Sedentary behaviour is an independent predictor of diabetic foot ulcer development: An 8-year prospective study

Open AccessPublished:May 28, 2021DOI:https://doi.org/10.1016/j.diabres.2021.108877

      Highlights

      • SED-time is a powerful predictor of risk of foot ulcer in people with DPN.
      • DPN patients who are likely to develop a foot ulcer spend at least 12 h of sedentary time.
      • The monitoring of SED-time should be included in the standard care of diabetic patients and strategies aimed at reducing it remain an unmet necessity.

      Abstract

      Aims

      To prospectively explore the association between sedentary time (SED-time) and the development of diabetic foot ulcer (DFU) in people with diabetic peripheral neuropathy (DPN).

      Methods

      175 DPN individuals who attended the annual evaluation for the SAMBA Study (2012–2019) were included. Main outcome measure was the first diagnosis of DFU. SED-time was measured by the PAS 2.1 questionnaire. Nerve function was evaluated by nerve conduction studies. Vascular function was assessed by Ankle-brachial index (ABI) and pedal pulses. Foot deformity and skin dryness were examined by visual inspection.

      Results

      62 participants (35.5%) developed a DFU during the study. SED-time was significantly higher in people who developed DFUs (12.8 ± 3.0 vs 9.4 ± 3.1 h/day). Logistic regression showed that among several nervous (motor amplitude, OR 0.33, 95% CI, 0.18–0.60; sensory amplitude, 0.85, 0.77–0.94) and vascular parameters (ABI, 0.23, 0.1–0.61; pedal pulses, 2.81, 0.12–0.63) and foot characteristics (deformity, 2.63, 1.30–5.32; skin dryness, 2.04, 0.95–4.37), SED-time was one of the strongest variables contributing to the development of DFUs (2.95, 1.45–6.44).

      Conclusions

      SED-time is an independent predictor of the risk of DFU in people with DPN. The monitoring of SED-time with strategies aimed at reducing it should be included in the standard care of diabetic patients.

      Keywords

      Abbreviations:

      ABI (Ankle-brachial index), BP (blood pressure), DFU (diabetic foot ulcer), DPN (diabetic peripheral neuropathy), EMG (electromyography), FG (fasting glucose), FM (fat mass), FFM (fat-free mass), METs (metabolic equivalents), PAD (peripheral artery disease), PMN (peroneal motor nerve), SED-time (sedentary time), SSN (sural sensory nerve), VPT (vibration perception threshold)

      1. Introduction

      Diabetic foot ulcers (DFUs) are among the most devastating complications of diabetes mellitus, affecting around one in four individuals with diabetes during their lifetime [
      • Boulton A.J.
      • Vileikyte L.
      • Ragnarson-Tennvall G.
      • Apelqvist J.
      The global burden of diabetic foot disease.
      ]. The International Diabetes Federation (IDF) has recently reported that between 9.1 and 26.1 million people with diabetes worldwide develop DFUs annually. Foot ulceration and its sequelae are not only responsible for a higher mortality rate but also a marked deterioration of quality of life [
      • Boulton A.J.
      • Vileikyte L.
      • Ragnarson-Tennvall G.
      • Apelqvist J.
      The global burden of diabetic foot disease.
      ,
      • Armstrong D.G.
      • Boulton A.J.M.
      • Bus S.A.
      Diabetic foot ulcers and their recurrence.
      ]. More than half of the people with a DFU will develop an infection [
      • Prompers L.
      • Huijberts M.
      • Apelqvist J.
      • Jude E.
      • Piaggesi A.
      • Bakker K.
      • et al.
      High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study.
      ], with a 40% risk of re-ulceration within a year [
      • Armstrong D.G.
      • Boulton A.J.M.
      • Bus S.A.
      Diabetic foot ulcers and their recurrence.
      ], and ~25% requiring a lower limb amputation [
      • Reiber G.E.
      • Lipsky B.A.
      • Gibbons G.W.
      The burden of diabetic foot ulcers.
      ,
      • Dubský M.
      • Jirkovská A.
      • Bem R.
      • Fejfarová V.
      • Skibová J.
      • Schaper N.C.
      • et al.
      Risk factors for recurrence of diabetic foot ulcers: prospective follow-up analysis in the Eurodiale subgroup.
      ]. In addition, frequent and long-term hospitalisations constitute a huge financial burden for national health systems [
      • Armstrong D.G.
      • Boulton A.J.M.
      • Bus S.A.
      Diabetic foot ulcers and their recurrence.
      ].
      The pathway to developing a DFU includes diabetic peripheral neuropathy (DPN), autonomic neuropathy and peripheral arterial disease (PAD) [
      • Boulton A.J.M.
      The pathway to foot ulceration in diabetes.
      ]. Pain insensitivity, loss of vibratory perception and proprioception, sudomotor dysfunction and impaired blood flow regulation are the main consequences of sensory and autonomic damage. PAD may result in impaired wound healing [
      • Boulton A.J.M.
      The pathway to foot ulceration in diabetes.
      ]. Motor dysfunction causes muscle weakness, limits joint mobility and may predispose individuals to foot deformity, both resulting in high focal areas of foot pressure, one of the main factors contributing to skin breakdown [
      • Orlando G.
      • Balducci S.
      • Bazzucchi I.
      • Pugliese G.
      • Sacchetti M.
      Neuromuscular dysfunction in type 2 diabetes: underlying mechanisms and effect of resistance training.
      ,
      • Reeves N.D.
      • Najafi B.
      • Crews R.T.
      • Bowling F.L.
      Aging and type 2 diabetes: consequences for motor control, musculoskeletal function, and whole-body movement.
      ,
      • Orlando G.
      • Sacchetti M.
      • D’Errico V.
      • Haxhi J.
      • Rapisarda G.
      • Pugliese G.
      • et al.
      Muscle fatigability in patients with type 2 diabetes: relation with long-term complications.
      ].
      Other non-clinical factors such as self-care management and lifestyle behaviours may also be important in the development of DFU [
      • Vileikyte L.
      • Pouwer F.
      • Gonzalez J.S.
      Psychosocial research in the diabetic foot: are we making progress?.
      ]. In recent years, sedentary behaviour has been the object of extensive research in diabetes and other chronic conditions [
      • Healy G.N.
      • Matthews C.E.
      • Dunstan D.W.
      • Winkler E.A.H.
      • Owen N.
      Sedentary time and cardio-metabolic biomarkers in US adults: NHANES 200306.
      ,
      • Wilmot E.G.
      • Edwardson C.L.
      • Achana F.A.
      • Davies M.J.
      • Gorely T.
      • Gray L.J.
      • et al.
      Sedentary time in adults and the association with diabetes, cardiovascular disease and death: systematic review and meta-analysis.
      ,
      • Balducci S.
      • D’Errico V.
      • Haxhi J.
      • Sacchetti M.
      • Orlando G.
      • Cardelli P.
      • et al.
      Effect of a behavioral intervention strategy on sustained change in physical activity and sedentary behavior in patients with type 2 diabetes: the IDES-2 randomized clinical trial.
      ]. These studies have shown that a sedentary lifestyle, independent of physical activity level, significantly increases the risk for type 2 diabetes and cardiovascular complications [
      • Healy G.N.
      • Matthews C.E.
      • Dunstan D.W.
      • Winkler E.A.H.
      • Owen N.
      Sedentary time and cardio-metabolic biomarkers in US adults: NHANES 200306.
      ,
      • Wilmot E.G.
      • Edwardson C.L.
      • Achana F.A.
      • Davies M.J.
      • Gorely T.
      • Gray L.J.
      • et al.
      Sedentary time in adults and the association with diabetes, cardiovascular disease and death: systematic review and meta-analysis.
      ]. There is also evidence that most individuals with type 2 diabetes spend more than nine hours in sedentary behaviour, and that also a small reduction in sedentary time (SED-time) maintained over a prolonged period may translate into significant improvements of cardiometabolic health [
      • Balducci S.
      • D’Errico V.
      • Haxhi J.
      • Sacchetti M.
      • Orlando G.
      • Cardelli P.
      • et al.
      Effect of a behavioral intervention strategy on sustained change in physical activity and sedentary behavior in patients with type 2 diabetes: the IDES-2 randomized clinical trial.
      ]. At present, there is a paucity of data describing sedentary behaviour in people suffering from DPN, with no studies focused on individuals at high risk of DFUs. In addition, SED-time is associated with marked cardiometabolic alterations [
      • Healy G.N.
      • Matthews C.E.
      • Dunstan D.W.
      • Winkler E.A.H.
      • Owen N.
      Sedentary time and cardio-metabolic biomarkers in US adults: NHANES 200306.
      ] and a chronic reduction of physical stress to the foot, which may lead to a deconditioning of plantar skin tissue [
      • Crews R.T.
      • Schneider K.L.
      • Yalla S.V.
      • Reeves N.D.
      • Vileikyte L.
      Physiological and psychological challenges of increasing physical activity and exercise in patients at risk of diabetic foot ulcers: a critical review.
      ]; thus there is need to investigate the impact of SED-time on the development of DFU.
      Therefore, this study sought to evaluate SED-time prospectively in a large cohort of individuals with moderate to severe DPN and to explore the association, if any, between SED-time and the development of DFUs. We hypothesise that people with diabetes who develop DFUs are more sedentary and less physically active than individuals who do not develop DFU, and that SED-time could be one of the independent predictors of foot ulceration in DPN.

      2. Methods

      2.1 Study population

      561 Caucasian individuals with diabetes – 479 with type 2 diabetes (age 48.6 ± 13.5 years) and 82 with type 1 diabetes (age 68.6 ± 10.9 years) – attending the yearly follow-up visit for the Study on the Assessment of determinants of Muscle and Bone strength Abnormalities in diabetes (the SAMBA Study, NCT01600924) between 2012 and 2019, were included in this prospective analysis [
      • Balducci S.
      • Sacchetti M.
      • Orlando G.
      • Salvi L.
      • Pugliese L.
      • Salerno G.
      • et al.
      Correlates of muscle strength in diabetes. The study on the assessment of determinants ofmuscle and bone strength abnormalities indiabetes (SAMBA).
      ]. The SAMBA is an ongoing Italian prospective cohort study aimed at assessing the correlates of muscle and bone strength in individuals with diabetes through the analysis of a wide range of measurements of vascular and nerve function.
      From the original cohort of 561 subjects, a subgroup of 193 participants with diabetes aged 40–80 years and with a moderate to severe DPN based on vibratory perception threshold (VPT) values >25 V at the malleoli and halluces, were included (Fig. 1) [
      • Boulton A.J.M.
      The pathway to foot ulceration in diabetes.
      ]. Participants were excluded if they had a history of DFUs or amputation at the time of the baseline screening. Among 193 participants, 15 withdrew from the study, 3 died and 175 completed the study (Fig. 1). The study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments, and the Ethics Committee of Sant’Andrea Hospital, Rome, approved the protocol. All participants gave written informed consent.

      2.2 Experimental procedures and measurement time-points

      Demographic, clinical and laboratory parameters and lifestyle habits were recorded using a standardised protocol published by our group [
      • Balducci S.
      • Sacchetti M.
      • Orlando G.
      • Salvi L.
      • Pugliese L.
      • Salerno G.
      • et al.
      Correlates of muscle strength in diabetes. The study on the assessment of determinants ofmuscle and bone strength abnormalities indiabetes (SAMBA).
      ]. As reported in Fig. 1, a structured interview and a comprehensive clinical evaluation encompassing a wide range of traditional cardiovascular risk factors, surrogate measures of vascular and nerve function and foot examination were carried one year apart. Evaluations for the entire cohort were evenly distributed throughout the year.
      For the current analysis, haemoglobin A1c (HbA1c), fasting glucose (FG), lipid profile, SED-Time and physical activity parameters corresponded to an overall mean of the follow-up measurements (Fig. 1). Nervous, vascular and foot measurements are referred to the year preceding the development of ulcers in the DFU group, whereas for the group without DFU the measurements corresponded to the final follow-up visit (Fig. 1).
      Diagnosis and treatment strategy of DFU were conducted by the appropriate clinical professionals including a diabetologist, podiatrist and neurologist during a clinical visit. The diagnosis of the first ulcer was the primary outcome measure of the study. A DFU was defined as a full-thickness loss of epidermis and dermis or involvement of deeper structures, to at least Texas classification stage 1, on the weight-bearing surface of the foot [
      • Oyibo S.
      • Jude E.
      • Tarawneh I.
      • Nguyen H.
      • Harkless L.
      • Boulton A.J.
      Comparison of two diabetic foot ulcer classification systems.
      ].

      2.3 Physical activity and sedentary time

      Physical activity level and SED-time over the previous seven days were assessed during the annual follow-up visit using the Physical Activity Scale (PAS 2.1) [
      • Andersen L.G.
      • Groenvold M.
      • Jørgensen T.
      • Aadahl M.
      Construct validity of a revised Physical Activity Scale and testing by cognitive interviewing.
      ]. This questionnaire measures daily physical activity in hours and minutes of sleep, sitting, standing or walking, and heavy physical work, going to and from work, and TV-viewing/reading. In addition, it measures weekly activity in hours and minutes of light, moderately strenuous, and strenuous activity. Each of these domains corresponds to a specific level of the Metabolic Equivalent (MET)-intensity according to The Compendium of Physical Activity [
      • Ainsworth B.E.
      • Haskell W.L.
      • Whitt M.C.
      • Irwin M.L.
      • Swartz A.M.
      • Strath S.J.
      • et al.
      Compendium of physical activities: an update of activity codes and MET intensities.
      ]. Daily MET-time was multiplied by 5 (to and from work) or 7 (sleep and TV). The questionnaire was translated (English to Italian) and completed by the researcher according to the participants’ answers. Participants were defined as physically active when they performed the recommended amount of exercise (150 min per week) [
      • Colberg S.R.
      • Sigal R.J.
      • Yardley J.E.
      • Riddell M.C.
      • Dunstan D.W.
      • Dempsey P.C.
      • et al.
      Physical activity/exercise and diabetes: a position statement of the American Diabetes Association.
      ] and inactive when they did not reach 150 min of exercise per week. Sedentary behaviour was defined as >8 h/day spent in any behaviour characterised by an energy expenditure ≤1.5 METs while sitting, reclining, or lying down postures [
      • Balducci S.
      • D’Errico V.
      • Haxhi J.
      • Sacchetti M.
      • Orlando G.
      • Cardelli P.
      • et al.
      Effect of a behavioral intervention strategy on sustained change in physical activity and sedentary behavior in patients with type 2 diabetes: the IDES-2 randomized clinical trial.
      ,
      • Matthews C.E.
      • Chen K.Y.
      • Freedson P.S.
      • Buchowski M.S.
      • Beech B.M.
      • Pate R.R.
      • et al.
      Amount of time spent in sedentary behaviors in the United States, 2003–2004.
      ].
      From 2016 we had the option of using accelerometers (MyWellnessKey, Technogym, Gambettola, IT) [
      • Sieverdes J.C.
      • Wickel E.E.
      • Hand G.A.
      • Bergamin M.
      • Moran R.R.
      • Blair S.N.
      Reliability and validity of the Mywellness Key physical activity monitor.
      ] to validate questionnaire assessment of SED-time. This was performed for a period of four years (2016–2019) and showed very good agreement between questionnaire and objective measurement for sedentary behaviour (10.6 ± 3.53 vs 11.3 ± 4.92 h/day, p = 0.127).

      2.4 Assessment of modifiable cardiovascular risk factors

      Body mass and height were measured, and BMI calculated. Waist circumference was measured at the umbilicus, and fat mass (FM, %) and free-fat mass (FFM, kg) were assessed by bioelectrical impedance (Tanita BF664, Vernon Hills, IL, USA). Blood pressure (BP) was measured with a sphygmomanometer with the participant seated with the arm at the heart level. HbA1c was assessed by a DCCT aligned high performance liquid chromatography method (Adams TMA1C HA‐8160, Menarini Diagnostics, Florence, Italy). FG, triglycerides, total, and HDL cholesterol were measured by standard analytical methods using the VITROS 5,1 FS Chemistry System (Ortho‐ClinicalDiagnostics, Inc, Raritan, NJ, USA), whereas LDL cholesterol was calculated by the Friedewald formula.

      2.5 Neurological and vascular evaluation

      Neurological evalution was performed by an experienced neurologist and the same procedure was replicated during the follow-up visit. Ths included the bilateral assessment of conduction velocities and amplitudes of the peroneal motor nerve (PMN) and sural sensory nerve (SSN) through electromyography (EMG) (Medelec MS 928 Neurostar, Oxford Instruments, Oxford, UK). Furthermore, VPT was measured using a biothesiometer (Horwell, Nottingham, UK) at the lateral malleoli and halluces of both feet. The average of the nerve conduction parameters and VPT measurements taken on both sides were included in the analysis.
      Ankle-brachial index (ABI) was assessed by colour coded duplex sonography (Agilent HP Image Point HX, Hewlett Packard, Rome, Italy) and a mercury sphygmomanometer plus a handheld continuous wave Doppler device (Super Doppler 2, HuntleightHealth care, Lewis Center, OH, US), respectively. Finally, skin dryness and deformity (i.e. presence of hammer and/or claw toes; prominent metatarsal heads; and high medial arch) and pedal pulse of both feet were examined by visual inspection and palpation, respectively. The measurements were conducted by a podiatrist and recorded as a dichotomous variable (present or absent).

      2.6 Statistical analysis

      Data are expressed as the mean ± SD for parametric variables, median and interquartile range (IQR) for non-parametric data, and percentages for categorical variables. All parameters were tested for normal distribution by visual inspection and using the Kolmogorov-Smirnov test. The relationship between history of ulcers and subject characteristics were assessed using analysis of variance (ANOVA) for parametric variables, or the corresponding Mann-Whitney U for non-parametric continuous variables, and the χ2 test for categorical variables. Binary logistic regression was performed to identify predictors of foot ulceration among a wide range of surrogate measures of nervous and vascular dysfunction, qualitative measures of feet status and lifestyle behaviour. Calculation of the sample size required was not possible due to the fact that the sample proceeds from the SAMBA study.
      As seen in Table 2, we defined seven bespoke regression models, each controlling appropriate covariates according to current literature and univariate associations between variables. This is increasingly recognised as a more appropriate approach than including all the variables in a single model and interpreting each covariate coefficient as if it was the sole independent variable of interest [
      • Westreich D.
      • Greenland S.
      The table 2 fallacy: presenting and interpreting confounder and modifier coefficients.
      ]. The following variables were examined: Model 1, SED-time (covariates: HbA1c, Pedal pulses, SSN amplitude, physical activity; Model 2, pedal pulses (covariates: age, diabetes duration, HbA1c, physical activity); Model 3, deformity (covariates: BMI, diabetes duration, SSN amplitude, PMN amplitude); Model 4, skin dryness (covariates: age, diabetes duration, HbA1c deformity); Model 5, PMN amplitude (covariates: age, diabetes duration, HbA1c, physical activity); Model 6, SSN amplitude (covariates: age, diabetes duration, HbA1c, physical activity) and Model 7, ABI (covariates: age, diabetes duration, HbA1c, physical activity). In the Model 1, physical activity was categorized in two levels: 1) physical active (150 min per week) and 2) physical inactive. In the Model 2, 5–7, physical activity was considered in four levels: 1) sedentary and physical inactive; 2) no sedentary and physical inactive; 3) sedentary and physical active and 4) no sedentary and physical active.

      3. Results

      The clinical characteristics of the participants who completed the study are shown in Table 1. One-hundred and seventy-five DPN participants (102 males and 73 females), of whom 165 with type 2 diabetes and 10 with type 1 diabetes completed the study (Fig. 1). Participants had a mean age of 72.6 ± 9.5 years and a diabetes duration of 21.6 ± 9.1 years. During the follow-up visits, of the 175 participants, 62 (57 type 2 diabetes and 5 type 1 diabetes) developed a DFU, whereas 113 (108 type 2 diabetes and 5 type 1 diabetes) participants did not develop any foot ulcers. The overall ulceration incidence were 35.5%. The annual distribution of ulcerations was 4 (6.5%) during the first year, 12 (19.4%) during the second year, 10 (16.1%) during the third year, 8 (12%) during the fourth year, 12 (19.4%) during the fifth year, 6 (9.7%) during the sixth year and 10 (16.1%) during the seventh year. Fourty-two ulcers occurred on the right foot (19 toe ulcers, 7 heel ulcers, and 16 ulcers under the metatarsal heads) and 22 on the left foot (8 toe ulcers, 6 heel ulcers, and 8 ulcers under metatarsal heads). Finally, there were 10 cases requiring amputation, 9 minor and 1 below the knee, giving an overall amputation incidence of 5.71% or an average annual amputation incidence of 0.71%. Therapeutic footwears were prescribed for 64 participants (36.6%), of which 33.9% (n = 21) for the group developed a DFU and 38.1% (n = 43) for the no DFU group (P = 0.097).
      Table 1Demographic and clinical characteristics of the study participants who completed the study.
      VariablesAllDFUNo DFUp values
      Number of cases17562113
      Gender m/f (n)102/7336/2666/47
      Age (years)72.6 ± 9.569.1 ± 9.774.6 ± 9<0.0001
      Diabetes duration (years)21.6 ± 9.122.1 ± 9.821.4 ± 8.80.585
      BMI (kg/m2)30.2 ± 630.4 ± 6.330.1 ± 5.90.633
      Fat mass (%)29.3 ± 10.529.3 ± 10.429.3 ± 10.60.880
      Fat free mass (kg)58.4 ± 11.957.9 ± 1358.7 ± 11.30.689
      Waist circumference (cm)106.2 ± 14.3104.8 ± 15.1107.1 ± 13.90.311
      HbA1c (mmol/mol)61 ± 1565 ± 1859 ± 130.013
      (%)7.7 ± 1.38.1 ± 1.67.5 ± 1.2
      FG (mg/dl)141.2 ± 60172 ± 68.7124.4 ± 47.1<0.0001
      Total cholesterol (mg/dl)177.7 ± 45.6181.5 ± 49.3175.7 ± 43.60.510
      Triglycerides, (mg/dl)150.7 ± 75.1176.6 ± 84.8136.5 ± 65.40.001
      HDL cholesterol (mg/dl)46.8 ± 12.144.8 ± 1448 ± 10.90.010
      LDL cholesterol (mg/dl)103 ± 40.9106.1 ± 43.9101.4 ± 39.30.517
      Systolic BP (mmHg)139.2 ± 20.2140 ± 20139 ± 200.558
      Diastolic BP (mmHg)74.7 ± 11.378 ± 1373 ± 100.002
      Ankle-brachial index (ABI)0.85 ± 0.160.78 ± 0.140.90 ± 0.16<0.0001
      PMN conduction velocity (m/s)40.8 ± 6.238.2 ± 6.442.4 ± 5.8<0.0001
      PMN amplitude (mV)1.7 ± 1.071.1 ± 0.52.0 ± 1.1<0.0001
      SSN conduction velocity (m/s)29.2 ± 13.522.9 ± 11.832.7 ± 13.2<0.0001
      SSN amplitude (µV)5.6 ± 4.63.3 ± 3.86.9 ± 4.5<0.0001
      VPT malleolus (V)39.6 ± 943.2 ± 8.837.7 ± 8.6<0.0001
      VPT hallux (V)38 ± 8.641.4 ± 8.436.3 ± 8.3<0.0001
      Foot status n (%)
      Deformity0.001
      present5827 (23.9)31 (50)
      absent11786 (76.1)31 (50)
      Skin dryness0.032
      present5631 (27.7)25 (40.3)
      absent11881 (72.3)37 (59.7)
      Pedal pulses<0.001
      present9675 (66.4)21 (33.9)
      absent7938 (33.6)41 (66.1)
      Physical activity
      Sedentary lifestyle n (%)105 (60)50 (80)55(49)0.028
      SED-time (h/day)10.6 ± 3.512.8 ± 3.09.4 ± 3.10.004
      SED-INA n (%)86 (49.1)50 (80.6)36 (31.9)<0.001
      NOSED-INA n (%)49 (28)11 (17.7)38 (33.6)0.012
      SED-ACT n (%)19 (10.9)019 (16.8)<0.001
      NOSED-ACT n (%)21 (12)1 (1.7)20 (17.7)<0.001
      Abbreviations: ACT = physically active; BMI = body mass index; BP = blood pressure; DFU = diabetic foot ulcer; FG = fasting glucose; INA = physically inactive; PMN = peroneal motor nerve; SED-time = sedentary time; SED = sedentary; NOSED = no sedentary; SSN = sural sensory nerve; VPT = vibration perception threshold.
      Table 2Multiple logistic regression analysis of clinical and non-clinical factors associated with the development of DFU.
      History of DFUOR95% CIp values
      Model 1
      SED-time2.951.45, 6.440.008
      Model 2
      Pedal pulses (absent)2.810.12, 0.630.002
      Model 3
      Deformity (present)2.631.30, 5.320.007
      Model 4
      Skin dryness (present)2.040.95, 4.370.037
      Model 5
      PMN amplitude0.330.18, 0.60<0.001
      Model 6
      SSN amplitude0.850.77, 0.940.002
      Model 7
      Ankle-brachial index (ABI)0.230.1, 0.610.001
      Model 1, covariates: HbA1c, pedal pulses, SSN amplitude, physical activity; Model 2, covariates: age; diabetes duration, HbA1c, physical activity; Model 3, covariates: BMI, diabetes duration, SSN amplitude, PMN amplitude; Model 4, covariates: age, diabetes duration, HbA1c deformity; Models 5 to 7, covariates: age, diabetes duration, HbA1c, physical activity.
      DFU participants were younger (69.1 ± 9.7 vs 74.6 ± 9 years, P = <0.0001), more sedentary (12.8 ± 3.0 vs 9.4 ± 3.1 h/day, P = 0.004; 80% vs 49%, P = 0.028), less physically active (1.7% vs 34.5% P = 0.001) and exhibited a worse glycaemic control (HbA1c 65 ± 18 vs 59 ± 13 mmol/mol, P = 0.013; FG 172 ± 68.7 vs 124.4 ± 47.1 mg/dl, P = <0.0001) than those without DFU (Table 1). There were significant differences among groups for the ABI and the presence of foot deformities, skin dryness and pedal pulses (Table 1). Participants with DFU also had a higher VPT at the malleoli (43.2 ± 8.8 vs 37.7 ± 8.6 Volts, P = <0.0001) and halluces (41.4 ± 8.4 vs 36.3 ± 8.3 Volts, P = <0.0001) and lower PMN conduction velocity (38.2 ± 6.4 vs 42.4 ± 5.8 m/s, P = <0.0001) and amplitude (1.1 ± 0.5 vs 2.0 ± 1.1 mV, P = <0.0001), SSN conduction velocity (22.9 ± 11.8 vs 32.7 ± 13.2 m/s, P = <0.0001) and amplitude (3.3 ± 3.8 vs 6.9 ± 4.5 µV, P = <0.0001) (Table 1). Groups were similar with respect to diabetes duration, BMI, FM, FFM, waist circumference, total and LDL cholesterol and systolic BP (Table 1).
      Seven logistic regression models (Table 2) were used to identify predictors of foot ulceration. Each model was established and controlled for appropriate covariates according to current literature and univariate associations between variables. SED-time (Model 1) was one of the strongest variables contributing to the development of DFUs, associated with an odds ratio of 2.95 (95% CI: 1.45–6.44). Non-palpable pedal pulses (Model 2) were associated with an odds ratio of 2.81 (95% CI: 0.12–0.63). The presence of deformity (Model 3) and skin dryness (Model 4) had an odds ratio of 2.63 (95% CI: 1.30–5.93) and 2.04 (95% CI: 0.95–4.37), respectively. A negative odds ratio of 0.23 (95% CI: 0.1–0.61), 0.33 (95% CI: 0.18–0.60), and 0.85 (SSN amplitude, 95% CI: 0.77–0.94) were found for ABI (Model 7), PMN (Model 5) and SSN amplitudes (Model 6), respectively.

      4. Discussion

      The most important result indicates that SED-time is an independent predictor of foot ulceration in people with diabetes and DPN. Accurate identification of patients with DPN who are at risk of DFU is of paramount importance for establishing effective preventive care measures. We aimed to explore prospectively several factors that could predispose patients with DPN to the development of DFUs, and in particular to investigate the relationship between sedentary behaviour measure (SED-time), and the development of DFUs. These data point to the determinant role of sedentary behaviour on the development of DFUs and they highlight the importance of monitoring and reducing SED-time during standard care in patients with diabetes.
      It is widely recognised that sedentary behaviour is associated with a greater risk of type 2 diabetes, metabolic syndrome, cardiovascular diseases and all-cause mortality [
      • Dempsey P.C.
      • Owen N.
      • Biddle S.J.H.
      • Dunstan D.W.
      Managing sedentary behavior to reduce the risk of diabetes and cardiovascular disease.
      ,
      • Tremblay M.S.
      • Colley R.C.
      • Saunders T.J.
      • Healy G.N.
      • Owen N.
      Physiological and health implications of a sedentary lifestyle.
      ]. Our findings show for the first time that prolonged SED-time predisposes people with DPN to an approximately three-fold higher odds of developing DFUs. SED-time is therefore an independent and powerful predictor of DFUs in people with DPN. We also confirm the current knowledge regarding the main clinical factors predisposing patients to DFU and found associations between DFU and several surrogate measures of sensory and motor denervation and foot perfusion, as well as the presence of foot deformities and skin abnormalities. These findings support our original hypothesis that sedentary behaviour may contribute together to DPN, PAD and the foot characteristics to the pathogenesis of DFU.
      Our analysis also shows that people who develop DFUs spend more than twelve hours in sedentary behaviour during the day, whereas those who spend up to nine hours sedentary rarely develop DFUs. These results for people without DFUs are in line with recent cross-sectional and longitudinal studies, which reported that approximately nine hours each day were spent in sedentary behaviour in a large population of type 2 diabetes patients [
      • Balducci S.
      • D’Errico V.
      • Haxhi J.
      • Sacchetti M.
      • Orlando G.
      • Cardelli P.
      • et al.
      Effect of a behavioral intervention strategy on sustained change in physical activity and sedentary behavior in patients with type 2 diabetes: the IDES-2 randomized clinical trial.
      ,
      • Maluf K.S.
      • Mueller M.J.
      Comparison of physical activity and cumulative plantar tissue stress among subjects with and without diabetes mellitus and a history of recurrent plantar ulcers.
      ]. Our data on physical activity also confirm current knowledge regarding people with DPN who develop DFUs since we found that more than 95% of participants did not reach the recommended daily amount of physical activity [
      • Maluf K.S.
      • Mueller M.J.
      Comparison of physical activity and cumulative plantar tissue stress among subjects with and without diabetes mellitus and a history of recurrent plantar ulcers.
      ,
      • Armstrong
      • et al.
      Variability in activity may precede.
      ]. Taken together, current and previous findings indicate that not only physical inactivity but also sedentary lifestyle is typical in individuals with DPN. We also propose that it is more important to look at the amount of time spent in sedentary activities, as our data show that mostly prolonged SED-time predisposes people with DPN to develop DFUs.
      Although factors explaining the relationship between SED-time and the incidence of DFUs, are not completely clear, it is generally recognised that sedentary behaviour may induce a multitude of deleterious effects [
      • Tremblay M.S.
      • Colley R.C.
      • Saunders T.J.
      • Healy G.N.
      • Owen N.
      Physiological and health implications of a sedentary lifestyle.
      ]. It has been shown that SED-time is associated with marked deterioration of cardiometabolic health, and impairment of the functions of the cardiovascular and neuromuscular systems, associated with morphological muscle abnormalities [
      • Tremblay M.S.
      • Colley R.C.
      • Saunders T.J.
      • Healy G.N.
      • Owen N.
      Physiological and health implications of a sedentary lifestyle.
      ]. These defects may occur synergistically with nervous system and vascular damage to exacerbate the clinical condition of DPN and to worsen physical function and mobility.
      Sedentary lifestyle may have an impact on foot health because of the dramatic decrease in physical stress on skin tissue of the feet due to the sharp decrease of weight-bearing activities. This ‘physical stress theory’ proposed by Mueller and Maluf [
      • Mueller M.J.
      • Maluf K.S.
      Tissue adaptation to physical stress: a proposed “Physical Stress Theory” to guide physical therapist practice, education, and research.
      ], is that prolonged levels of low physical stress decrease the tolerance of the skin tissues. It is therefore likely that prolonged reduction of physical stress on the feet resulting from a sedentary lifestyle, could lead to a deconditioning of plantar skin tissue which may decrease the capacity of the skin to tolerate stress. As a consequence, prolonged SED-time may predispose patients to high susceptibility to skin injuries to the feet on occasions when weight-bearing physical activity does occur [
      • Armstrong
      • et al.
      Variability in activity may precede.
      ]. There is a paucity of information regarding the adaptability of skin tissue to physical stress, and no studies have investigated the chronic effects of the lack of weight-bearing activities on neuropathic skin tissue in humans. Only one experimental study explored structural changes of skin after specific physical stresses where an increase in the diameter of collagen fibres and hyperplasia of the epithelium were reported in animal models during six weeks of compressive and shear stresses. It has been proposed that chronic physical stress induces structural changes in foot skin [
      • Sanders J.E.
      • Goldstein B.S.
      Collagen fibril diameters increase and fibril densities decrease in skin subjected to repetitive compressive and shear stresses.
      ]. Although these results are promising, new investigations are required to elucidate the effects of sedentary behaviour and weight-bearing activities on the structure and function of foot skin.
      It has been shown that exercise training is a safe and effective tool that can prevent or treat DPN [
      • Balducci S.
      • Iacobellis G.
      • Parisi L.
      • Di Biase N.
      • Calandriello E.
      • Leonetti F.
      • et al.
      Exercise training can modify the natural history of diabetic peripheral neuropathy.
      ]. This is because exercise offers multiple beneficial effects in the metabolic, vascular, muscular and nervous systems [
      • Zanuso S.
      • Sacchetti M.
      • Sundberg C.J.
      • Orlando G.
      • Benvenuti P.
      • Balducci S.
      Exercise in type 2 diabetes: Genetic, metabolic and neuromuscular adaptations. A review of the evidence.
      ,
      • Matos M.
      • Mendes R.
      • Silva A.B.
      • Sousa N.
      Physical activity and exercise on diabetic foot related outcomes: a systematic review.
      ]. Weight-bearing exercise has also been shown to reduce by up to 80% the risk of re-ulceration [
      • LeMaster J.W.
      • Mueller M.J.
      • Reiber G.E.
      • Mehr D.R.
      • Madsen R.W.
      • Conn V.S.
      Effect of weight-bearing activity on foot ulcer incidence in people with diabetic peripheral neuropathy: feet first randomized controlled trial.
      ]. Current guidelines of the International Working Group on the Diabetic Foot (IWGDF) on physical activity recommend that people with at low or moderate risk of DFU should progressively increase the level of walking-related weight-bearing daily activity up to 1000 steps/day [
      • Bus S.A.
      • Armstrong D.G.
      • Gooday C.
      • Jarl G.
      • Caravaggi C.F.
      • Viswanathan V.
      • et al.
      IWGDF guideline on offloading foot ulcers in persons with diabetes.
      ]. In addition, the joint position statement of the American College of Sports Medicine (ACSM) and the American Diabetes Association (ADA) recommends that individuals with diabetes perform at least 150 min/week of moderate to vigorous aerobic exercise, plus moderate to vigorous resistance training at least 2–3 days/week [
      • Colberg S.R.
      • Sigal R.J.
      • Yardley J.E.
      • Riddell M.C.
      • Dunstan D.W.
      • Dempsey P.C.
      • et al.
      Physical activity/exercise and diabetes: a position statement of the American Diabetes Association.
      ]. It is important to note, however, that adherence to intervention programmes and attainment of exercise recommendations generally pose challenges to patients with diabetes and particularly to those with DPN because many of them have multiple comorbidities. A number of studies have explored the long-term effects of interruption of prolonged SED-time with different types of physical activity on metabolic control in different populations [
      • Benatti F.B.
      • Ried-Larsen M.
      The effects of breaking up prolonged sitting time: a review of experimental studies.
      ]. It has been shown that breaking up long periods of SED-time with light-intensity activities (e.g. walking) is associated with improvements in glycaemic control, insulin levels, lipid metabolism and blood viscosity, and it results in a significant reduction of cardiometabolic risk and a decrease in all-cause mortality risk [
      • Dempsey P.C.
      • Owen N.
      • Biddle S.J.H.
      • Dunstan D.W.
      Managing sedentary behavior to reduce the risk of diabetes and cardiovascular disease.
      ,
      • Benatti F.B.
      • Ried-Larsen M.
      The effects of breaking up prolonged sitting time: a review of experimental studies.
      ]. A recent clinical trial by the Italian Diabetes and Exercise Study 2 (IDES-2), has investigated the effectiveness of a behaviour intervention reduction in SED-time and the promotion of physical activity in a large cohort of type 2 diabetes patients [
      • Balducci S.
      • D’Errico V.
      • Haxhi J.
      • Sacchetti M.
      • Orlando G.
      • Cardelli P.
      • et al.
      Effect of a behavioral intervention strategy on sustained change in physical activity and sedentary behavior in patients with type 2 diabetes: the IDES-2 randomized clinical trial.
      ]. This intervention increased the amount of physical activity undertaken by type 2 diabetes patients in which they reallocated SED-time to light-intensity physical activities and, to a lesser extent, to other intensities of activity. These changes resulted in a significant decrease in cardiovascular risk factors and an improvement in cardiorespiratory functions and musculoskeletal health. Although more research is required, our and previous studies suggest that strategies that are aimed at the reallocation of SED-time to light-intensity activities could be a useful and suitable tool for the improvement of cardiometabolic health and, potentially, could decrease the risk of development of DFUs in people with DPN.
      This study presents strengths and limitations. Its main strengths include the detailed clinical characterisation of the participants and the long duration of the analysis (2012–2019). Limitations include the inclusion of a maximum of four covariates into regression models because of statistical limitations due to sample size and the use of non-objective measure for the quantification of SED-time. However, to validate the physical activity data obtained from questionnaires, in year 2016–2019 of the study, we used accelerometers to track physical activity across the patient cohort. This showed good agreement between the two measures, providing confidence in the questinonnaire data.
      In conclusion, this prospective study shows that sedentary behaviour is an independent, previously not considered, predictor of risk of foot ulceration in patients with DPN. The amount of time spent in sedentary behaviour is a powerful predictor of the risk of DFUs in people with DPN. Further research is needed to fully understand the effects of sedentary behaviour on the structure and function of foot skin tissue. There is an unmet need to achieve durable lifestyle changes in this group of patients so physical activity counselling in clinical practice could play an important role in achieving sustained behaviour change.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      The authors thank Calvin Heal (Centre for Biostatistics, University of Manchester) for his assistance on the statistical analysis. GO and SB are responsible for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

      Funding

      This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

      Author contributions

      GO and SB: concept and design, collection and interpretation of data and preparation of manuscript. NR and AB: concept and design, interpretation of data and critical revision of the manuscript. JA, GF and AF: collection of data and critical revision of the manuscript. GP and AI: critical revision of the manuscript. All authors have given final approval of the version to be published.

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