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Declining Skeletal Muscle Function in Diabetic Peripheral Neuropathy

  • Prodromos Parasoglou
    Correspondence
    Address correspondence to: Prodromos Parasoglou, PhD, Bernard and Irene Schwartz Center for Biomedical Imaging, New York University Langone Medical Center, 660 First Avenue, 2nd Floor, Room 204, New York, NY 10016.
    Affiliations
    Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, New York

    Center for Advanced Imaging Innovation and Research (CAI2R), Department of Radiology, New York University School of Medicine, New York, New York
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  • Smita Rao
    Affiliations
    Department of Physical Therapy, New York University, New York, New York
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  • Jill M. Slade
    Affiliations
    Department of Radiology, Michigan State University, East Lansing, Michigan

    Biomedical Imaging Research Center, Michigan State University, East Lansing, Michigan
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      Abstract

      Purpose

      The present review highlights current concepts regarding the effects of diabetic peripheral neuropathy (DPN) in skeletal muscle. It discusses the lack of effective pharmacologic treatments and the role of physical exercise intervention in limb protection and symptom reversal. It also highlights the importance of magnetic resonance imaging (MRI) techniques in providing a mechanistic understanding of the disease and helping develop targeted treatments.

      Methods

      This review provides a comprehensive reporting on the effects of DPN in the skeletal muscle of patients with diabetes. It also provides an update on the most recent trials of exercise intervention targeting DPN pathology. Lastly, we report on emerging MRI techniques that have shown promise in providing a mechanistic understanding of DPN and can help improve the design and implementation of clinical trials in the future.

      Findings

      Impairments in lower limb muscles reduce functional capacity and contribute to altered gait, increased fall risk, and impaired balance in patients with DPN. This finding is an important concern for patients with DPN because their falls are likely to be injurious and lead to bone fractures, poorly healing wounds, and chronic infections that may require amputation. Preliminary studies have shown that moderate-intensity exercise programs are well tolerated by patients with DPN. They can improve their cardiorespiratory function and partially reverse some of the symptoms of DPN. MRI has the potential to bring new mechanistic insights into the effects of DPN as well as to objectively measure small changes in DPN pathology as a result of intervention.

      Implications

      Noninvasive exercise intervention is particularly valuable in DPN because of its safety, low cost, and potential to augment pharmacologic interventions. As we gain a better mechanistic understanding of the disease, more targeted and effective interventions can be designed.

      Key words

      Introduction

      Diabetes mellitus (DM) affects 26 million people in the United States alone, while approximately another 79 million have prediabetes.
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      NIH Publication No: 11-3892.
      Approximately 30% to 50% of patients with DM develop diabetic peripheral neuropathy (DPN).
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      Metabolic and microvascular (MV) impairments in DPN damage the endoneurial capillaries that supply the peripheral nerves and lead to sensory loss, pain, and muscle weakness (Figure 1).
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      Figure AU: Please review all images carefully to make sure they are clear and in focus. Revise text labels and legends as needed.1
      Figure 1Postulated pathogenesis of diabetic peripheral neuropathy (DPN) and therapeutic effect of exercise. Various metabolic factors have been implicated in the pathogenesis of DPN, as well as vascular factors, such as decreased nerve blood flow and damaged nerve fibers. Prolonged DPN leads to sensory loss, muscle atrophy, and physical disability. Exercise therapy has been shown to improve clinical outcomes by affecting key metabolic and microvascular (MV) pathways, by activating nitric oxide (NO) production, and by reducing oxidative stress and inhibiting aldose reductase (AR), hence relieving the nerves of their hypoxic state. CV = cardiovascular.
      Individuals with long-standing DM are at high risk for devastating foot complications such as plantar ulcers, Charcot arthropathy, and amputations. DPN plays a key role in the development of diabetic foot complications. Nearly 30% of patients with DPN will develop a foot ulcer within 2 years of diagnosis of severe DPN.
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      Patients with chronic wounds account for 10% of the entire diabetic Medicare population and are responsible for a 4-fold increase in annual per capita health care expenditures, compared with patients with DM without these complications.
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      Approximately 70% of patients with DPN die at 10 years after the initial diagnosis of DPN, with 50% of these deaths being cardiovascular related.
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      A significant consequence of DPN on the skeletal muscle is the accelerated loss of muscle mass, compared with DM alone.
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      Deficits in lower limb muscles reduce functional capacity and contribute to altered gait, increased fall risk, and impaired balance in patients with DPN. This scenario is an important concern for patients with DPN because their falls are likely to be injurious and lead to bone fractures, poorly healing wounds, and chronic infections that may require amputation.
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      The benefits of combining moderate-intensity aerobic exercise with resistance training to improve glycemic control and insulin sensitivity in individuals with DM are well documented.
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      However, little is known about the benefits of exercise in individuals with DPN. Exercise in DPN has been predominantly discouraged in the past because it was considered as a hazard to further exacerbate DPN and risk of falling or injury. However, recent studies have shown that moderate-intensity exercise programs can improve the cardiorespiratory function of patients with DPN and can partially reverse some of their symptoms.
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      It has been hypothesized that exercise can partially reverse DPN progression because it promotes MV dilation, reduces oxidative stress, and increases the abundance of neurotrophic factors, all of which are compromised in DPN.
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      Exercise can also improve lower limb muscle function by inhibiting key metabolic pathways that cause hypoxia. Furthermore, activation of nitric oxide production as a result of exercise is a key mechanism to improve endothelial function in DPN (Figure 1).
      The present review describes the current knowledge of the effects of DPN in the skeletal muscle, as well as promising results from exercise interventions targeted at improving DPN muscle function and symptom reversal. We also highlight the mechanistic insights acquired by using noninvasive magnetic resonance imaging (MRI) techniques that can help assess the efficacy of future interventions for DPN.

      The Effects of DPN on Skeletal Muscle Function

      Prolonged DPN is known to result in significant skeletal muscle deficits in this patient population, including neurogenic muscle atrophy, loss of muscle strength, power, and endurance.
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      • Andersen H.
      Muscle weakness a progressive late complication in diabetic distal symmetric polyneuropathy.
      These factors synergistically contribute to altered gait and impaired balance, which is particularly important for patients with DPN given that their falls often lead to bone fractures and chronic infections
      • Horlings C.G.
      • Van Engelen B.G.
      • Allum J.H.
      • Bloem B.R.
      A weak balance: the contribution of muscle weakness to postural instability and falls.
      • Schwartz A.V.
      • Vittinghoff E.
      • Sellmeyer D.E.
      • et al.
      Diabetes-related complications, glycemic control, and falls in older adults.
      • Schwartz A.
      Diabetes mellitus: does it affect bone?.
      that may require an amputation.
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      Pathways to diabetic limb amputation: basis for prevention.
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      Long-term prognosis for diabetic patients with foot ulcers.
      Here we report on the current state of knowledge in terms of the effects of DPN in skeletal muscle impairment.
      A significant consequence of DPN on skeletal muscle is the accelerated loss of motor axons.
      • Ramji N.
      • Toth C.
      • Kennedy J.
      • Zochodne D.W.
      Does diabetes mellitus target motor neurons?.
      • Allen M.D.
      • Kimpinski K.
      • Doherty T.J.
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      Length dependent loss of motor axons and altered motor unit properties in human diabetic polyneuropathy.
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      Skeletal muscle morphology and contractile function in relation to muscle denervation in diabetic neuropathy.
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      The loss of motor units has been reported in the intrinsic foot muscles
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      and the dorsiflexors of the leg,
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      • Kimpinski K.
      • Doherty T.J.
      • Rice C.L.
      Length dependent loss of motor axons and altered motor unit properties in human diabetic polyneuropathy.
      • Allen M.D.
      • Major B.
      • Kimpinski K.
      • et al.
      Skeletal muscle morphology and contractile function in relation to muscle denervation in diabetic neuropathy.
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      Motor unit loss and weakness in association with diabetic neuropathy in humans.
      as well as intrinsic hand muscles.
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      Skeletal muscle morphology and contractile function in relation to muscle denervation in diabetic neuropathy.
      The loss can approach 50% compared with age-matched healthy control subjects.
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      Length dependent loss of motor axons and altered motor unit properties in human diabetic polyneuropathy.
      • Allen M.D.
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      • et al.
      Skeletal muscle morphology and contractile function in relation to muscle denervation in diabetic neuropathy.
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      Motor unit loss and weakness in association with diabetic neuropathy in humans.
      Patients with DPN have been shown to have greater motor unit losses compared with patients with DM with no neuropathy.
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      The size of existing motor units indicated by the motor unit potential is increased
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      Motor unit loss and weakness in association with diabetic neuropathy in humans.
      through the traditional pattern of reinnervation after denervation.
      Electromyography studies have shown that DPN results in greater fiber density in the dorsiflexor muscles.
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      Association of muscle strength and electrophysiological measures of reinnervation in diabetic neuropathy.
      This pattern of denervation is accelerated in DPN, compared with nonneuropathic DM. It is clear that complete reinnervation cannot offset the loss of motor neurons, as muscle mass is highly reduced with DPN.
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      Does diabetes mellitus target motor neurons?.
      Furthermore, accelerated reinnervation is associated with greater loss in dorsiflexor muscle strength.
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      The incomplete reinnervation in DPN may partially be attributed to declines in neurotrophic factors.
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      The loss of motor units results in muscle weakness, atrophy, and intramuscular fatty infiltration.
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      Motor unit loss is directly correlated with loss of muscle mass and increased intermuscular fat.
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      Skeletal muscle morphology and contractile function in relation to muscle denervation in diabetic neuropathy.
      Motor neuron axon excitability is decreased in DM, although the muscle fiber excitability seems to be preserved in DPN.
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      It has been known for 50 years that DM is associated with slower nerve conduction velocity.
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      In addition, motor unit discharge frequencies are reduced in DPN. These findings collectively show that the intact motor neurons in DPN have reduced function.
      Reduced muscle volume of the intrinsic foot muscles,
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      as well as the muscles in the leg,
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      Accelerated atrophy of lower leg and foot muscles—a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI).
      occurs with DPN. Over a 12-year period, patients with DPN had a 57% decline in dorsiflexor muscle volume (4.5% per year), a 61% decline in plantar flexion volume (5% per year), and a 29% loss in foot muscle volume (3% per year).
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      Accelerated atrophy of lower leg and foot muscles—a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI).
      These declines were greater for DPN compared with DM without neuropathy. Furthermore, the annual decline of muscle volume was related to neuropathy impairment scores at follow-up.
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      Accelerated atrophy of lower leg and foot muscles—a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI).
      Muscle atrophy is length dependent, with more distal muscle areas showing greater losses.
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      Muscular atrophy in diabetic neuropathy: a stereological magnetic resonance imaging study.
      Skeletal muscle atrophy may be related to increased advanced glycation end products and receptors
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      Advanced glycation end-products induce skeletal muscle atrophy and dysfunction in diabetic mice via a RAGE-mediated, AMPK-down-regulated, Akt pathway.
      or reduced insulin signaling in skeletal muscle.
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      Absence of insulin signalling in skeletal muscle is associated with reduced muscle mass and function: evidence for decreased protein synthesis and not increased degradation.
      Adipose tissue in the muscle is increased in DPN, in particular in the posterior leg.
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      • Kimpinski K.
      • et al.
      Skeletal muscle morphology and contractile function in relation to muscle denervation in diabetic neuropathy.
      • Hilton T.N.
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      • Bohnert K.L.
      • et al.
      Excessive adipose tissue infiltration in skeletal muscle in individuals with obesity, diabetes mellitus, and peripheral neuropathy: association with performance and function.
      • Bittel D.C.
      • Bittel A.J.
      • Tuttle L.J.
      • et al.
      Adipose tissue content, muscle performance and physical function in obese adults with type 2 diabetes mellitus and peripheral neuropathy.
      Increases in intermuscular adipose tissue are tied to reduced physical function and ability to complete daily activities.
      • Hilton T.N.
      • Tuttle L.J.
      • Bohnert K.L.
      • et al.
      Excessive adipose tissue infiltration in skeletal muscle in individuals with obesity, diabetes mellitus, and peripheral neuropathy: association with performance and function.
      Declines in muscle strength with DPN have been reported in several muscles, including the ankle extensors (dorsiflexors),
      • Andreassen C.S.
      • Jakobsen J.
      • Andersen H.
      Muscle weakness a progressive late complication in diabetic distal symmetric polyneuropathy.
      • Allen M.D.
      • Kimpinski K.
      • Doherty T.J.
      • Rice C.L.
      Length dependent loss of motor axons and altered motor unit properties in human diabetic polyneuropathy.
      • Allen M.D.
      • Choi I.H.
      • Kimpinski K.
      • et al.
      Motor unit loss and weakness in association with diabetic neuropathy in humans.
      • Andreassen C.S.
      • Jakobsen J.
      • Ringgaard S.
      • et al.
      Accelerated atrophy of lower leg and foot muscles—a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI).
      • Andreassen C.S.
      • Jakobsen J.
      • Flyvbjerg A.
      • Andersen H.
      Expression of neurotrophic factors in diabetic muscle—relation to neuropathy and muscle strength.
      • Andersen H.
      • Gjerstad M.D.
      • Jakobsen J.
      Atrophy of foot muscles: a measure of diabetic neuropathy.
      • Andersen H.
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      • Mogensen C.E.
      • Jakobsen J.
      Isokinetic muscle strength in long-term IDDM patients in relation to diabetic complications.
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      • et al.
      Reduced skeletal muscle quantity and quality in patients with diabetic polyneuropathy assessed by magnetic resonance imaging.
      ankle plantar flexors,
      • Andersen H.
      • Gadeberg P.
      • Brock B.
      • Jakobsen J.
      Muscular atrophy in diabetic neuropathy: a stereological magnetic resonance imaging study.
      • Andreassen C.S.
      • Jakobsen J.
      • Andersen H.
      Muscle weakness a progressive late complication in diabetic distal symmetric polyneuropathy.
      • Andersen H.
      • Gjerstad M.D.
      • Jakobsen J.
      Atrophy of foot muscles: a measure of diabetic neuropathy.
      • Andersen H.
      • Poulsen P.L.
      • Mogensen C.E.
      • Jakobsen J.
      Isokinetic muscle strength in long-term IDDM patients in relation to diabetic complications.
      knee extensors,
      • Orlando G.
      • Balducci S.
      • Bazzucchi I.
      • et al.
      The impact of type 1 diabetes and diabetic polyneuropathy on muscle strength and fatigability.
      • Andersen H.
      • Poulsen P.L.
      • Mogensen C.E.
      • Jakobsen J.
      Isokinetic muscle strength in long-term IDDM patients in relation to diabetic complications.
      and knee flexors.
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      Atrophy of foot muscles: a measure of diabetic neuropathy.
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      • Jakobsen J.
      Isokinetic muscle strength in long-term IDDM patients in relation to diabetic complications.
      As expected, the more distal ankle muscles experience greater losses in strength compared with the muscles of the thigh.
      • Andreassen C.S.
      • Jakobsen J.
      • Ringgaard S.
      • et al.
      Accelerated atrophy of lower leg and foot muscles—a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI).
      Ankle dorsiflexors
      • Allen M.D.
      • Major B.
      • Kimpinski K.
      • et al.
      Skeletal muscle morphology and contractile function in relation to muscle denervation in diabetic neuropathy.
      • Allen M.D.
      • Choi I.H.
      • Kimpinski K.
      • et al.
      Motor unit loss and weakness in association with diabetic neuropathy in humans.
      • Andersen H.
      • Gjerstad M.D.
      • Jakobsen J.
      Atrophy of foot muscles: a measure of diabetic neuropathy.
      • Andersen H.
      • Poulsen P.L.
      • Mogensen C.E.
      • Jakobsen J.
      Isokinetic muscle strength in long-term IDDM patients in relation to diabetic complications.
      generally exhibit a 15% to 30% reduction compared with healthy control subjects. Declines in strength of the leg muscles are between 3% and 6% per year, depending on the severity of the neuropathy.
      • Andreassen C.S.
      • Jakobsen J.
      • Andersen H.
      Muscle weakness a progressive late complication in diabetic distal symmetric polyneuropathy.
      • Andreassen C.S.
      • Jakobsen J.
      • Ringgaard S.
      • et al.
      Accelerated atrophy of lower leg and foot muscles—a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI).
      Strength losses across the lower limb are more severe in DPN compared with DM without neuropathy.
      • Andreassen C.S.
      • Jakobsen J.
      • Andersen H.
      Muscle weakness a progressive late complication in diabetic distal symmetric polyneuropathy.
      • Andreassen C.S.
      • Jakobsen J.
      • Ringgaard S.
      • et al.
      Accelerated atrophy of lower leg and foot muscles—a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI).
      • Andreassen C.S.
      • Jakobsen J.
      • Flyvbjerg A.
      • Andersen H.
      Expression of neurotrophic factors in diabetic muscle—relation to neuropathy and muscle strength.
      Thigh muscle strength has shown reductions in patients with DPN
      • Andersen H.
      • Gjerstad M.D.
      • Jakobsen J.
      Atrophy of foot muscles: a measure of diabetic neuropathy.
      • Andersen H.
      • Poulsen P.L.
      • Mogensen C.E.
      • Jakobsen J.
      Isokinetic muscle strength in long-term IDDM patients in relation to diabetic complications.
      but not in those with DM without neuropathy.
      • Andersen H.
      • Poulsen P.L.
      • Mogensen C.E.
      • Jakobsen J.
      Isokinetic muscle strength in long-term IDDM patients in relation to diabetic complications.
      Importantly, muscle strength losses across the thigh and leg muscles are associated with neuropathy scores.
      • Andreassen C.S.
      • Jakobsen J.
      • Andersen H.
      Muscle weakness a progressive late complication in diabetic distal symmetric polyneuropathy.
      • Andreassen C.S.
      • Jakobsen J.
      • Ringgaard S.
      • et al.
      Accelerated atrophy of lower leg and foot muscles—a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI).
      • Andersen H.
      • Gjerstad M.D.
      • Jakobsen J.
      Atrophy of foot muscles: a measure of diabetic neuropathy.
      • Andersen H.
      • Poulsen P.L.
      • Mogensen C.E.
      • Jakobsen J.
      Isokinetic muscle strength in long-term IDDM patients in relation to diabetic complications.
      Muscle performance is generally diminished in DPN. Muscle atrophy directly contributes to the declines in muscle force.
      • Andersen H.
      Muscular endurance in long-term IDDM patients.
      • Allen M.D.
      • Kimpinski K.
      • Doherty T.J.
      • Rice C.L.
      Length dependent loss of motor axons and altered motor unit properties in human diabetic polyneuropathy.
      • Allen M.D.
      • Major B.
      • Kimpinski K.
      • et al.
      Skeletal muscle morphology and contractile function in relation to muscle denervation in diabetic neuropathy.
      • Martinelli A.R.
      • Mantovani A.M.
      • Nozabieli A.J.
      • et al.
      Muscle strength and ankle mobility for the gait parameters in diabetic neuropathies.
      Muscle relaxation rates are prolonged,
      • Bayley J.S.
      • Pedersen T.H.
      • Nielsen O.B.
      Skeletal muscle dysfunction in the db/db mouse model of type 2 diabetes.
      partially attributed to decreased calcium handling as the smooth endoplasmic reticulum ATPase (SERCA) protein content is reduced with DPN.
      • Bayley J.S.
      • Pedersen T.H.
      • Nielsen O.B.
      Skeletal muscle dysfunction in the db/db mouse model of type 2 diabetes.
      The rate of force development is also reduced with DPN, as indicated by a longer time to reach peak force.
      • Allen M.D.
      • Kimpinski K.
      • Doherty T.J.
      • Rice C.L.
      Length dependent loss of motor axons and altered motor unit properties in human diabetic polyneuropathy.
      • Bayley J.S.
      • Pedersen T.H.
      • Nielsen O.B.
      Skeletal muscle dysfunction in the db/db mouse model of type 2 diabetes.
      Specific force relative to muscle area in the dorsiflexors has also been reported in DPN,
      • Allen M.D.
      • Major B.
      • Kimpinski K.
      • et al.
      Skeletal muscle morphology and contractile function in relation to muscle denervation in diabetic neuropathy.
      • Moore C.W.
      • Allen M.D.
      • Kimpinski K.
      • et al.
      Reduced skeletal muscle quantity and quality in patients with diabetic polyneuropathy assessed by magnetic resonance imaging.
      suggesting declines in muscle quality. However, the voluntary activation of skeletal muscle or ability to fully recruit the muscle seems to be preserved in DPN.
      • Allen M.D.
      • Major B.
      • Kimpinski K.
      • et al.
      Skeletal muscle morphology and contractile function in relation to muscle denervation in diabetic neuropathy.
      • Allen M.D.
      • Doherty T.J.
      • Rice C.L.
      • Kimpinski K.
      Physiology in medicine: neuromuscular consequences of diabetic neuropathy.
      Muscle performance declines in DPN include enhanced muscle fatigue of the dorsiflexors
      • Allen M.D.
      • Stashuk D.W.
      • Kimpinski K.
      • et al.
      Increased neuromuscular transmission instability and motor unit remodelling with diabetic neuropathy as assessed using novel near fibre motor unit potential parameters.
      and the knee extensors,
      • Orlando G.
      • Balducci S.
      • Bazzucchi I.
      • et al.
      The impact of type 1 diabetes and diabetic polyneuropathy on muscle strength and fatigability.
      indicated by a shorter time to task failure. This reduced muscular endurance is greater in DPN compared with DM without neuropathy.
      • Orlando G.
      • Balducci S.
      • Bazzucchi I.
      • et al.
      The impact of type 1 diabetes and diabetic polyneuropathy on muscle strength and fatigability.
      The diminished endurance time is also related to slower motor nerve conduction velocity.
      • Orlando G.
      • Balducci S.
      • Bazzucchi I.
      • et al.
      The impact of type 1 diabetes and diabetic polyneuropathy on muscle strength and fatigability.
      Few data are available on striated muscle fiber type changes in DPN. Surprisingly, muscle fiber size was reportedly not reduced in DPN
      • Andreassen C.S.
      • Jensen J.M.
      • Jakobsen J.
      • et al.
      Striated muscle fiber size, composition, and capillary density in diabetes in relation to neuropathy and muscle strength.
      ; however, these patients had a high body mass index, which may have offset changes in fiber diameter. Nonetheless, the results are in agreement with a major role of neurogenic atrophy in decreased muscle strength. Patients with DM type 1 have an increased proportion of type II fibers, which could result in reduced muscular endurance. Other data from electromyography studies suggest that DPN is associated with decreases in fast motor units, as the postactivation potentiation is reduced in DPN and twitch relaxation time is prolonged.
      • Allen M.D.
      • Kimpinski K.
      • Doherty T.J.
      • Rice C.L.
      Length dependent loss of motor axons and altered motor unit properties in human diabetic polyneuropathy.
      However, fiber type proportion is not related to neuropathy scores or any measure of glucose control or duration of DM.
      • Andreassen C.S.
      • Jensen J.M.
      • Jakobsen J.
      • et al.
      Striated muscle fiber size, composition, and capillary density in diabetes in relation to neuropathy and muscle strength.
      DPN is associated with reduced ankle joint motion for both plantar and dorsiflexion.
      • Andersen H.
      • Gadeberg P.
      • Brock B.
      • Jakobsen J.
      Muscular atrophy in diabetic neuropathy: a stereological magnetic resonance imaging study.
      • Martinelli A.R.
      • Mantovani A.M.
      • Nozabieli A.J.
      • et al.
      Muscle strength and ankle mobility for the gait parameters in diabetic neuropathies.
      Decreased muscle strength of the ankle plantar and dorsiflexors is associated with shorter stride length and reduced walking speed.
      • Martinelli A.R.
      • Mantovani A.M.
      • Nozabieli A.J.
      • et al.
      Muscle strength and ankle mobility for the gait parameters in diabetic neuropathies.
      Reaction time of the knee and ankle joint muscles is also reduced with DPN.
      • Andersen H.
      • Gadeberg P.
      • Brock B.
      • Jakobsen J.
      Muscular atrophy in diabetic neuropathy: a stereological magnetic resonance imaging study.
      In addition, reduced dorsiflexion range of motion has been tied to declines in mobility
      • Martinelli A.R.
      • Mantovani A.M.
      • Nozabieli A.J.
      • et al.
      Muscle strength and ankle mobility for the gait parameters in diabetic neuropathies.
      and decreased neuropathy scores.
      • Andersen H.
      • Gadeberg P.
      • Brock B.
      • Jakobsen J.
      Muscular atrophy in diabetic neuropathy: a stereological magnetic resonance imaging study.
      Changes in ankle joint range of motions, strength, and reaction time are likely critical factors in balance impairments and fall risk associated with DPN.
      Declines in muscle performance in DPN may also be influenced by blood flow and perfusion. Blood flow reductions occur with DPN
      • Petrofsky J.
      • Lee S.
      • Cuneo M.
      Effects of aging and type 2 diabetes on resting and post occlusive hyperemia of the forearm; the impact of rosiglitazone.
      and may contribute to reduced muscle endurance. Vascular impairments include increased carotid artery intima media thickness and decreased brachial artery flow–mediated dilation with DM.
      • Ravikumar R.
      • Deepa R.
      • Shanthirani C.
      • Mohan V.
      Comparison of carotid intima-media thickness, arterial stiffness, and brachial artery flow mediated dilatation in diabetic and nondiabetic subjects (The Chennai Urban Population Study [CUPS-9]).
      MV density
      • Andreassen C.S.
      • Jensen J.M.
      • Jakobsen J.
      • et al.
      Striated muscle fiber size, composition, and capillary density in diabetes in relation to neuropathy and muscle strength.
      and function
      • Bauer T.A.
      • Reusch J.E.
      • Levi M.
      • Regensteiner J.G.
      Skeletal muscle deoxygenation after the onset of moderate exercise suggests slowed microvascular blood flow kinetics in type 2 diabetes.
      • Slade J.M.
      • Towse T.F.
      • Gossain V.V.
      • Meyer R.A.
      Peripheral microvascular response to muscle contraction is unaltered by early diabetes but decreases with age.
      • Womack L.
      • Peters D.
      • Barrett E.J.
      • et al.
      Abnormal skeletal muscle capillary recruitment during exercise in patients with type 2 diabetes mellitus and microvascular complications.
      are compromised in DPN. L-arginine, an important substrate used in nitric oxide–dependent vasodilation, is reduced in DM and importantly related to the development of peripheral neuropathy and microangiopathies.
      • Ganz T.
      • Wainstein J.
      • Gilad S.
      • Limor R.
      • Boaz M.
      • Stern N.
      Serum asymmetric dimethylarginine and arginine levels predict microvascular and macrovascular complications in type 2 diabetes mellitus.
      Increased advanced glycation end products occurring in DPN may diminish vascular endothelial function through decreasing nitric oxide bioavailability.
      • Wautier J.L.
      • Schmidt A.M.
      Protein glycation: a firm link to endothelial cell dysfunction.
      Skeletal muscle metabolism is also decreased in DPN. Resting levels of high-energy phosphates are reduced in the diabetic foot.
      • Dinh T.
      • Doupis J.
      • Lyons T.E.
      • et al.
      Foot muscle energy reserves in diabetic patients without and with clinical peripheral neuropathy.
      • Greenman R.L.
      • Panasyuk S.
      • Wang X.
      • et al.
      Early changes in the skin microcirculation and muscle metabolism of the diabetic foot.
      Muscle oxidative capacity is reduced by >50% in DPN compared with DM without neuropathy.
      • Tecilazich F.
      • Dinh T.
      • Lyons T.E.
      • et al.
      Postexercise phosphocreatine recovery, an index of mitochondrial oxidative phosphorylation, is reduced in diabetic patients with lower extremity complications.
      The reduced mitochondrial function in DPN is related to increased inflammatory cytokines. A reduction in oxidative enzymes and mitochondria content has also been reported in striated muscle of DM (see Review).
      • Rabol R.
      • Boushel R.
      • Dela F.
      Mitochondrial oxidative function and type 2 diabetes.
      Declines in oxidative capacity are also reflected in slower rates of oxygen consumption during exercise in DM.
      • Regensteiner J.G.
      • Bauer T.A.
      • Reusch J.E.
      • et al.
      Abnormal oxygen uptake kinetic responses in women with type II diabetes mellitus.
      Taken together, patients with DPN have shown greater skeletal muscle deficits compared with patients with DM. These deficits reduce functional capacity and result in impaired balance, making these patients susceptible to injuries that can lead to amputation.

      The Lack of Effective Treatments for DPN and the Role of Physical Exercise

      Hyperglycemia is an important factor in the development of DPN. However, the pathophysiologic processes through which hyperglycemia causes DPN are not fully understood. Furthermore, large clinical studies (ACCORD [Action to Control Cardiovascular Risk in Diabetes],
      • Gerstein H.C.
      • Miller M.E.
      • Byington R.P.
      • et al.
      Action to Control Cardiovascular Risk in Diabetes Study Group
      Effects of intensive glucose lowering in type 2 diabetes.
      ADVANCE [Action in Diabetes and Vascular Disease: PreterAx and Diamicron Controlled Evaluation],
      • Patel A.
      • MacM.ahon S.
      • Chalmers J.
      • et al.
      ADVANCE Collaborative Group
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      and VADT [Veterans Affairs Diabetes Trial]
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      ) have shown that good glucose control alone is insufficient to reduce the occurrence of foot complications, including DPN. There are no US Food and Drug Administration–approved treatment options that target the underlying pathogenesis of DPN.
      • Boulton A.J.
      • Kempler P.
      • Ametov A.
      • Ziegler D.
      Whither pathogenetic treatments for diabetic polyneuropathy?.
      • Malik R.A.
      Which test for diagnosing early human diabetic neuropathy?.
      Several treatments that specifically target pathogenic DPN mechanisms have been tested both on animal models and humans.
      • Albers J.W.
      • Pop-Busui R.
      Diabetic neuropathy: mechanisms, emerging treatments, and subtypes.
      Most therapies under evaluation attempt to block key metabolic pathways linked to DPN progression
      • Albers J.W.
      • Pop-Busui R.
      Diabetic neuropathy: mechanisms, emerging treatments, and subtypes.
      and/or improve nerve blood flow by stimulating angiogenesis.
      • Boulton A.
      The diabetic foot: from art to science. The 18th Camillo Golgi lecture.
      These include agents such as α-lipoic acid (an antioxidant targeting hyperglycemia-induced oxidative stress)
      • Papanas N.
      • Ziegler D.
      New diagnostic tests for diabetic distal symmetric polyneuropathy.
      and actovegin (an agent believed to stimulate oxygen use and cellular energy metabolism).
      • Ziegler D.
      • Movsesyan L.
      • Mankovsky B.
      • et al.
      Treatment of symptomatic polyneuropathy with actovegin in type 2 diabetic patients.
      Some revascularization studies suggest that improving tissue blood flow may alleviate DPN.
      • Veves A.
      • Donaghue V.
      • Sarnow M.
      • et al.
      The impact of reversal of hypoxia by revascularization on the peripheral nerve function of diabetic patients.
      However, despite encouraging early results,
      • Papanas N.
      • Ziegler D.
      New diagnostic tests for diabetic distal symmetric polyneuropathy.
      • Ziegler D.
      • Movsesyan L.
      • Mankovsky B.
      • et al.
      Treatment of symptomatic polyneuropathy with actovegin in type 2 diabetic patients.
      • Ziegler D.
      • Nowak H.
      • Kempler P.
      • et al.
      Treatment of symptomatic diabetic polyneuropathy with the antioxidant α‐lipoic acid: a meta‐analysis.
      • Mijnhout G.S.
      • Kollen B.J.
      • Alkhalaf A.
      • et al.
      Alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials.
      • Machicao F.
      • Muresanu D.F.
      • Hundsberger H.
      • et al.
      Pleiotropic neuroprotective and metabolic effects of actovegin’s mode of action.
      • Winkler G.
      • Pál B.
      • Nagybégányi E.
      • et al.
      Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy.
      • Fraser D.A.
      • Diep L.M.
      • Hovden I.A.
      • et al.
      The effects of long-term oral benfotiamine supplementation on peripheral nerve function and inflammatory markers in patients with type 1 diabetes: a 24-month, double-blind, randomized, placebo-controlled trial.
      there are no therapies to prevent or reverse its progress.
      • Boulton A.J.
      • Kempler P.
      • Ametov A.
      • Ziegler D.
      Whither pathogenetic treatments for diabetic polyneuropathy?.
      • Tavakoli M.
      • Petropoulos I.N.
      • Malik R.A.
      Corneal confocal microscopy to assess diabetic neuropathy: an eye on the foot.
      A growing body of literature supports the benefits of combining moderate-intensity aerobic exercise with resistance training to improve glycemic control and insulin sensitivity in individuals with DM.
      • Sigal R.J.
      • Kenny G.P.
      • Boulé N.G.
      • et al.
      Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial.
      Current practice guidelines endorsed by the American Diabetes Association and the American College of Sports Medicine recommend 150 minutes per week of combination (ie, aerobic and resistance) training.
      • Colberg S.R.
      • Sigal R.J.
      • Fernhall B.
      • et al.
      American College of Sports Medicine, American Diabetes Association
      Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement.
      Key parameters related to exercise prescription include the following: (1) intensity (50%–80% the maximum rate of oxygen consumption as measured during incremental exercise); (2) frequency (3–4 times per week); and (3) duration (30–60 min per session). The total length of programs ranges from 10 to 26 weeks. Evidence from the DARE (Diabetes Aerobic and Resistance Exercise) and HART-D (Health Benefits of Aerobic and Resistance Training in Individuals With Type 2 Diabetes) clinical trials
      • Sigal R.J.
      • Kenny G.P.
      • Boule N.G.
      • et al.
      Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial.
      • Church T.S.
      • Blair S.N.
      • Cocreham S.
      • et al.
      Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial.
      showed that a combination of aerobic and resistance training improved glycosylated hemoglobin levels, which was not achieved by aerobic or resistance training alone. Prescription of resistance training includes a consideration of the following: (1) intensity (usually 2–3 sets of 12 repetitions each); (2) number of exercises (between 3 and 9 exercises that involve large muscle groups such as bench press, seated row, leg press, back extensions); and (3) frequency (2–3 sessions per week). The total length of programs ranges from 26 to 36 weeks, with weekly increments in 10 or 12 repetition maximum weight. Supervision has been linked to adherence, and adherence, in turn, has been linked to the extent of improvements in postintervention glucose tolerance.
      American Diabetes Association
      Physical activity/exercise and diabetes.
      • Nicolucci A.
      • Balducci S.
      • Cardelli P.
      • et al.
      Italian Diabetes Exercise Study Investigators
      Relationship of exercise volume to improvements of quality of life with supervised exercise training in patients with type 2 diabetes in a randomised controlled trial: the Italian Diabetes and Exercise Study (IDES).
      Preliminary studies have shown that moderate-intensity supervised exercise programs that include aerobic and resistance training are well tolerated by patients with DPN. The patients can significantly improve their cardiorespiratory function and can also improve DPN symptoms, including nerve function and cutaneous innervation.
      • Kluding P.M.
      • Pasnoor M.
      • Singh R.
      • et al.
      Safety of aerobic exercise in people with diabetic peripheral neuropathy: single-group clinical trial.
      • Kluding P.M.
      • Pasnoor M.
      • Singh R.
      • et al.
      The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy.
      • Balducci S.
      • Iacobellis G.
      • Parisi L.
      • et al.
      Exercise training can modify the natural history of diabetic peripheral neuropathy.
      In addition, exercise may lead to an improved vascular endothelial function in DPN.
      • Billinger S.A.
      • Sisante J.F.
      • Alqahtani A.S.
      • et al.
      Aerobic exercise improves measures of vascular health in diabetic peripheral neuropathy.
      It has been hypothesized that exercise can partially reverse DPN progression because it promotes MV dilation, reduces oxidative stress, and increases the abundance of neurotrophic factors, all of which are compromised in DPN.
      • Dixit S.
      • Maiya A.G.
      • Shastry B.
      Effect of aerobic exercise on peripheral nerve functions of population with diabetic peripheral neuropathy in type 2 diabetes: a single blind, parallel group randomized controlled trial.
      It has been suggested that moderate-intensity aerobic exercise has an anti-inflammatory effect in patients with DM.
      • Kadoglou N.P.
      • Fotiadis G.
      • Kapelouzou A.
      • et al.
      The differential anti-inflammatory effects of exercise modalities and their association with early carotid atherosclerosis progression in patients with type 2 diabetes.
      However, these effects have not been confirmed in patients with DPN. Exercise may be able to improve lower limb muscle function by inhibiting key metabolic pathways that cause hypoxia. Furthermore, activation of nitric oxide production as a result of exercise is a key mechanism to improve endothelial function in DPN.
      Resistance training in DPN has the potential to increase muscle mass and muscle strength that are severely reduced with DPN. Recently, functional rates of force development were improved after resistance training in DPN.
      • Handsaker J.C.
      • Brown S.J.
      • Bowling F.L.
      • et al.
      Resistance exercise training increases lower limb speed of strength generation during stair ascent and descent in people with diabetic peripheral neuropathy.
      The effect of resistance exercise and increased muscle mass is essential to improve glycemic control because skeletal muscle is typically responsible for the majority of whole body glucose uptake. Therefore, substantial increases in skeletal muscle mass alone would be expected to lower blood glucose levels. Furthermore, aerobic exercise is associated with improvements in glucose uptake through increases in glucose transporters. Aerobic exercise combined with resistance has been shown to increase metabolic flexibility in type 2 DM, allowing the body to increase glucose metabolism.
      • Meex R.C.
      • Schrauwen-Hinderling V.B.
      • Moonen-Kornips E.
      • et al.
      Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity.
      Aerobic exercise has clearly been shown to improve mitochondrial function across many diseases and conditions. Improving mitochondrial function not only stands to increase glucose uptake and clearance but also induces improvements in oxidative capacity. The improvements in oxidative capacity for DPN would increase muscular endurance and functional performance.

      Safety of Physical Exercise in Individuals With DPN

      Safety of physical exercise in patients with DPN has been assessed in small clinical studies, during which adverse events (AEs) have been recorded.
      • Kluding P.M.
      • Pasnoor M.
      • Singh R.
      • et al.
      Safety of aerobic exercise in people with diabetic peripheral neuropathy: single-group clinical trial.
      In a 16-week supervised aerobic exercise, the intensity of the exercise session was individually prescribed on the basis of the heart rate response at the corresponding 50% to 70% oxygen uptake (VO2R) reserve from a graded exercise test. Sessions were supervised by licensed health care professionals or health care professional students, with no more than 4 participants per supervisor. The number of AEs was reported. The majority of them (56%) occurred in the first 8 weeks of the 16-week exercise program. These included joint or muscle pain that affected exercise duration or attendance, significant hypoglycemia (blood level <70 mg/dL), chest pain, and shortness of breath. There were also AEs reported that were not related to the study procedures but affected participation in exercise. For example, hyperglycemia (blood glucose level >300 mg/dL) was not caused by exercise but resulted in close monitoring during exercise for safety, and cold/flu symptoms occasionally caused cancellation of exercise sessions. Several other issues were noted by the team and resulted in physician referral. These included a significant foot swelling (n = 1), hyperglycemia with a positive urine ketone test result (n = 1), and significant hypertension at rest (n = 1). Of 20 enrolled participants, 18 (90%) completed the study, and no serious AEs occurred as a result of the intervention.
      An additional consideration in moderate-intensity exercise prescription in DPN is whether the intervention may contribute to an increased risk of foot ulcers.
      • Mueller M.J.
      • Tuttle L.J.
      • Lemaster J.W.
      • et al.
      Weight-bearing versus nonweight-bearing exercise for persons with diabetes and peripheral neuropathy: a randomized controlled trial.
      These concerns stem from data showing that repetitive and elevated plantar stress sustained in DPN contributes to ulcer risk.
      • Cavanagh P.R.
      • Bus S.A.
      Off-loading the diabetic foot for ulcer prevention and healing.
      However, assessment of plantar pressure by itself has modest sensitivity and specificity, underscoring the multifactorial etiology of foot ulcer development.
      • Lavery L.A.
      • Armstrong D.G.
      • Wunderlich R.P.
      • et al.
      Predictive value of foot pressure assessment as part of a population-based diabetes disease management program.
      • Crawford F.
      • Inkster M.
      • Kleijnen J.
      • Fahey T.
      Predicting foot ulcers in patients with diabetes: a systematic review and meta-analysis.
      The Feet First Trial demonstrated that a community-based relatively low-intensity weight-bearing intervention was safe in individuals with DPN.
      • Lemaster J.W.
      • Mueller M.J.
      • Reiber G.E.
      • et al.
      Effect of weight-bearing activity on foot ulcer incidence in people with diabetic peripheral neuropathy: feet first randomized controlled trial.
      A subsequent follow-up study demonstrated that moderate-intensity weight-bearing exercise (1 hour per session, 3 sessions per week) was as safe as nonweight-bearing exercise. Adverse effect monitoring included visual inspection of feet and footwear, as well as skin temperature monitoring. Although the feasibility of skin temperature monitoring is promising,
      • Skafjeld A.
      • Iversen M.M.
      • Holme I.
      • et al.
      A pilot study testing the feasibility of skin temperature monitoring to reduce recurrent foot ulcers in patients with diabetes—a randomized controlled trial.
      Lemaster et al
      • Lemaster J.W.
      • Mueller M.J.
      • Reiber G.E.
      • et al.
      Effect of weight-bearing activity on foot ulcer incidence in people with diabetic peripheral neuropathy: feet first randomized controlled trial.
      noted a high rate of false-positive findings (foot temperature differential of >2.2° C in response to walking) with skin temperature monitoring.
      Taken together, these studies illustrate that moderate-intensity supervised exercise is well tolerated by patients with DPN. However, care providers must carefully prescribe exercise intensity and closely monitor and address anticipated adverse effects, including joint or muscle pain, hypoglycemia, and ulcer risk.

      The Effects of Exercise on DPN Symptom Reversal

      In a separate study, a 10-week, moderate-intensity supervised exercise program that included aerobic and resistance training was prescribed in 17 patients with DPN.
      • Kluding P.M.
      • Pasnoor M.
      • Singh R.
      • et al.
      The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy.
      Despite the short duration of the intervention, exercise significantly improved participants’ scores on the Michigan Neuropathy Screening Instrument. In addition, skin biopsy specimens revealed increases in intraepidermal nerve fiber density. Consistent with these findings, a recent pilot study showed that participation in a 16-week, moderate-intensity exercise program was accompanied by reduced pain interference in individuals with DPN.
      • Yoo M.
      • D’Silva L.J.
      • Martin K.
      • et al.
      Pilot study of exercise therapy on painful diabetic peripheral neuropathy.
      In a follow-up study, preliminary results regarding the effects of physical exercise on vascular endothelial function improvement were reported in patients with DPN.
      • Billinger S.A.
      • Sisante J.F.
      • Alqahtani A.S.
      • et al.
      Aerobic exercise improves measures of vascular health in diabetic peripheral neuropathy.
      Participation in a 16-week, moderate-intensity resistance training intervention (1 hour per week; exercises included leg press, leg extension, and ankle press) was accompanied by faster torque development during stair negotiation.
      • Handsaker J.C.
      • Brown S.J.
      • Bowling F.L.
      • et al.
      Resistance exercise training increases lower limb speed of strength generation during stair ascent and descent in people with diabetic peripheral neuropathy.
      Taken together, these studies indicate that moderate-intensity aerobic and resistance training have significant potential to improve symptoms and mitigate strength deficits in individuals with DPN.

      The Effects of Exercise on Balance in DPN

      Interventions focusing on balance training are heterogeneous. Although some include aspects of resistance training,
      • Morrison S.
      • Colberg S.R.
      • Mariano M.
      • et al.
      Balance training reduces falls risk in older individuals with type 2 diabetes.
      others have focused on activities such as standing on a trampoline for dynamic balance or catching a ball to train anticipatory balance.
      • Song C.H.
      • Petrofsky J.S.
      • Lee S.W.
      • et al.
      Effects of an exercise program on balance and trunk proprioception in older adults with diabetic neuropathies.
      Overall, these exercise programs have been 8 to 10 weeks in duration, 60 minutes per session, 1 to 3 times per week.
      • Morrison S.
      • Colberg S.R.
      • Mariano M.
      • et al.
      Balance training reduces falls risk in older individuals with type 2 diabetes.
      • Song C.H.
      • Petrofsky J.S.
      • Lee S.W.
      • et al.
      Effects of an exercise program on balance and trunk proprioception in older adults with diabetic neuropathies.
      • Akbari M.
      • Jafari H.
      • Moshashaee A.
      • Forugh B.
      Do diabetic neuropathy patients benefit from balance training?.
      Significant postintervention effects in reaction time and static and dynamic balance have been reported. Most recently, exercises using real-time feedback have shown promising results in individuals with DPN.
      • Grewal G.S.
      • Schwenk M.
      • Lee-Eng J.
      • et al.
      Sensor-based interactive balance training with visual joint movement feedback for improving postural stability in diabetics with peripheral neuropathy: a randomized controlled trial.
      Wearable sensors were combined with a virtual environment in a short 4-week intervention, and resulted in a significant improvement in balance in individuals with DM. Longer term follow-up is warranted.

      Effects of Targeted Exercise in DPN

      Due to the distal to proximal distribution of symptoms and muscle atrophy in diabetic neuropathy,
      • Andreassen C.S.
      • Jakobsen J.
      • Flyvbjerg A.
      • Andersen H.
      Expression of neurotrophic factors in diabetic muscle—relation to neuropathy and muscle strength.
      one group has proposed exercise intervention targeted to the distal lower extremity in DPN.
      • Sartor C.D.
      • Hasue R.H.
      • Cacciari L.P.
      • et al.
      Effects of strengthening, stretching and functional training on foot function in patients with diabetic neuropathy: results of a randomized controlled trial.
      • Sartor C.D.
      • Watari R.
      • Passaro A.C.
      • et al.
      Effects of a combined strengthening, stretching and functional training program versus usual-care on gait biomechanics and foot function for diabetic neuropathy: a randomized controlled trial.
      In their clinical trial, the experimental group received a 12-week intervention (40–60 minutes per session, 2 sessions per week) with exercises to improve range of motion and strength of the foot and ankle, as well as gait training. The control group received standard foot care and medical management but no exercises. Although modest changes in gait-related variables were noted, no changes in neuropathy symptoms or self-reported foot function were found. The modest results accompanying targeted exercise may be explained, at least in part, by recent data showing substantial proximal impairments in DPN and challenging the assumptions related to the distribution of symptoms and impairments.
      • Almurdhi M.M.
      • Reeves N.D.
      • Bowling F.L.
      • et al.
      Reduced lower-limb muscle strength and volume in patients with type 2 diabetes in relation to neuropathy, intramuscular fat, and vitamin D levels.
      • Ferreira J.P.
      • Sartor C.D.
      • Leal A.M.
      • et al.
      The effect of peripheral neuropathy on lower limb muscle strength in diabetic individuals.

      Alternative Exercise Interventions in DPN

      Mind/body practices such as tai chi and yoga reportedly have positive effects on glycemic control and balance in individuals with DPN.
      • Ahn S.
      • Song R.
      Effects of tai chi exercise on glucose control, neuropathy scores, balance, and quality of life in patients with type 2 diabetes and neuropathy.
      A 12-week tai chi program (1 hour per session, 2 sessions per week) was accompanied by a reduction in neuropathy symptoms and improved glycemic control and balance.
      • Ahn S.
      • Song R.
      Effects of tai chi exercise on glucose control, neuropathy scores, balance, and quality of life in patients with type 2 diabetes and neuropathy.
      Participation in a 3-month yoga intervention (3 sessions per week) was accompanied by modest decreases in body mass index, improvements in glycemic control, and a more marked reduction in oxidative stress.
      • Hegde S.V.
      • Adhikari P.
      • Kotian S.
      • et al.
      Effect of 3-month yoga on oxidative stress in type 2 diabetes with or without complications: a controlled clinical trial.

      Current Limitations in Assessing Intervention Efficacy in DPN

      One of the obstacles for the development of effective treatments for DPN is the lack of sensitive and objective tests to detect small changes in symptoms and signs seen in interventions.
      • Boulton A.J.
      • Kempler P.
      • Ametov A.
      • Ziegler D.
      Whither pathogenetic treatments for diabetic polyneuropathy?.
      Typically, a diagnosis of DPN is based on the patient’s description of pain. Abnormal findings from clinical examinations are used to determine a neuropathy score.
      • Papanas N.
      • Ziegler D.
      New diagnostic tests for diabetic distal symmetric polyneuropathy.
      Symptoms can be assessed by using composed scores (ie, Total Symptom Score,
      • Bastyr III, E.J.
      • Price K.L.
      • Bril V.
      Development and validity testing of the neuropathy total symptom score-6: questionnaire for the study of sensory symptoms of diabetic peripheral neuropathy.
      Toronto Clinical Neuropathy Score,
      • Bril V.
      • Perkins B.A.
      Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy.
      Neuropathy Symptom Score
      • Meijer J.
      • Smit A.
      • Sonderen E.
      • et al.
      Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the Diabetic Neuropathy Symptom score.
      ). Other diagnostic scores focus on neuropathic impairments, such as the appearance of the feet, neuropathic ulceration, loss of Achilles tendon reflexes, and reduced vibration perception when tested using a tuning fork.
      • Moghtaderi A.
      • Bakhshipour A.
      • Rashidi H.
      Validation of Michigan neuropathy Screening Instrument for diabetic peripheral neuropathy.
      These often-used scores, which rely on patients’ subjective experience, are extremely variable with poor reproducibility and are considered unsuitable for the successful performance of clinical trials.
      • Dyck P.J.
      • Overland C.J.
      • Low P.A.
      • et al.
      Signs and symptoms vs nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs. NPhys trial.
      Motor nerve conduction velocities have been used as surrogate end points in clinical trials. They are highly reproducible and correlate well with underlying structural abnormalities. Although smaller sensory fibers play a large role early in the development of DPN and thus play a greater role in early DPN compared with larger motor nerve fibers, motor nerve conduction velocity is reduced with the further progression of DPN.
      • Hansen S.
      • Ballantyne J.P.
      Axonal dysfunction in the neuropathy of diabetes mellitus: a quantitative electrophysiological study.
      • Andreassen C.S.
      • Jakobsen J.
      • Ringgaard S.
      • et al.
      Accelerated atrophy of lower leg and foot muscles—a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI).
      • Hussain G.
      • Rizvi S.A.
      • Singhal S.
      • et al.
      Cross sectional study to evaluate the effect of duration of type 2 diabetes mellitus on the nerve conduction velocity in diabetic peripheral neuropathy.
      • Hussain G.
      • Rizvi S.A.
      • Singhal S.
      • et al.
      Serum levels of TGF-beta1 in patients of diabetic peripheral neuropathy and its correlation with nerve conduction velocity in type 2 diabetes mellitus.
      • Orlando G.
      • Balducci S.
      • Bazzucchi I.
      • et al.
      The impact of type 1 diabetes and diabetic polyneuropathy on muscle strength and fatigability.
      • Andreassen C.S.
      • Jakobsen J.
      • Flyvbjerg A.
      • Andersen H.
      Expression of neurotrophic factors in diabetic muscle—relation to neuropathy and muscle strength.
      Minimally invasive skin biopsies can assess intraepidermal fiber density, but the results have shown considerable variability, even among controls, and their invasive nature remains a burden for patients and researchers.
      • Engelstad J.K.
      • Taylor S.W.
      • Witt L.V.
      • et al.
      Epidermal nerve fibers confidence intervals and continuous measures with nerve conduction.
      • Lauria G.
      • Bakkers M.
      • Schmitz C.
      • et al.
      Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study.
      Corneal confocal microscopy has shown early promising results for noninvasive detection and stratification of the severity of DPN.
      • Tavakoli M.
      • Quattrini C.
      • Abbott C.
      • et al.
      Corneal confocal microscopy: a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy.
      • Edwards K.
      • Pritchard N.
      • Vagenas D.
      • et al.
      Utility of corneal confocal microscopy for assessing mild diabetic neuropathy: baseline findings of the LANDMark study.
      However, the sensitivity and specificity of the technique for feet at risk of ulceration are moderate.
      • Papanas N.
      • Ziegler D.
      Corneal confocal microscopy: a new technique for early detection of diabetic neuropathy.

      Noninvasive MRI Techniques to Assess DPN Features

      Several MRI techniques have been used to assess different aspects of DPN, including skeletal muscle structure, function, and peripheral nerves (Table). These tools have the potential to bring new mechanistic insights into the effects of DPN as well as to objectively measure small changes in DPN pathology as a result of intervention.
      TableMagnetic resonance imaging studies in diabetic peripheral neuropathy (DPN).
      Authors (Year)PopulationMR AssessmentOutcome
      Allen et al (2014)
      • Allen M.D.
      • Major B.
      • Kimpinski K.
      • et al.
      Skeletal muscle morphology and contractile function in relation to muscle denervation in diabetic neuropathy.
      12/DPN, 12/controlsTA CSA and % contractile muscleSignificant loss in contractile muscle in DPN in TA
      Allen et al (2016)
      • Allen M.D.
      • Doherty T.J.
      • Rice C.L.
      • Kimpinski K.
      Physiology in medicine: neuromuscular consequences of diabetic neuropathy.
      Almurdhi et al (2016)
      • Almurdhi M.M.
      • Reeves N.D.
      • Bowling F.L.
      • et al.
      Reduced lower-limb muscle strength and volume in patients with type 2 diabetes in relation to neuropathy, intramuscular fat, and vitamin D levels.
      20/diabetic, 20/controlsUpper/lower leg muscle CSAProximal muscle strength impairment relates to severity of DPN
      Andersen et al (1997)
      • Andersen H.
      • Gadeberg P.
      • Brock B.
      • Jakobsen J.
      Muscular atrophy in diabetic neuropathy: a stereological magnetic resonance imaging study.
      8/DPN, 8/diabetic, 16 controlsLower leg muscle CSASignificantly lower CSA in dorsal/plantar flexors in DPN at distal and mid-part of lower leg
      Andersen et al (2004)
      • Andersen H.
      • Gjerstad M.D.
      • Jakobsen J.
      Atrophy of foot muscles: a measure of diabetic neuropathy.
      15/DPN, 8/diabetic, 23 controlsFoot muscle CSASignificant foot muscle atrophy in DPN
      Foot muscle atrophy relates to DPN severity
      Andreassen et al (2009)
      • Andreassen C.S.
      • Jakobsen J.
      • Ringgaard S.
      • et al.
      Accelerated atrophy of lower leg and foot muscles—a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI).
      8/diabetic (type 1), 4/DPN (type 1)Leg muscle volumeSignificant dorsal flexor and plantar flexor volume loss in DPN compared with diabetes without neuropathy
      7/diabetic (type 1), 7/DPN (type 1)Foot muscle volumeSignificant foot muscle volume loss both in DPN and diabetes without neuropathy
      Bittel et al (2015)
      • Bittel D.C.
      • Bittel A.J.
      • Tuttle L.J.
      • et al.
      Adipose tissue content, muscle performance and physical function in obese adults with type 2 diabetes mellitus and peripheral neuropathy.
      54/DPM, 13/diabetic, 24/obeseLeg IMAT/SQATDPN relates to shift from SQAT to IMAT
      Bus et al (2002)
      • Bus S.A.
      • Yang Q.X.
      • Wang J.H.
      • et al.
      Intrinsic muscle atrophy and toe deformity in the diabetic neuropathic foot: a magnetic resonance imaging study.
      8/DPN, 8/controlsFoot muscle CSA/muscle T2Significant muscle tissue loss distally in DPN
      Cheuy et al (2013)
      • Cheuy V.A.
      • Hastings M.K.
      • Commean P.K.
      • et al.
      Intrinsic foot muscle deterioration is associated with metatarsophalangeal joint angle in people with diabetes and neuropathy.
      23/DPN, 12/controlsFoot IMATSignificantly higher in IMAT in foot muscles of patients with DPN
      Dinh et al (2009)
      • Dinh T.
      • Doupis J.
      • Lyons T.E.
      • et al.
      Foot muscle energy reserves in diabetic patients without and with clinical peripheral neuropathy.
      18/DPM, 22/diabetic, 24/controlsPCr/Pi in metatarsal headPCr/Pi were lower in DPN compared with diabetes without neuropathy and healthy control subjects
      Lipid/water in metatarsal headLipid/water ratios lower in DPN but similar in patients with diabetes and healthy control subjects
      Greenman et al (2005)
      • Greenman R.L.
      • Panasyuk S.
      • Wang X.
      • et al.
      Early changes in the skin microcirculation and muscle metabolism of the diabetic foot.
      5/DPM, 7/diabetic, 8/controlsPi/PCr in foot musclesHigher Pi/PCr in DPN and diabetes compared with control subjects
      Greenman et al (2005)
      • Greenman R.L.
      • Khaodhiar L.
      • Lima C.
      • et al.
      Foot small muscle atrophy is present before the detection of clinical neuropathy.
      12/DPM, 9/diabetic, 12/controlsFoot muscle CSA/31PFoot muscle area correlates to clinical measures of DPN. 31P levels different in the 3 groups
      Moore et al (2016)
      • Moore C.W.
      • Allen M.D.
      • Kimpinski K.
      • et al.
      Reduced skeletal muscle quantity and quality in patients with diabetic polyneuropathy assessed by magnetic resonance imaging.
      9/DPN, 8/diabeticMTR/T2 in TAIncreased muscle atrophy in DPN compared with healthy control subjects
      Lower MTR in DPN compared with healthy control subjects
      Pham et al (2015)
      • Pham M.
      • Oikonomou D.
      • Hornung B.
      • et al.
      Magnetic resonance neurography detects diabetic neuropathy early and with proximal predominance.
      35/DPN, 15/diabetic, 25/controlsNerve lesion/proton densityTotal burden of nerve lesion increases with DPN severity, particularly at thigh level
      From spinal nerve to ankle levelIncreased nerve proton density with DPN severity at thigh level
      Tecilazich et al (2013)
      • Tecilazich F.
      • Dinh T.
      • Lyons T.E.
      • et al.
      Postexercise phosphocreatine recovery, an index of mitochondrial oxidative phosphorylation, is reduced in diabetic patients with lower extremity complications.
      10/DPN, 7/DPN + PAD, 11/diabeticPostexercise recovery of Pi/PCrSignificantly increased recovery time of Pi/PCr in DPN and DPN + PAD compared with diabetic and control subjects
      14/controls
      Wu et al (2016)
      • Wu C.
      • Wang G.
      • Zhao Y.
      • et al.
      Assessment of tibial and common peroneal nerves in diabetic peripheral neuropathy by diffusion tensor imaging: a case control study.
      10/DPN, 12/controlsFA and ADC of TN and CPNFA lower in DPN patients than healthy control subjects and correlates positively with MCV
      ADC significantly higher in DPN patients and correlates negatively with MCV
      31P = phosphorus 31; ADC = apparent diffusion coefficient; CPN = common peroneal nerve; CSA = cross-sectional area; FA = fractional anisotropy; IMAT = intramuscular adipose tissue; MCV = motor nerve conduction velocity; MTR = magnetization transfer ratio; SQAT = subcutaneous adipose tissue; PAD = peripheral arterial disease; PCr = phosphocreatine; Pi = inorganic phosphate; T2 = transverse relaxation time; TA = tibialis anterior; TN = tibial nerve.

      Magnetic Resonance Neurography

      High-resolution magnetic resonance neurography (MRN) has excellent anatomic capability.
      • Viallon M.
      • Vargas M.
      • Jlassi H.
      • et al.
      High-resolution and functional magnetic resonance imaging of the brachial plexus using an isotropic 3D T2 STIR (Short Term Inversion Recovery) SPACE sequence and diffusion tensor imaging.
      With improved detection of nerve anatomy and pathology, the value of MRN as a potential biomarker of the nerve effects of DPN has been increasingly recognized.
      • Chhabra A.
      • Andreisek G.
      • Soldatos T.
      • et al.
      MR neurography: past, present, and future.
      • Chhabra A.
      • Zhao L.
      • Carrino J.A.
      • et al.
      MR neurography: advances.
      MRN is aimed at supressing the vascular and fat signal to create unique tissue selective images. This method is based on T2-weighted sequences with fat suppression, which provides excellent depiction of the peripheral nerves.
      • Thawait S.
      • Chaudhry V.
      • Thawait G.
      • et al.
      High-resolution MR neurography of diffuse peripheral nerve lesions.
      Intraneural T2-weighted contrast and nerve caliber allows localization and diagnosis of peripheral neuropathy.
      • Bendszus M.
      • Stoll G.
      Technology insight: visualizing peripheral nerve injury using MRI.
      Nerve T2 signal has been shown to have a high diagnostic accuracy.
      • Bäumer P.
      • Dombert T.
      • Staub F.
      • et al.
      Ulnar neuropathy at the elbow: MR neurography—nerve T2 signal increase and caliber.
      During the early stages of the disease, sensory signs and symptoms typically occur first at the tip of the toes and in the feet and are later more severe in these distal regions (eg, loss of sensation across modalities, tingling, burning, pain, paresthesia, numbness). Progression of DPN may be associated with the proximal extension of sensory and/or motor signs and symptoms involving the ankle or further proximal levels. Therefore, MRN can play a key role in understanding the spatiotemporal distribution and propagation of microstructural nerve alterations in DPN and for early monitoring of microstructural effects of therapeutic interventions.
      • Pham M.
      • Oikonomou D.
      • Hornung B.
      • et al.
      Magnetic resonance neurography detects diabetic neuropathy early and with proximal predominance.
      More recently, several variations of MRN sequences have been proposed, which can achieve both high resolution and good fat suppression on 3T scanners.
      • Thakkar R.S.
      • Del Grande F.
      • Thawait G.K.
      • et al.
      Spectrum of high-resolution MRI findings in diabetic neuropathy.

      Diffusion Tensor Imaging

      Diffusion tensor imaging (DTI) is a powerful noninvasive MRI technique that allows quantitative assessment of neuronal architecture.
      • Breckwoldt M.O.
      • Stock C.
      • Xia A.
      • et al.
      Diffusion tensor imaging adds diagnostic accuracy in magnetic resonance neurography.
      As an additional functional technique, DTI is increasingly being investigated with regard to its potential to help detect nerve injury and monitor reinnervation.
      • Takagi T.
      • Nakamura M.
      • Yamada M.
      • et al.
      Visualization of peripheral nerve degeneration and regeneration: monitoring with diffusion tensor tractography.
      • Lehmann H.C.
      • Zhang J.
      • Mori S.
      • Sheikh K.A.
      Diffusion tensor imaging to assess axonal regeneration in peripheral nerves.
      • Sheikh K.A.
      Non-invasive imaging of nerve regeneration.
      • Kamath S.
      • Venkatanarasimha N.
      • Walsh M.
      • Hughes P.
      MRI appearance of muscle denervation.
      More recent research has shown that DTI can be used for the diagnosis of neuropathy,
      • Bäumer P.
      • Pham M.
      • Ruetters M.
      • et al.
      Peripheral neuropathy: detection with diffusion-tensor imaging.
      as well as bring new insights to the involvement of the central nervous system in DPN.
      • Tesfaye S.
      • Selvarajah D.
      • Gandhi R.
      • et al.
      Diabetic peripheral neuropathy may not be as its name suggests: evidence from magnetic resonance imaging.
      • Wilkinson I.D.
      • Selvarajah D.
      • Greig M.
      • et al.
      Magnetic resonance imaging of the central nervous system in diabetic neuropathy.
      The quantitative parameters of DTI include fractional anisotropy and apparent diffusion coefficient values, which reflect the diffusion characteristics of water molecules and are altered with loss of integrity of the nervous tissue. Water molecules diffuse easily along the direction of the nerve fiber bundle, and the diffusion perpendicular to the fiber bundle is limited as a result of nerve sheath covering. The directional preference of free water proton diffusion leads to high fractional anisotropy values in intact peripheral nerves. The pathologic conditions of the peripheral nerves lead to loss of structural integrity and directional coherence of the nerve fibers, which can be measured as decreased fractional anisotropy values.
      • Wu C.
      • Wang G.
      • Zhao Y.
      • et al.
      Assessment of tibial and common peroneal nerves in diabetic peripheral neuropathy by diffusion tensor imaging: a case control study.
      The apparent diffusion coefficient reflects the degree of diffusion of a molecule and is an index to indirectly assess diffusion barriers such as the cell membrane or myelin sheath. Inflammation, edema, and injury can lead to increased apparent diffusion coefficient in patients with DPN (Figure 2).
      Figure 2
      Figure 2Axial diffusion tensor imaging (DTI). Nerve fiber tracts of the tibial and common peroneal nerves at the level of the right knee of (A) a healthy control subject and (B) a patient with diabetic peripheral neuropathy (DPN). DTI detected decreased fractional anisotropy and increased apparent diffusion coefficient in patients with DPN. Reprinted with permission Wu et al.
      • Wu C.
      • Wang G.
      • Zhao Y.
      • et al.
      Assessment of tibial and common peroneal nerves in diabetic peripheral neuropathy by diffusion tensor imaging: a case control study.

      Fat Infiltration Assessment

      DPN is closely linked to muscle weakness, atrophy, and excess fat infiltration in the extremities.
      • Allen M.D.
      • Major B.
      • Kimpinski K.
      • et al.
      Skeletal muscle morphology and contractile function in relation to muscle denervation in diabetic neuropathy.
      • Hilton T.N.
      • Tuttle L.J.
      • Bohnert K.L.
      • et al.
      Excessive adipose tissue infiltration in skeletal muscle in individuals with obesity, diabetes mellitus, and peripheral neuropathy: association with performance and function.
      Skeletal muscle in DPN has been shown to directly result in greater muscle atrophy compared with DM alone.
      • Boulton A.
      • Ward J.
      Diabetic neuropathies and pain.
      • Bril V.
      • Werb M.R.
      • Greene D.A.
      • Sima A.A.
      Single‐fiber electromyography in diabetic peripheral polyneuropathy.
      An MRI can be used to depict unique patterns of muscle infiltration in DPN.
      • Bittel D.C.
      • Bittel A.J.
      • Tuttle L.J.
      • et al.
      Adipose tissue content, muscle performance and physical function in obese adults with type 2 diabetes mellitus and peripheral neuropathy.
      Insulin resistance has been associated with the amount of ectopic lipids, including intramyocellular lipids
      • Machann J.
      • Häring H.
      • Schick F.
      • Stumvoll M.
      Intramyocellular lipids and insulin resistance.
      and intrahepatic lipids,
      • Chan D.
      • Watts G.
      • Ng T.
      • et al.
      Measurement of liver fat by magnetic resonance imaging: relationships with body fat distribution, insulin sensitivity and plasma lipids in healthy men.
      as well as the amount and the distribution of fat in different body regions, including visceral adipose tissue
      • Cefalu W.T.
      • Wang Z.Q.
      • Werbel S.
      • et al.
      Contribution of visceral fat mass to the insulin resistance of aging.
      and intermuscular adipose tissue (IMAT).
      • Gallagher D.
      • Kuznia P.
      • Heshka S.
      • et al.
      Adipose tissue in muscle: a novel depot similar in size to visceral adipose tissue.
      IMAT infiltration in large muscle groups of the lower extremity is a particularly important etiologic factor in the onset and progression of type 2 DM and its complications due to its hormonal and structural influences on skeletal muscle, which is responsible for 90% of peripheral glucose uptake.
      • DeFronzo R.A.
      • Tripathy D.
      Skeletal muscle insulin resistance is the primary defect in type 2 diabetes.
      IMAT can be quantified by using MR spectroscopy,
      • Machann J.
      • Häring H.
      • Schick F.
      • Stumvoll M.
      Intramyocellular lipids and insulin resistance.
      high-spatial resolution T1-weighted sequences,
      • Boettcher M.
      • Machann J.
      • Stefan N.
      • et al.
      Intermuscular adipose tissue (IMAT): association with other adipose tissue compartments and insulin sensitivity.
      and, more recently, chemical shift-based water fat separation MRI techniques.
      • Karampinos D.C.
      • Baum T.
      • Nardo L.
      • et al.
      Characterization of the regional distribution of skeletal muscle adipose tissue in type 2 diabetes using chemical shift‐based water/fat separation.
      IMAT accumulation has been shown to be higher in patients with DPN compared with those with type 2 DM without DPN and body mass index–matched control subjects.
      • Bittel D.C.
      • Bittel A.J.
      • Tuttle L.J.
      • et al.
      Adipose tissue content, muscle performance and physical function in obese adults with type 2 diabetes mellitus and peripheral neuropathy.
      In addition to the IMAT accumulation, the distribution of adipose tissue deposition may also change with the severity and progression of DM complications. The expansion of visceral adipose tissue depots, as opposed to subcutaneous depots, has been associated with peripheral insulin resistance, hyperglycemia, and cardiovascular disease in obese populations.
      • Lebovitz H.E.
      • Banerji M.A.
      Point: visceral adiposity is causally related to insulin resistance.
      The progression of obesity (control) to type 2 DM with DPN and the accompanying loss of subcutaneous depots, accumulation of IMAT, loss of muscle volume (gastroc-soleus % volume), and reduced physical function is shown in Figure 3. IMAT has been a useful index for monitoring intervention related to exercise and nutrition
      • Durheim M.T.
      • Slentz C.A.
      • Bateman L.A.
      • et al.
      Relationships between exercise-induced reductions in thigh intermuscular adipose tissue, changes in lipoprotein particle size, and visceral adiposity.
      • Mojtahedi M.C.
      • Thorpe M.P.
      • Karampinos D.C.
      • et al.
      The effects of a higher protein intake during energy restriction on changes in body composition and physical function in older women.
      and could become a powerful tool in understanding the effects of intervention in DPN.
      Figure 3
      Figure 3Cross-sectional images of the legs of a control subject, a patient with type 2 diabetes mellitus (T2DM), and a patient with type 2 DM and diabetic peripheral neuropathy (T2DMPN) . These images exemplify the progression of obesity (control) to T2DMPN and the accompanying loss of subcutaneous adipose tissue (SQAT), accumulation of intermuscular adipose tissue (IMAT), loss of muscle volume (gastroc-soleus % volume), and reduced physical function (PPT). Reprinted with permission from Bittel et al.
      • Bittel D.C.
      • Bittel A.J.
      • Tuttle L.J.
      • et al.
      Adipose tissue content, muscle performance and physical function in obese adults with type 2 diabetes mellitus and peripheral neuropathy.

      MRI for Assessment of Perfusion and Microvascular Function in DPN

      Blood flow and perfusion reductions may also contribute to the effects of DPN in skeletal muscle.
      • Petrofsky J.
      • Lee S.
      • Cuneo M.
      Effects of aging and type 2 diabetes on resting and post occlusive hyperemia of the forearm; the impact of rosiglitazone.
      MV density
      • Andreassen C.S.
      • Jensen J.M.
      • Jakobsen J.
      • et al.
      Striated muscle fiber size, composition, and capillary density in diabetes in relation to neuropathy and muscle strength.
      and function
      • Bauer T.A.
      • Reusch J.E.
      • Levi M.
      • Regensteiner J.G.
      Skeletal muscle deoxygenation after the onset of moderate exercise suggests slowed microvascular blood flow kinetics in type 2 diabetes.
      • Slade J.M.
      • Towse T.F.
      • Gossain V.V.
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      Abnormal skeletal muscle capillary recruitment during exercise in patients with type 2 diabetes mellitus and microvascular complications.
      are compromised in DPN. Blood-oxygenation level-dependent (BOLD) MRI can probe MV function in skeletal muscle
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      Dual gradient‐echo MRI of post‐contraction changes in skeletal muscle blood volume and oxygenation.
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      Absence of a significant extravascular contribution to the skeletal muscle BOLD effect at 3 T.
      Typically, the experiment involves a brief muscle contraction, which places a small metabolic load on the muscle and results in a postcontraction increase in blood flow. The postcontractile BOLD signal can be a measure of primarily small vessel reactivity and peripheral MV function.
      • Damon B.M.
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      Dual gradient‐echo MRI of post‐contraction changes in skeletal muscle blood volume and oxygenation.
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      BOLD MRI mapping of transient hyperemia in skeletal muscle after single contractions.
      In a preliminary study, it was shown that BOLD MRI is sensitive in identifying MV impairment in patients with type 2 DM and MV disease (ie, DPN, retinopathy). MRI can be useful in assessing reversal of MV function in DPN.

      Phosphorus Magnetic Resonance Spectroscopy for Metabolic Assessment of Skeletal Muscle

      Phosphorus magnetic resonance spectroscopy (31P-MRS) allows direct measurement of important high-energy phosphates in human tissue,
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      Point: visceral adiposity is causally related to insulin resistance.
      such as adenosine triphosphate (ATP), phosphocreatine (PCr), and inorganic phosphate. Resting levels of high-energy phosphates are reduced in the diabetic foot.
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      Foot small muscle atrophy is present before the detection of clinical neuropathy.
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      Abnormal mitochondrial function and muscle wasting, but normal contractile efficiency, in haemodialysed patients studied non-invasively in vivo.
      During exercise, ATP is consumed and maintained at a constant level through PCr hydrolysis. This action leads to a reduction in PCr and an increase in inorganic phosphate, which can be directly observed in 31P-MRS. During recovery, ATP, and thus PCr, is resynthesized through oxidative phosphorylation, which takes place in the mitochondria.
      • Kemp G.J.
      • Crowe A.V.
      • Anijeet H.K.
      • et al.
      Abnormal mitochondrial function and muscle wasting, but normal contractile efficiency, in haemodialysed patients studied non-invasively in vivo.
      • Chance B.
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      P31 NMR-studies of control of mitochondrial-function in phosphofructokinase-deficient human skeletal muscle.
      • Prompers J.J.
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      • Kemp G.J.
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      MITOCHONDRIA: investigation of in vivo muscle mitochondrial function by 31P magnetic resonance spectroscopy.
      • Kemp G.J.
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      • et al.
      Muscle oxygenation and ATP turnover when blood flow is impaired by vascular disease.
      The recovery of PCr is considered a valid index of mitochondrial oxidative phosphorylation.
      • Prompers J.J.
      • Wessels B.
      • Kemp G.J.
      • Nicolay K.
      MITOCHONDRIA: investigation of in vivo muscle mitochondrial function by 31P magnetic resonance spectroscopy.
      • Arnold D.L.
      • Matthews P.M.
      • Radda G.K.
      Metabolic recovery after exercise and the assessment of mitochondrial function in vivo in human skeletal-muscle by means of 31P NMR.
      • Kemp G.J.
      • Taylor D.J.
      • Radda G.K.
      Control of phosphocreatine resynthesis during recovery from exercise in human skeletal-muscle.
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      • Jeneson J.A.L.
      • Drost M.R.
      • et al.
      Dynamic MRS and MRI of skeletal muscle function and biomechanics.
      One study showed that the postexercise time of recovery of PCr was prolonged in patients with DPN compared with patients with type 2 DM without neuropathy.
      • Tecilazich F.
      • Dinh T.
      • Lyons T.E.
      • et al.
      Postexercise phosphocreatine recovery, an index of mitochondrial oxidative phosphorylation, is reduced in diabetic patients with lower extremity complications.
      This impairment in oxidative capacity was ~50% in DPN compared with DM without neuropathy and was not affected by the presence of peripheral arterial disease.

      Conclusions

      DPN is associated with neurogenic muscle atrophy, a reduced rate of muscle contraction, and muscle wasting. In addition, changes in muscle metabolism and blood flow associated with DPN increase fatigability. Impairments in lower limb muscles reduce functional capacity and contribute to altered gait, increased fall risk, and impaired balance in patients with DPN. This is an important concern for patients with DPN because their falls are likely to be injurious. Several treatments that specifically target pathogenic DPN mechanisms have been tested both on animal models and humans. However, despite encouraging early results, there are no therapies to prevent or reverse its progress. A growing body of literature supports the benefits of combining moderate-intensity aerobic exercise with resistance training to improve glycemic control and insulin sensitivity in individuals with DM. Recently, several studies have shown that moderate-intensity supervised exercise is well tolerated by patients with DPN and can help them improve both their cardiovascular function and partially reverse DPN symptoms. Advanced MRI techniques can provide mechanistic insight into the adaptations in peripheral nerve structure and skeletal muscle function after physical exercise interventions.

      Conflicts of Interest

      The authors have indicated that they have no conflicts of interest regarding the content of this article.

      Acknowledgments

      This work was supported by a grant from the National Institutes of Health (R01DK106292).
      All authors contributed in the writing and reviewing of the manuscript.

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