Influence of Peripheral Neuropathy and Microangiopathy on Skin Hydration in the Feet of Patients With Diabetes Mellitus

Introduction. Maintaining adequate skin hydration is crucial in the feet of patients with diabetes because xerotic skin may crack and develop fissures, thereby increasing vulnerability to ulceration and infection. The nervous system is considered the powerhouse for maintaining adequate skin hydration; however, no clinical study has assessed the effect of the nervous system on skin hydration. In addition, it is hypothesized that microcirculation may play an important role in maintaining adequate hydration in patients with diabetes. Objective. This study aims to evaluate the influence of peripheral nerve function and microvascularity on skin hydration in the feet of patients with diabetes mellitus and compare the effects of these 2 functions on skin hydration. Materials and Methods. This study included 266 patients with diabetic foot disease. Skin hydration was evaluated using corneometry and microvascularity by measuring the transcutaneous oximetry (TcpO₂) of the foot. The Semmes-Weinstein 5.07/10-g monofilament test, electromyography, and nerve conduction velocity test were conducted to evaluate peripheral neuropathy. Patient data were divided into 3 subgroups according to test values, and statistical comparisons were performed using the linear-by-linear association trend and Pearson’s chi-square tests. Results. There was a significant (P < .001) correlation between skin hydration and TcpO₂. However, there was no significant correlation between skin hydration and peripheral nerve function (P = .338). Conclusions. The results of this study demonstrated that skin hydration in the feet of patients with diabetes mellitus mainly is influenced by microcirculation rather than peripheral nerve function.

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Xerosis, defined as abnormal dryness and scaling of the skin, is a common cutaneous disorder frequently observed in patients with diabetes.¹ Ultimately, the skin may crack and develop fissures, which are a potential gateway for the entry of bacteria, thereby increasing vulnerability to ulceration and infection.^2,3 Therefore, maintaining adequate skin hydration is crucial in patients with diabetes.

The nervous system is considered the powerhouse for the maintenance of adequate skin hydration.^4-10 Peripheral neuropathy, due to damage to small sympathetic nerves, is known to result in atrophy of sweat glands and decreased sudomotor response. This may affect the suppleness and flexibility of the skin and thus can lead to ulceration in patients with diabetic foot disease. Theoretically, peripheral nerve function should be associated with skin hydration level, because sweat glands are innervated by the sudomotor, postganglionic, unmyelinated cholinergic sympathetic C-fibers.^11,12 However, to the best of the authors’ knowledge, no clinical study has assessed the influence of peripheral nerve function on skin hydration. 

In addition, when the skin of patients with compromised microcirculation was examined, the authors found that the skin was extremely dry, rough, shiny, and desquamated. Based on these clinical findings, the authors also hypothesized that microvascular function might play a major role in maintaining adequate hydration of diabetic feet. Therefore, this study aims to evaluate the influence of the peripheral nervous system and microcirculation on skin hydration and to compare the influence of these 2 functions on skin hydration of diabetic feet.

Materials
The medical records of 361 patients with diabetes mellitus who were treated at the Diabetic Wound Center of Korea University Guro Hospital (Seoul, South Korea) between June 2012 and May 2015 were reviewed. Patients who met the following criteria were included in the study: (1) data of the Semmes-Weinstein monofilament test as well as electromyography (EMG) and nerve conduction velocity (NCV) of both motor and sensory fibers; (b) transcutaneous oximetry (TcpO₂) findings; (c) corneometry findings; and (d) medical history of diabetes > 5 years. Patients who had wound infections or cellulitis while undergoing the tests were excluded. 

Overall, 266 patients (200 men, 66 women) with a mean age of 63.0 ± 2.9 years (range, 30–91 years) met the inclusion criteria (Table 1). Among those 266 patients, 228 (85.7%) had ulcers. The degree of xerosis was graded as severe, moderate, or acceptable. Severe was defined as having corneometry values < 21 arbitrary units (a.u.; n = 88), moderate as having corneometry values of 21 a.u. to 30 a.u. (n = 156), and acceptable as having corneometry values > 30 a.u. (n = 22).

The degree of diabetic neuropathy was graded as severe, moderate, or acceptable. Severe was defined as having monofilament test values < 7, with positive neuropathy findings on the EMG/NCV test (n = 26). Moderate was defined as having monofilament test values < 7, with negative neuropathy findings on the EMG/NCV tests; or monofilament test values ≥ 7, with positive neuropathy findings on the EMG/NCV tests (n = 157). Acceptable was defined as having monofilament test values ≥ 7, with negative neuropathy findings on the EMG/NCV tests (n = 83).

The degree of microcirculation was graded as severe, moderate, or acceptable. Severe was defined as having a TcpO₂ value < 21 mm Hg (n = 52), whereas moderate had TcpO₂ values of 21 mm Hg to 40 mm Hg (n = 103) and acceptable had values > 40 mm Hg (n = 111).

Measurement of skin hydration
Skin hydration was evaluated objectively using a corneometry device (Elasticity & Moisture Sensor; Bomtech Electronics Co Ltd, Seoul, Korea). 

Hydration of the stratum corneum was measured on the dorsum of the foot at the most proximal point adjacent to the ulcer (Figure 1); patients with ulcers were placed in supine position for measurement. Skin hydration was always measured on the dorsum of the foot in an area directly opposite the lesion, even if the ulcer was present on the plantar aspect. In cases without an ulcer, hydration was measured at the tarsometatarsal level with the patient in a supine position. All patients were asked to refrain from washing with soap, using detergents, or applying cosmetics 24 hours prior to the test in order to eliminate the effect of these substances on skin moisture. All measurements were taken under standard climate conditions (25 ± 1°C; 50% ± 5% relative humidity) by a trained, experienced investigator (Y-N Lee) after a calibration check was performed. The mean value of 3 recordings at each site was used as the data, and all 3 recordings were completed at 1 visit (Figure 2). 

Measurement of neuropathy
The assessment of peripheral neuropathy included evaluation of quantitative sensory testing using the 5.07/10-g monofilament test and the EMG/NCV test.

For the Semmes-Weinstein monofilament test, each filament was applied perpendicular to the skin surface with enough force so that it buckles. Testing was performed at 10 different sites on each foot as recommended.^13,14 The EMG/NCV values of both sensory and motor fibers also were recorded by a physiatrist in the Department of Rehabilitation at Korea University Guro Hospital. Motor NCV tests were performed in the median, ulnar, peroneal, and tibial nerves, and F waves were recorded for each nerve. Sensory NCV tests were performed in the median, ulnar, and sural nerves. H reflex studies also were performed. Needle EMG was carried out in 3 muscles: vastus lateralis, tibialis anterior, and gastrocnemius medialis. Based on the suggestions from the Diabetes Control and Complications Trial, the following criteria were included as the diagnostic criteria for diabetic neuropathy^15,16: amplitude of the sural nerve was < 5 µV; amplitude of the median sensory nerve was < 10 µV; amplitude of the peroneal motor nerve was < 1 mV; latency was > 6 ms, or conduction velocity was < 40 m/s; the F wave latency was absent or > 55 ms; the H reflex was absent; and fibrillations were observed in the lower extremity muscles. 

Measurement of TcpO₂
To evaluate microcirculation of the feet, TcpO₂ was measured using a PF 5040 TcpO₂ (PeriFlux System 5040; Perimed AB, Stockholm, Sweden) paired with the PeriSoft program (PeriSoft for Windows 2.50; Perimed AB). Measurement of TcpO₂ was performed at the same site as that at which corneometry was performed (Figure 1) by the fourth study author (Y-N Lee).¹⁷ The TcpO₂ levels were recorded at 43°C after a 20-minute equilibration period.

Ethical considerations
The study protocol was approved by the institutional review board of Korea University Guro Hospital (Approval No. KUGH 15092-001). This study was performed in accordance with the Declaration of Helsinki.

Statistical analyses

All data were expressed as mean ± standard deviation. Statistical comparisons were performed using the linear-by-linear association trend test and Pearson’s chi-square test. A P value < .05 was considered statistically significant. Statistical analysis was performed using SAS 9.3 statistical software (SAS Institute, Cary, NC).

The subgroup of patients with acceptable skin hydration levels tended to have an acceptable microcirculation state (68.2%, 15/22 patients; Table 2). However, only 31.8% of patients (7/22; Table 3) in this subgroup showed an acceptable diabetic neuropathy state. With respect to the severe xerosis subgroup, the highest proportion of patients (43.2%, 38/88; Table 2) demonstrated severe microangiopathy, but only 12.5% (11/88; Table 3) of patients in this subgroup showed severe peripheral neuropathy. There was a significant correlation between skin hydration and microcirculation (P < .001) but no significant correlation between skin hydration and peripheral nerve function (P = .338; Table 2 and Table 3).

Human skin is an organ composed of layered composite tissues, and it acts as an essential physical and chemical barrier to the external environment.¹⁸ The outermost layer of the skin, or the stratum corneum, regulates water loss and protects the underlying living tissue from environmental pathogens and insults. Upon rupture, the stratum corneum loses its function and becomes ineffective in regulating water loss¹⁸ or preventing external pathogens from infecting the underlying living tissue.¹⁹ Therefore, preserving skin integrity is essential, particularly in patients with diabetes mellitus.

There is an extensive body of literature implicating the importance of adequate hydration for maintaining the integrity of the skin.^2,3,11,20,21 Papanas et al² demonstrated that abnormally dry skin develops fissures, thereby increasing vulnerability to ulceration and infection. Further, Boulton et al³ found a strong relationship between xerosis and ulceration of the skin. Adequately hydrated skin acts as a primary barrier to external pathogens and creates an optimal environment for effective wound healing. It has long been observed that mucosal wounds, in which healing occurs in a moist environment, heal with minimal scarring and exhibit early return to baseline expression levels of inflammatory cytokines.^22,23 These observations highlight the importance of epithelial hydration in wound healing. As such, balancing skin hydration levels is important not only as a primary defender of skin integrity but also as a regulator of cutaneous homeostasis in wound healing. The authors undertook this study to focus on the important issues that have not been addressed previously and to evaluate and compare the influence of nerve function and microcirculation on skin hydration of diabetic feet. 

The results of this study demonstrate that skin hydration is little influenced by nerve function in diabetic feet. This result contradicts the traditional concepts in skin hydration. Nerve function is regarded as the powerhouse for maintaining adequate skin hydration; contrary to this conventional concept, the present study showed that nerve function was not significantly correlated with skin hydration, whereas microvascular function was significantly correlated with skin hydration. This study may be the first clinical report to demonstrate a correlation between microcirculation and skin hydration in patients with diabetic foot disease.

Different types of peripheral neuropathy have been identified depending on the damage to the type of nerve (ie, motor, sensory, or autonomic). According to the traditional concept of sweating and skin hydration, the activity of sweat glands is controlled by the division of the sympathetic system, the postsympathetic cholinergic nerve fibers, which release acetylcholine and provoke sweat output.^5,24 The results of this study demonstrated that nerve function is not a sufficient condition for adequately maintaining skin hydration. In other words, the results indicate unimpaired peripheral nerve function alone does not guarantee a moist environment in diabetic feet. This may be attributed to the fact that the skin hydration level is regulated by many factors other than the activity of sweat glands, such as the epidermal function in cutaneous homeostasis, specifically, mechanical and cytoskeletal activities of epithelial ion channels that regulate water loss; hyperosmotic stress related to diffusion through the ion channels^25,26; and the barrier function to prevent moisture loss through the high lipid content in the stratum corneum. Throughout the body, sodium homeostasis is highly regulated through the combination of specialized sodium channels and aquaporins, which indirectly regulate sodium concentration by water transport; consequently so, nerve function was not significantly related to the skin hydration level in the present study. 

The reason for the strong correlation between skin hydration and microcirculation can be inferred. There are several reports on skin hydration that discuss the effect of interstitial fluid transfer through the dermal collagen unfolding mechanism. McGee et al²⁷ demonstrated that collagen unfolding accelerates water influx, determining skin hydration. Collagen organizes and supports the extracellular matrix of blood vessels. In the dermis, the collagen bundle structure mediates the interchange of water nutrients between the blood, lymph, interstitial cell network, and epidermal layers.^28,29 When microcirculation is well maintained, water transport through the collagen unfolding mechanism occurs smoothly, and the resulting higher hydration potential and accelerated fluid influx can be explained by emerging surface tension gradients and decreased resistance to local flow; therefore, an adequate skin hydration level can be maintained.²⁹ However, when the microcirculation is poor, fluid transfer between the blood, lymph, interstitial cell network, and epidermal layers is not efficient. In the present study, patients with poor microcirculation tended to show decreased skin hydration levels.

The results of this study also can be applied to the assessment of microcirculation in patients with diabetic foot disease. It is beyond dispute that microcirculation needs to be assessed early in order to decide the treatment plan for patients with diabetic foot disease. It is evident that early detection and appropriate diagnosis of ischemia and impaired microcirculation in the lower limb is an important research field. For this purpose, several diagnostic modalities have been used, including the ankle-brachial index, Doppler ultrasound, angiography imaging, and TcpO₂. Unlike in individuals without diabetes, microcirculation in patients with diabetes is commonly compromised, regardless of the status of the macrocirculation.³⁰ Hence, assessment of the microvascular state in diabetic feet is essential, and TcpO₂, which represents the actual tissue oxygen perfusion, is widely acknowledged to be a reliable method for evaluating microcirculation in patients with diabetes.²⁹ Even so, the method of measuring TcpO₂ is very cumbersome, because it requires expensive equipment and trained personnel. 

On the contrary, corneometry, an established method for the determination of skin hydration, is an efficient instrument to measure the water content in the stratum corneum in a straightforward manner.^32,33 The advantages of corneometry are its high reproducibility, easy handling, short measurement time, and economic feasibility.^34-36 A corneometry device registers the electrical conductance of the skin surface as an indication of stratum corneum hydration, which is dependent on the high dielectric constant of water content relative to other skin components. Thus, it may be possible to use this device to conveniently assess the microcirculation state in diabetic feet.

Preexisting states, complications, therapies, and medications also may be factors for the development of xerosis. Preexisting states that may contribute to xerosis include end-stage renal disease, nutritional deficiency (especially zinc and essential fatty acids), thyroid disease, neurological disorders, human immunodeficiency virus, malignancy, radiation, antiandrogen medications, and diuretic therapy.³⁷ Unfortunately, the authors could not investigate these factors in the present retrospective study, and further studies are needed in the near future. 

Another limitation of the present study is that diabetic neuropathy was assessed using the monofilament test and EMG/NCV test rather than the sudomotor test. There are limitations to sudomotor axon testing in a clinical setting, and electrophysiological tests usually are not recommended for establishing the diagnosis of diabetic neuropathy.^6,13,38 The diagnosis of diabetic neuropathy usually is based on physical examination and the EMG/NCV test.^6,13,39 Further studies might help specifically reveal the relationship between skin hydration and sudomotor nerve function. In addition, the present study did not divide patients into ulcer and nonulcer groups. Ulceration in diabetic foot disease could affect the microcirculation around the ulcerations. Further studies are required to clarify the influence of ulcerations on microcirculation.

There is insufficient research evidence to suggest skin hydration is influenced by nerve function. In particular, to the best of the authors’ knowledge, no clinical study has been performed to assess the influence of peripheral nervous system on skin hydration. In addition, no clinical study has reported the influence of microcirculation on skin hydration. 

The results of this study demonstrated that skin hydration is more influenced by microcirculation, rather than peripheral nerve function, in diabetic feet. This study may be the first to demonstrate a correlation between microcirculation and skin hydration in a large number of patients with diabetes treated using an identical management protocol at a single center.

Authors: Sik Namgoong, MD, PhD; Jong-Phil Yang, MD; Seung-Kyu Han, MD, PhD; Ye-Na Lee, MSc, RN, CWCN; and Eun Sang Dhong, MD, PhD

Affiliation: Department of Plastic Surgery, Korea University College of Medicine, Seoul, South Korea 

Correspondence: Seung-Kyu Han, MD, PhD, Department of Plastic Surgery, Korea University Guro Hospital, 148 Guro-dong, Guro-gu, Seoul 08308, South Korea; pshan@kumc.or.kr

Disclosure: The authors disclose no financial or other conflicts of interest.