Diabetic Neuropathy: A cross-sectional study of the relationships among tests of neurophysiology

OBJECTIVE — To determine the relationships among large, small, and autonomic fiber neurophysiological measures in a cross-sectional study of patients with diabetes. RESEARCH DESIGN AND METHODS — We assessed 130 individuals: 25 healthy subjects and 105 subjects with diabetes. Subjects were classified by the presence or absence of neuropathy by physical examination. All subjects underwent autonomic testing, nerve conduc-tion studies, quantitative sensory testing, and nerve-axon reflex vasodilation in addition to quantifiable neurological examination and symptom scores. Correlation and cluster analysis were used to determine relationships between and among different neurophysiological testing parameters. RESULTS — Results of neurophysiological tests were abnormal in patients with clinical evi-dence of diabetic neuropathy compared with results in healthy control subjects and in those without neuropathy (P 0.01, all tests). The correlations among individual tests varied widely, both within (r range0.5–0.9, NS to0.001) and between test groups (r range0.2–0.5, NS to0.01). A two-step hierarchical cluster analysis revealed that neurophysiological tests do not aggregate by typical “small, ” “large, ” or “autonomic ” nerve fiber subtypes

Minimally invasive surgery for diabetic plantar foot ulcerations

Complications of diabetes mellitus constitute the most common indications for hospitalization and non-traumatic amputations in the USA. The most important risk factors for the development of diabetic foot ulcerations include the presence of peripheral neuropathy, vasculopathy, limited joint mobility, and pre-existing foot deformities. In our study, 500 diabetic patients treated for plantar forefoot ulcerations were enrolled in a prospective study from 2000 to 2008 at the Federal University of São Paulo, Brazil. Fifty-two patients in the study met the criteria and underwent surgical treatment consisting of percutaneous Achilles tendon lengthening to treat plantar forefoot ulcerations. The postoperative follow-up demonstrated prevention of recurrent foot ulcerations in 92% of these diabetic patients that maintained an improved foot function. In conclusion, our study supports that identification and treatment of ankle equinus in the diabetic population may potentially lead to decreased patient morbidity, including reduced risk for both reulceration, and potential lower extremity amputation

Impaired Distal Thermoregulation in Diabetes and Diabetic Polyneuropathy

Objective: To determine how thermoregulation of the feet is affected by diabetes and diabetic polyneuropathy in both wakefulness and sleep. Research Design and Methods: Normal subjects, diabetic subjects without neuropathy, diabetic subjects with small-fiber diabetic polyneuropathy, and those with advanced diabetic polyneuropathy were categorized based on neurological examination, nerve conduction studies, and quantitative sensory testing. Subjects underwent foot temperature monitoring using an iButton device attached to the foot and a second iButton for recording of ambient temperature. Socks and footwear were standardized, and subjects maintained an activity diary. Data were collected over a 32-h period and analyzed. Results: A total of 39 normal subjects, 28 patients with diabetes but without diabetic polyneuropathy, 14 patients with isolated small-fiber diabetic polyneuropathy, and 27 patients with more advanced diabetic polyneuropathy participated. No consistent differences in foot temperature regulation between the four groups were identified during wakefulness. During sleep, however, multiple metrics revealed significant abnormalities in the diabetic patients. These included reduced mean foot temperature (P < 0.001), reduced maximal temperature (P < 0.001), increased rate of cooling (P < 0.001), as well as increased frequency of variation (P = 0.005), supporting that patients with diabetic polyneuropathy and even those with only diabetes but no diabetic polyneuropathy have impaired nocturnal thermoregulation. Conclusions: Nocturnal foot thermoregulation is impaired in patients with diabetes and diabetic polyneuropathy. Because neurons are highly temperature sensitive and because foot warming is part of the normal biology of sleep onset and maintenance, these findings suggest new potentially treatable mechanisms of diabetes-associated nocturnal pain and sleep disturbance

Foot Muscle Energy Reserves in Diabetic Patients Without and With Clinical Peripheral Neuropathy

Objective: To investigate changes in the foot muscle energy reserves in diabetic non-neuropathic and neuropathic patients. Research Design and Methods: We measured the phosphocreatinine (PCr)/inorganic phosphate (Pi) ratio, total $^{31}$P concentration, and the lipid/water ratio in the muscles in the metatarsal head region using MRI spectroscopy in healthy control subjects and non-neuropathic and neuropathic diabetic patients. Results: The PCr/Pi ratio was higher in the control subjects (3.23 $\pm$ 0.43) followed by the non-neuropathic group (2.61 $\pm$ 0.36), whereas it was lowest in the neuropathic group (0.60 $\pm$ 1.02) (P < 0.0001). There were no differences in total $^{31}$P concentration and lipid/water ratio between the control and non-neuropathic groups, but both measurements were different in the neuropathic group (P < 0.0001). Conclusions: Resting foot muscle energy reserves are affected before the development of peripheral diabetic neuropathy and are associated with the endothelial dysfunction and inflammation

Genome-wide DNA methylation analysis identifies a metabolic memory profile in patient-derived diabetic foot ulcer fibroblasts

Diabetic foot ulcers (DFUs) are a serious complication of diabetes. Previous exposure to hyperglycemic conditions accelerates a decline in cellular function through metabolic memory despite normalization of glycemic control. Persistent, hyperglycemia-induced epigenetic patterns are considered a central mechanism that activates metabolic memory; however, this has not been investigated in patient-derived fibroblasts from DFUs. We generated a cohort of patient-derived lines from DFU fibroblasts (DFUF), and site- and age-matched diabetic foot fibroblasts (DFF) and non-diabetic foot fibroblasts (NFF) to investigate global and genome-wide DNA methylation patterns using liquid chromatography/mass spectrometry and the Illumina Infinium HumanMethylation450K array. DFFs and DFUFs demonstrated significantly lower global DNA methylation compared to NFFs (p = 0.03). Hierarchical clustering of differentially methylated probes (DMPs, p = 0.05) showed that DFFs and DFUFs cluster together and separately from NFFs. Twenty-five percent of the same probes were identified as DMPs when individually comparing DFF and DFUF to NFF. Functional annotation identified enrichment of DMPs associated with genes critical to wound repair, including angiogenesis (p = 0.07) and extracellular matrix assembly (p = 0.035). Identification of sustained DNA methylation patterns in patient-derived fibroblasts after prolonged passage in normoglycemic conditions demonstrates persistent metabolic memory. These findings suggest that epigenetic-related metabolic memory may also underlie differences in wound healing phenotypes and can potentially identify therapeutic targets

An anatomically-based masking protocol for the assessment of in-shoe plantar pressure measurement of the forefoot

Background The area beneath the metatarsal heads is a common location of foot pain, which is often associated with high plantar pressures. Current plantar pressure assessment protocols focus mainly on the gross area of the forefoot with minimal attention paid to specific areas such as the metatarsal heads. The aim of this study was to develop and assess a new anatomically-based masking protocol that is clinically relevant to measure forefoot plantar pressure during shod conditions based on the anatomical positions of the metatarsal heads. Methods Initially, we developed a masking protocol to measure forefoot plantar pressure during shod conditions based on the anatomical positions of the metatarsal heads. This new masking protocol divided the forefoot into three sub-areas (proximal, beneath, and distal to the metatarsal heads) as determined by the position of each metatarsal head. Following development of the new masking protocol, we compared the new protocol against a traditional protocol, which defines the forefoot as between 51 and 81% of the foot length. To compare the two masking protocols, we tested two experimental conditions: (i) a control condition (i.e. no metatarsal pad), and (ii) a metatarsal pad condition. We then compared plantar pressure differences between the two experimental conditions for the two masking protocols. Participants for this component of the study included 36 community dwelling older adults (mean age 75.6 years ±5.4) with a history of forefoot pain. Forefoot plantar pressure data were measured while walking using the pedar®-X in-shoe system. Peak pressure, maximum force and contact area at the time of peak pressure were determined and results were compared between the two masking protocols. Results The traditional masking protocol showed that the metatarsal pad significantly decreased peak pressure and increased contact area in the forefoot area (i.e. within the entire mask area), but maximum force was not significantly different between the two conditions. In contrast, the newly developed anatomically-based masking protocol indicated that the metatarsal pad decreased peak plantar pressures distal to and beneath the metatarsal heads by increasing force and contact area proximal to the metatarsal heads. Conclusions An anatomically-based masking protocol that is clinically relevant was developed to assess forefoot plantar pressure during shod conditions based on the anatomical positions of metatarsal heads. We propose that the new forefoot masking protocol will provide greater interpretability of forefoot plantar pressure data, which will aid clinicians and researchers for diagnostic, prognostic and therapeutic purposes

Effects of articaine on [3H]noradrenaline release from cortical and spinal cord slices prepared from normal and streptozotocin-induced diabetic rats and compared to lidocaine.

Since a significant proportion of diabetic patients have clinical or subclinical neuropathy, there may be concerns about the use of local anaesthetics. The present study was designed to determine and compare the effects of articaine, a widely used anaesthetic in dental practice, and lidocaine on the resting and axonal stimulation-evoked release of [3H]noradrenaline ([3H]NA) in prefrontal cortex slices and the release of [3H]NA in spinal cord slices prepared from non-diabetic and streptozocin (STZ)-induced diabetic (glucose level=22.03+/-2.31mmol/l) rats. The peak of allodynia was achieved 9 weeks after STZ-treatment. Articaine and lidocaine inhibited the stimulation-evoked release in a concentration-dependent manner and increased the resting release by two to six times. These effects indicate an inhibitory action of these anaesthetics on Na+- and K+-channels. There was no difference in clinically important nerve conduction between non-diabetic and diabetic rats, as measured by the release of transmitter in response to axonal stimulation. The uptake and resting release of NA was significantly higher in the brain slices prepared from diabetic rats, but there were no differences in the spinal cord. For the adverse effects, the effects of articaine on K+ channels (resting release) are more pronounced compared to lidocaine. In this respect, articaine has a thiophene ring with high lipid solubility, which may present potential risks for some patients