [66].

 

Balance and gait characteristics change as one’s age progresses and presence of DPN in elderly populations plays a significant role in the incidence of falls. Static as well as dynamic balance both are affected in DPN. Various factors that affect the balance in this population are a result of significantly impaired sensation, proprioception impairment, movement strategy impairment, biomechanical structural disorders, and disorientation. Examination of static balance includes measurement of one leg stance, tandem stance and centre of pressure (COP) postural sway while for dynamic balance, forward reach, stance on the trampoline or bosu ball measures have been in use. Time up and go (TUG) test has also been used as dynamic balance measure but is more relevant as a mobility and functional task. Patients with diabetic peripheral neuropathy show alterations in the parameters of balance and gait [67]. 39 % of diabetic peripheral neuropathy subjects take more than 10 sec during unilateral leg stance as reported by Goldberg, Russell, & Alexander [68]while Cimbiz and Cakir found maximal reduction in the dominant leg stance time during one leg stance with eyes open and head rotation during static and dynamic balance testing [16]. Cimbiz and Cakir also found reductions in the functional reach in DPN patients on comparison with healthy controls [16], while Camargo et al., found similar results with no differences between the dominant and non dominant sides [69]. DPN patients take more time in TUG test [68-70], also, DPN women are slower when compared with DPN men and control [70]. The time required to perform the TUG is strongly related to the risk of falls. Healthy adults who are able to perform this test in maximum 10 secs have lesser risk of falls [71]. The presence of neuropathy is associated with an increased body sway [72,73], faster sway speed and greater sway dispersion [72] during bilateral stance with eyes open while the values exceed with eyes closed when compared to controls. Maximal step length which has correlation with balance and mobility is found to be reduced in patients with DPN [68]. Proprioception is one of the main causes for alteration in balance in this population and Goldberg, Russell, & Alexander found significantly greater trunk repositioning errors (TREs) in these people [68]. Lower extremity balance performance is found to be lower in diabetic participants when assessed using various scales such as Berg Balance scale (BBS) [70] Short Physical Performance Battery (SPPB) scores [74] (physical performance test) (Table 1).

Patients with DPN walk slower [69,75-77] with shorter stride length [69,75,78] and lower cadence [69] when compared with healthy controls during self-paced as well as maximal speed conditions due to prolonged double limb support and widened base [77,79] so as to increase stability during walking. Petro sky and colleagues found reaction time to be two times higher in diabetic patients versus age-matched controls as one of the factors for widened base and slower gait [79]. Although researchers found increased gait variability [24] (stride time variability as well as stride length variability) in DPN subjects which suggested that they have lesser stable walking pattern [77]. Ko et al., found proportionally longer gait cycle duration in DPN patients on comparison with non-neuropathy diabetic people [78] (Table 1).

Table 1: Outcomes measures examined for balance and gait impairment in DPN.

Authors and year	Sample size / group	Mean age + SD	Outcome measures
Cimbiz and Cakir, 2005  [16]	60 30 DPN 30 CG	DPN: 57.6 ± 3.9 CG: 55.6 ± 6.1	∗ Static one leg stance with eyes open and eyes closed  (dominant as well as non dominant leg) ∗ Dynamic one leg stance with eyes open and eyes closed  (dominant as well as non dominant leg) ∗ Physical fitness tests ∗ FRT
Goldberg, Russell, &  Alexander, 2008 [68]	16 8 DPN 8 CG (age matched)	DPN: 60.1 ± 2.4 CG : 60.0 ± 2.6	∗ One leg stance ↔ TUG ↔ Maximal step length ∗ Trunk reposition errors (degrees)
Camargo et al., 2015[69]	60 30 DPN 30 CG	DPN: 59 ± 8      CG: 65 ± 5	∗ TUG ∗ FRT ∗ Muscle strength (planter flexors and dorsi flexors) ∗ Step length ∗ Cadence ∗ Gait speed
Vaz et al., 2013 [70]	62 13 DPN 19 DM 30 NC	DPN: 54.6 ± 5.5 DM: 53.8 ± 7.7 NC: 54.1 ± 5.7	* BBS * TUG ↔ Maximum AP displacement of trunk during FTSST * Time spent to perform the FTSST * Maximum AP displacements of the trunk during the  upright balance (unstable platform eyes closed) ↔ Maximum ML of the trunk during the upright balance
Boucher et al., 1995[72]	29 17 DPN 12 CG	DPN: 62.5 ± 7.4 CG: 60.6 ± 5.6	∗ AP range of sway (mm)  ∗ ML range of sway (mm) ∗ Scalar range of sway (mm) ∗ Sway speed (mm/s) ∗ Dispersion of sway (%) (presence as well as absence of vision)
Chiles et al., 2014[74]	983 126 Diabetes 107 IFG 750 No diabetes	Diabetes: 75.4 ± 7.5 IFG: 74.8 ± 6.8 No diabetes: 74.6 ± 7.4	* Nerve conduction velocity ↔ CMAP * 4.31 Monofilament ↔ 4.56 Monofilament ↔ Vibration sensitivity * Neuropathy score Physical performance test  * SPPB score  * Walk score  * Balance score  * Chair score  * Usual walking speed
Mueller et al., 1994[75]	20 10 DPN 10 CG (age matched)	DPN: 57.7 ± 14.5 CG: 56.8 ± 11.3	* Ankle ROM (gait) * Ankle ROM (goniometer) * Ankle moment ↔ Hip and Knee moment * GRF (AP and ML) * Walking velocity * Stride length * Planter-flexor peak torque ↔ Cadence ↔ Gait cycle time
Katoulis et al., 1997[76]	80 20 NC 20 DM 20 DPN 20 DNU	NC: 50.6 ± 8.6 DC: 47.6 ± 10.7 DN: 52.9 ± 8.8 DNU: 54.1 ± 7.1	DPN Vs NC and DM ∗ Moment arm (meters) at hip joint in frontal plane ∗ Moment (Newton-meter) at ankle joint and hip joint DNU Vs NC and DM ∗ Ankle angle in sagittal plane ∗ Knee angle in sagittal plane ∗ GRF total ∗ GRF vertical ∗ GRF antero-posterior
Ko et al., 2011[78]	186 26 DM 160 NC	DM: 70.00 ± 1.43 NC: 70.45 ± 0.58	↔ Speed ↔ Stride length ↔ Cadence ∗% gait cycle ↔ Stride width
DPN: Diabetic peripheral neuropathy; CG: Control Group; NC: Normal control; DM: Diabetes mellitus; DNU: Diabetic neuropathy with ulceration; IFG:  Impaired fasting glucose; FRT: Forward reach test; TUG: Time up and go test; AP: Antero-posterior; ML: Medio-lateral; FTSST: Five times sit to stand  tests; BBS: Berg balance Scale; GRF: Ground reaction force; CMAP: Compound muscle action potential; SPPB: Short Physical Performance Battery; * :  shows significant difference; ↔: shows no difference

Table 2: Balance training interventions in DPN.

Authors and year	Study design  (Sample size)	Type of exercise	Duration /  frequency	Outcome measures
Akbari et al., 2010[80]	CCT (age matched) 10 IG 10 CG	Progressive Biodex stability and rocker  and wobble-board training	10 session / 2 times  per session	Eyes open  ↑ Over all stability index  ↑ Antero-posterior stability index  ↑ Left-right stability index Eye closed  ↑ Over all stability index  ↑ Antero-posterior stability index
Allet et al., 2010[81]	RCT 35 IG 36 CG	Gait and balance exercises with function  orientated strengthening	12 weeks / twice  weekly	↑ Walking speed ↑ Walk over beam ↑ Biodex sway index ↑ Performance oriented mobility ↑ Ankle plantar flexor strength ↑ Hip flexor strength ↑ Degree of concern about falling
Song et al., 2011[82]	RCT 19 IG 19 CG	Balance exercise program for 60 min.	8 weeks / 2 times per  week	↑ Postural sway (eyes open and eyes  closed) ↑ One leg stance (eyes open, eyes  closed and head rotation) ↑ FRT  ↑ TUG ↑ 10 m walk ↑ BBS score
Salsabili et al., 2013 [83]	QE-TS design 19 IG	Standing balance trainings on Biodex Stability System for 30 min.	10 sessions / 3 times  per week	Eyes open  ↑ Medio-lateral sway ↔ Antero-posterior sway Eyes closed  ↔ Medio-lateral sway ↔ Antero-posterior sway
Richardson et al., 2001 [84]	CCT  10 IG 10 CG	Balance exercises	3 weeks / 5 or more  per week	↑ Unipedal stance ↑ Tandem stance ↑ FRT ↔ ABC Scale
Lee, Lee & Song, 2013 [85]	RCT 19 IG-1 18 IG-2 18 CG	IG-1: Whole body vibration (WBV) for 3  min. + balance exercise (BE) for 60 min. IG-2: Balance exercise for 60 min.	6 weeks / balance  exercise - twice  weekly  WBV - three times  per week	WBV+BE with BE and CG ↑ Postural sway (all conditions) ↑ One leg stance ↑ FRT ↑ TUG ↑ Five times sit to stand ↑ BBS BE with CG ↔ Postural sway ↑ One leg stance ↑ FRT
Kruse et al., 2010[86]	RCT  41 IG 38 CG	Leg strengthening and balance exercises  and a graduated, self-monitored walking  program for 20 min.	3 months / twice per  week	↔ one leg stance ↔ TUG ↔ Rt. Ankle Strength ↔ BBS ↔ FFIDSS ↔ FESS
Raghav et al., 2013 [87]	CCT (two  intervention) 15 IG-1 15 IG-2	IG-1: Focussed balance exercise for 30 min. IG-2: Strengthening exercise 3 set of 10  repetitions	3 weeks / 5 times  per week	IG-1 ↑ Stride length ↑ Cadence ↑ Dynamic gait index
Mueller et al., 2013[88]	RCT (two  intervention) 15 IG-1 14 IG-2	IG-1: Progressive balance, flexibility,  strengthening, and aerobic exercise conducted standing and walking  (WB)  IG-2: Progressive balance, flexibility,  strengthening, and aerobic exercise conducted sitting or lying (NWB)	12 weeks / 3 times  per week	IG-1 ↑ 6MWD ↑ Daily step counts ↑ HBA1C
Morrison et al., 2010 [89]	CCT (age matched) 16 type 2 diabetic  patients 21 CG	Both group: Balance exercise and  resistance strength training	6 weeks / three times  per week	↑ Proprioception ↑ Quadriceps and Hamsting strength ↑ Hand and foot reaction time ↑ Risk of fall
Londhe and Ferzandi,  2012[90]	RCT (two  intervention) 12 IG-1 12 IG-2	IG-1: balance + resistive exercise for 45 to  60 min. IG-2: balance exercise for 45 to 60 min.	8 weeks / 6 days per  week	IG-1 ↑ BBS  ↑ ABC
Abbreviations: CCT: Clinical Control Trial; RCT: Randomised Control Trial; QE-TS: Quasi Experimental - Time Series; IG: Intervention Group; CG:  Control Group; WB: Weight Bearing; NWB: Non-Weight Bearing; FRT: Forward Reach Test; TUG: Time up and Go Test; ABC: Activities Specific  Balance Confidence Scale; BBS: Berg Balance Scale; FFIDSS: Foot Function Index Disability Scale Score; FESS: Falls Efficacy Scale Score 6MWD: Six  Minute Walk Distance; ↑ shows improvement; ↔ Shows No Improvement

 

Balance training is considered to be a very important tool for prevention of falls in older population. It has been shown to produce improvements in different aspects of postural control, balance and gait. Previous researches have studied balance exercises as an intervention in DPN patient and have demonstrated its efficacy when used individually or in combination with other interventions. More specifically, balance training enhanced balance sway index [80-83], with significant improvement in antero-posterior sway index, medio-lateral sway index and overall sway index with eyes open as well as eyes closed condition [80,82]. There was improvement in static balance such as one leg stance [82,84-86], tandem stance [84] as well as in the dynamic balance such as forward reached test [82,84,85], walk over beam [81] and five times sit to stand [85]. A marked progress in the gait parameters such as gait speed [81], stride length [87] and cadence [87] as well as in 10 min walk time [82], 6 min walk distance [88], was also recorded following balance training. Functional and mobility task as a dynamic balance measure like time up and go test or performance oriented mobility also improved post balance training [81,82,85,86]. Balance exercise also helped in decreasing reaction time [89], consequently reducing the risk of falls [81,89]. (Table 2)

Balance training has also shown improvements in balance performance scales like Berg balance Scale (BBS) [82,90] and activities specific balance confidence (ABC) scale [90]. It has been shown that balance exercises when used along with other exercises show better results. Lee, Lee & Song compared two interventions; whole body vibration with balance exercise in experimental group and balance exercises alone in control group [85]. The combination group was found to exhibit significant improvement in balance measures when compared to only balance exercise group. Kruse et al., and Mueller et al., chose a combination of aerobic exercises and strengthening exercises along with progressive balance exercises [86,88]. Mueller and colleagues compared weight bearing group with non-weight bearing group [88] while Kruse and colleagues compared leg strengthening, balance exercise and graduated, self-monitored walking program with control group [86]. Mueller et al., found significant improvement in 6 min walk distance and daily steps count in weight bearing group in comparison to the non-weight bearing group [88] where as Kruse et al., found no significant improvement in the strength and balance measures, which may be accounted to the assessment of measures that were taken 6 month and 12 month following an intervention that was provided for a duration of 3 months (twice/week) [86] (Table 2).

Kruse and colleagues reported no adverse effect of exercises [86] while Mueller and colleagues reported calf pain in one patient [88] and Allet and colleagues reported pain in Achilles tendon in two patients [81]. Other than these, none of the researchers reported adverse events with balance training in DPN population.

Future studies investigating balance exercise training in patients with DPN should present higher levels of evidence. Randomized control trials with an adequate sample size enhance the quality of research. Furthermore, the studies should discuss the precise training protocol with progression of exercise and heterogeneousity in nature; also information regarding duration, intensity and frequency is imperative to assist replication and examine efficacy. Detailed inclusion, exclusion criteria and meaningful outcome measures could also influence the effects. More studies must explore the role of balance training as a preventive measure rather than just a rehabilitative tool.

Current data suggests that balance exercises are feasible and safe, and have the potential to improve balance and gait. Also reduction in the risk of fall and fall-related injuries in DPN patients can be achieved. These exercises can be use in clinical setup if the patient is affected with DPN. Therefore, balance exercises should be used as a supportive therapy along with medication and diet control in DPN patients.

Conception and design of study: Irshad Ahmad, Ejaz Hussain, DeepikaSingla, ShaliniVerma,

Acquisition of data: Irshad Ahmad, Ejaz Hussain

Analysis and interpretation of data: Irshad Ahmad, Ejaz Hussain, Shalini Verma

Drafting of article: Irshad Ahmad, Shalini Verma, Deepika Singhla, Kamran Ali

Critical revision and proof reading: Shalini Verma, Deepika Singla, Kamran Ali

Final Approval of article: Irshad Ahmad, Ejaz Hussain, Deepika Singhla, Shalini Verma

Irshad Ahmad (irshi.ahmad@gmail.com) takes full responsibility for the integrity of the work as a whole, from inception to finished article.

1. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014; 103: 137-149.

2. Ramachandran A, Snehalatha C, Ma RC. Diabetes in South-East Asia: an update. Diabetes Res Clin Pract. 2014; 103: 231-237.

3. Boulton AJ, Gries FA, Jervell JA. Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy. Diabet Med. 1998; 15: 508-514.

4. National Diabetes Fact Sheet. Centers for Disease Control and Prevention. 2010.

5. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes care. 2005 Apr 1; 28: 956-962.

6. Goodman CC, Fuller KS. Pathology: implications for the physical therapist. Elsevier Health Sciences; 2014 Nov 5.

7. Ribu L, Hanestad BR, Moum T, Birkeland K, Rustoen T. A comparison of the health-related quality of life in patients with diabetic foot ulcers, with a diabetes group and a nondiabetes group from the general population. Qual Life Res. 2007; 16: 179-189.

8. Tesfaye S, Stevens LK, Stephenson JM, Fuller JH, Plater M, IonescuTirgoviste C, et al. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study. Diabetologia. 1996; 39: 1377-1384.

9. Davies M, Brophy S, Williams R, Taylor A. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care. 2006; 29: 1518-1522.

10. Katulanda P, Ranasinghe P, Jayawardena R, Constantine GR, Sheriff MR, Matthews DR. The prevalence, patterns and predictors of diabetic peripheral neuropathy in a developing country. Diabetol Metab Syndr. 2012; 4: 21.

11. Pradeepa R, Rema M, Vignesh J, Deepa M, Deepa R, Mohan V. Prevalence and risk factors for diabetic neuropathy in an urban south Indian population: the Chennai Urban Rural Epidemiology Study (CURES-55). Diabet Med. 2008; 25: 407-412.

12. Bansal D, Gudala K, Muthyala H, Esam HP, Nayakallu R, Bhansali A. Prevalence and risk factors of development of peripheral diabetic neuropathy in type 2 diabetes mellitus in a tertiary care setting. J Diabetes Investig. 2014; 5: 714-721.

13. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes care. 2009; 32: 193-203.

14. Ahmad S, Mittal M. Diabetic Neuropathies. JIMSA. 2015; 28: 51-53.

15. Stevens KN, Lang IA, Guralnik JM, Melzer D. Epidemiology of balance and dizziness in a national population: findings from the English Longitudinal Study of Ageing. Age Ageing. 2008; 37: 300-305.

16. Cimbiz A, Cakir O. Evaluation of balance and physical fitness in diabetic neuropathic patients. J Diabetes Complications. 2005; 19: 160-164.

17. Vinik AI, Strotmeyer ES, Nakave AA, Patel CV. Diabetic neuropathy in older adults. Clin Geriatr Med. 2008; 24: 407-435.

18. Lin SI, Chen YR, Liao CF, Chou CW. Association between sensorimotor function and forward reach in patients with diabetes. Gait Posture. 2010; 32: 581-585.

19. Gutierrez EM, Helber MD, Dealva D, Ashton-Miller JA, Richardson JK. Mild diabetic neuropathy affects ankle motor function. Clin Biomech (Bristol, Avon). 2001; 522-528.

20. Richardson JK. Factors associated with falls in older patients with diffuse polyneuropathy. J Am Geriatr Soc. 2002; 50: 1767-1773.

21. Schwartz AV, Hillier TA, Sellmeyer DE, Resnick HE, Gregg E, Ensrud KE, et al. Older women with diabetes have a higher risk of falls: a prospective study. Diabetes Care. 2002; 25: 1749-1754.

22. Gregg EW, Sorlie P, Paulose-Ram R, Gu Q, Eberhardt MS, Wolz M, et al. Prevalence of lower-extremity disease in the US adult population>= 40 years of age with and without diabetes 1999-2000 National Health and Nutrition Examination Survey. Diabetes care. 2004; 27: 1591- 1597.

23. Tilling LM, Darawil K, Britton M. Falls as a complication of diabetes mellitus in older people. J Diabetes Complications. 2006; 20: 158-162.

24. Allet L, Armand S, Golay A, Monnin D, de Bie RA, de Bruin ED. Gait characteristics of diabetic patients: a systematic review. Diabetes Metab Res Rev. 2008; 24: 173-191.

25. Ites KI, Anderson EJ, Cahill ML, Kearney JA, Post EC, Gilchrist LS. Balance interventions for diabetic peripheral neuropathy: a systematic review. J Geriatr Phys Ther. 2011; 34: 109-116.

26. Liu H, Frank A. Tai chi as a balance improvement exercise for older adults: a systematic review. J Geriatr Phys Ther. 2010; 33: 103-109.

27. Streckmann F, Zopf EM, Lehmann HC, May K, Rizza J, Zimmer P, et al. Exercise intervention studies in patients with peripheral neuropathy: a systematic review. Sports Med. 2014; 44: 1289-1304.

28. Thrainsdottir S, Malik RA, Dahlin LB, Wiksell P, Eriksson KF, Rosn I, et al. Endoneurial capillary abnormalities presage deterioration of glucose tolerance and accompany peripheral neuropathy in man. Diabetes. 2003; 52: 2615-2622.

29.Yang Q, Kaji R, Takagi T, Kohara N, Murase N, Yamada Y, et al. Abnormal axonal inward rectifier in streptozocin-induced experimental diabetic neuropathy. Brain. 2001; 124: 1149-1155.

30. Cade WT. Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Phys Ther. 2008; 88: 1322-1335.

31. Cotter MA, Jack AM, Cameron NE. Effects of the protein kinase C Beta Inhibitor LY333531 on Neural and vascular function in rats with streptozotocin-induced diabetes. Clin Sci (Lond). 2002; 8: 311-321.

32. Nakamura J, Kato K, Hamada Y, Nakayama M, Chaya S, Nakashima E, et al. A protein kinase C-beta-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats. Diabetes. 1999; 48: 2090-2095.

33. Vlassara H, Brownlee M, Cerami A. Accumulation of diabetic rat peripheral nerve myelin by macrophages increases with the presence of advanced glycosylation endproducts. J Exp Med. 1984; 160: 197- 207.

34. Dyck PJ, Giannini C. Pathologic alterations in the diabetic neuropathies of humans: a review. J Neuropathol Exp Neurol. 1996; 55: 1181-1193.

35. Ibrahim S, Harris ND, Radatz M, Selmi F, Rajbhandari S, Brady L, et al. A new minimally invasive technique to show nerve ischaemia in diabetic neuropathy. Diabetologia. 1999; 42: 737-742.

36.Young MJ, Veves A, Walker MG, Boulton AJ. Correlations between nerve function and tissue oxygenation in diabetic patients: further clues to the aetiology of diabetic neuropathy?. Diabetologia. 1992; 35: 1146-1150.

37.Malik RA, Tesfaye S, Thompson SD, Veves A, Sharma AK, Boulton AJ, et al. Endoneurial localisation of microvascular damage in human diabetic neuropathy. Diabetologia. 1993; 36: 454-459.

38. Caselli A, Spallone V, Marfia GA, Battista C, Pachatz C, Veves A, et al. Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction. J Neurol Neurosurg Psychiatry. 2006; 77: 927-932.

39. Said G, Slama G, Selva J. Progressive centripetal degeneration of axons in small fibre diabetic polyneuropathy. Brain. 1983; 106: 791-807.

40. Guy RJ, Clark CA, Malcolm PN, Watkins PJ. Evaluation of thermal and vibration sensation in diabetic neuropathy. Diabetologia. 1985; 28: 131-137.

41. Andreassen CS, Jakobsen J, Andersen H. Muscle weakness: a progressive late complication in diabetic distal symmetric polyneuropathy. Diabetes. 2006; 55: 806-812.

42. Horak FB. Clinical measurement of postural control in adults. Phys Ther. 1987; 67: 1881-1885.

43. Shumway-Cook A, Woollacott MH. Motor control: theory and practical applications. Lippincott Williams & Wilkins; 1995.

44. Alexander NB. Postural control in older adults. J Am Geriatr Soc. 1994; 42: 93-108.

45. Pollock AS, Durward BR, Rowe PJ, Paul JP. What is balance? Clin Rehabil. 2000; 14: 402-406.

46. Era P, Schroll M, Ytting H, Gause-Nilsson I, Heikkinen E, Steen B. Postural balance and its sensory-motor correlates in 75-year-old men and women: a cross-national comparative study. J Gerontol A Biol Sci Med Sci. 1996; 51: M53-63.

47. Massion J. Movement, posture and equilibrium: interaction and coordination. Prog Neurobiol. 1992; 38: 35-56.

48. Roll JP, Vedel JP, Roll R. Eye, head and skeletal muscle spindle feedback in the elaboration of body references. Prog Brain Res. 1989; 80: 113- 23; discussion 57-60.

49. Kavounoudias A, Gilhodes JC, Roll R, Roll JP. From balance regulation to body orientation: two goals for muscle proprioceptive information processing? Exp Brain Res. 1999; 124: 80-88.

50. Kavounoudias A, Roll R, Roll JP. The plantar sole is a ‘dynamometric map’ for human balance control. Neuroreport. 1998; 9: 3247-3252.

51. Wang TY, Lin SI. Sensitivity of plantar cutaneous sensation and postural stability. Clin Biomech (Bristol, Avon). 2008; 23: 493-499.

52. Priplata A, Niemi J, Salen M, Harry J, Lipsitz LA, Collins JJ. Noiseenhanced human balance control. Phys Rev Lett. 2002 Dec 2; 89: 238101.

53. Inglis JT, Horak FB, Shupert CL, Jones-Rycewicz C. The importance of somatosensory information in triggering and scaling automatic postural responses in humans. Exp Brain Res. 1994; 101: 159-164.

54. Diener HC, Dichgans J, Bootz F, Bacher M. Early stabilization of human posture after a sudden disturbance: influence of rate and amplitude of displacement. Experimental Brain Research. 1984; 56(1): 126-134.

55. Jáuregui-Renaud K, Kovacsovics B, Vrethem M, Odjvist LM, Ledin T. Dynamic and randomized perturbed posturography in the follow-up of patients with polyneuropathy. Arch Med Res. 1998; 29: 39-44.

56. Amblard B, Crémieux J, Marchand AR, Carblanc A. Lateral orientation and stabilization of human stance: static versus dynamic visual cues. Exp Brain Res. 1985; 61: 21-37..

57. Ivers RQ, Cumming RG, Mitchell P, Attebo K. Visual impairment and falls in older adults: the Blue Mountains Eye Study. J Am Geriatr Soc. 1998; 46: 58-64.

58. Tran TH, Nguyen Van Nuoi D, Baiz H, Baglin G, Leduc JJ, Bulkaen H. [Visual impairment in elderly fallers]. J Fr Ophtalmol. 2011; 34: 723- 728.

59. Pozzo T, Berthoz A, Lefort L. Head stabilization during various locomotor tasks in humans. I. Normal subjects. Exp Brain Res. 1990; 82: 97-106.

60. Pozzo T, Levik Y, Berthoz A. Head and trunk movements in the frontal plane during complex dynamic equilibrium tasks in humans. Exp Brain Res.1995; 106: 327-338.

61. Creath R, Kiemel T, Horak F, Jeka JJ. The role of vestibular and somatosensory systems in intersegmental control of upright stance. J Vestib Res. 2008; 18: 39-49.

62. Massion J. Postural changes accompanying voluntary movements. Normal and pathological aspects. Hum Neurobiol. 1984; 2: 261-267.

63. Hasan Z. The human motor control system’s response to mechanical perturbation: should it, can it and does it ensure stability? J Mot Behav. 2005; 37: 484-493.

64. Horlings CG, Van Engelen BG, Allum JH, Bloem BR. A weak balance: the contribution of muscle weakness to postural instability and falls. Nat Clin Pract Neurol. 2008; 4: 504-515.

65. Lin D, Nussbaum MA, Seol H, Singh NB, Madigan ML, Wojcik LA. Acute effects of localized muscle fatigue on postural control and patterns of recovery during upright stance: influence of fatigue location and age. Eur J Appl Physiol. 2009 ; 106: 425-434.

66. Whipple R, Wolfson L, Derby C, Singh D, Tobin J. Altered Sensory Function and Balance in Older Persons. J Gerontol.. 1993 ; 48: 71-76.

67. Bonnet C, Carello C, Turvey MT. Diabetes and postural stability: review and hypotheses. J Mot Behav. 2009; 41: 172-190.

68. Goldberg A, Russell JW, Alexander NB. Standing Balance and Trunk Position Sense in Impaired Glucose Tolerance (IGT)-Related Peripheral Neuropathy. J Neurol Sci.. 2008 ; 270: 165-171.

69. Camargo MR, Barela JA, Nozabieli AJ, Mantovani AM, Martinelli AR, Fregonesi CE. Balance and ankle muscle strength predict spatiotemporal gait parameters in individuals with diabetic peripheral neuropathy. Diabetes & Metabolic Syndrome: Diabetes Metab Syndr. 2015; 9: 79-84.

70. Vaz MM, Costa GC, Reis JG, Junior WM, de Paula FJ, Abreu DC. Postural control and functional strength in patients with type 2 diabetes mellitus with and without peripheral neuropathy. Arch Phys Med Rehabil. 2013 ; 94: 2465-2470.

71. Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991; 39: 142-148.

72. Boucher P, Teasdale N, Courtemanche R, Bard C, Fleury M. Postural stability in diabetic polyneuropathy. Diabetes Care. 1995; 18: 638- 645.

73. Katoulis EC, Ebdon-Parry M, Hollis S, Harrison AJ, Vileikyte L, Kulkarni J, et al. Postural instability in diabetic neuropathic patients at risk of foot ulceration. Diabet Med. 1997 ; 14: 296-300.

74. Chiles NS, Phillips CL, Volpato S, Bandinelli S, Ferrucci L, Guralnik JM, et al. Diabetes, peripheral neuropathy, and lower-extremity function. J Diabetes Complications. 2014; 28: 91-95.

75. Mueller MJ, Minor SD, Sahrmann SA, Schaaf JA, Strube MJ. Differences in the gait characteristics of patients with diabetes and peripheral neuropathy compared with age-matched controls. Phys Ther. 1994; 74: 299-308; 309-313.

76. Katoulis EC, Ebdon-Parry M, Lanshammar H, Vileikyte L, Kulkarni J, Boulton AJ. Gait abnormalities in diabetic neuropathy. Diabetes Care. 1997; 20: 1904-1907.

77. Wuehr M, Schniepp R, Schlick C, Huth S, Pradhan C, Dieterich M, et al. Sensory loss and walking speed related factors for gait alterations in patients with peripheral neuropathy. Gait Posture. 2014; 39: 852-858.

78. Ko SU, Stenholm S, Chia CW, Simonsick EM, Ferrucci L. Gait pattern alterations in older adults associated with type 2 diabetes in the absence of peripheral neuropathy-results from the Baltimore Longitudinal Study of Aging. Gait Posture.2011; 34: 548-552.

79. Petrofsky J, Lee S, Bweir S. Gait characteristics in people with type 2 diabetes mellitus. Eur J Appl Physiol. 2005; 93: 640-647.

80. Akbari M, Jafari H, Moshashaee A, Forugh B. Do diabetic neuropathy patients benefit from balance training? J Rehabil Res Dev. 2012; 49: 333-338.

81. Allet L, Armand S, de Bie RA, Golay A, Monnin D, Aminian K, et al. The gait and balance of patients with diabetes can be improved: a randomised controlled trial. Diabetologia. 2010; 53: 458-466.

82. Song CH, Petrofsky JS, Lee SW, Lee KJ, Yim JE. Effects of an exercise program on balance and trunk proprioception in older adults with diabetic neuropathies. Diabetes Technol Ther. 2011; 13: 803-811.

83. Salsabili H, Bahrpeyma F, Esteki A, Karimzadeh M, Ghomashchi H. Spectral characteristics of postural sway in diabetic neuropathy patients participating in balance training J Diabetes Metab Disord. 2013; 12: 29.

84. Richardson JK, Sandman D, Vela S. A focused exercise regimen improves clinical measures of balance in patients with peripheral neuropathy. Arch Phys Med Rehabil. 2001; 82: 205-209.

85. Lee K, Lee S, Song C. Whole-body vibration training improves balance, muscle strength and glycosylated hemoglobin in elderly patients with diabetic neuropathy. Tohoku J Exp Med. 2013; 231: 305-314.

86. Kruse RL, LeMaster JW, Madsen RW. Fall and balance outcomes after an intervention to promote leg strength, balance, and walking in people with diabetic peripheral neuropathy: “feet first” randomized controlled trial. Phys Ther. 2010; 90: 1568-15679.

87. Raghav D, Sharma M, Rathore P, Panjee K. Efficacy of schematic exercises over strengthening exercises on walking abilities, stride length and cadence in diabetic neuropathy. Indian journal of physical therapy. 2013; 1.

88. Mueller MJ, Tuttle LJ, LeMaster JW, Strube MJ, McGill JB, Hastings MK, et al. Weight-bearing versus nonweight-bearing exercise for persons with diabetes and peripheral neuropathy: a randomized controlled trial. Arch Phys Med Rehabil. 2013; 94: 829-838.

89. Morrison S, Colberg SR, Parson HK, Vinik AI. Exercise improves gait, reaction time and postural stability in older adults with type 2 diabetes and neuropathy. J Diabetes Complications. 2014; 28: 715-722.

90. Londhe AA, Ferzandi ZD. Comparison of balance and resistive.