Clinical and biomechanical effectiveness of foot-ankle exercise programs and weight-bearing activity in people with diabetes and neuropathy: A systematic review and meta-analysis.

BACKGROUND: Most interventions to prevent foot ulcers in people with diabetes do not seek to reverse the foot abnormalities that led to the ulcer. Foot-ankle exercise programs target these clinical and biomechanical factors, such as protective sensation and mechanical stress. Multiple RCTs exist investigating the effectiveness of such programs, but these have never been summarised in a systematic review and meta-analysis. METHODS: We searched the available scientific literature in PubMed, EMBASE, CINAHL, Cochrane databases and trial registries for original research studies on foot-ankle exercise programs for people with diabetes at risk of foot ulceration. Both controlled and non-controlled studies were eligible for selection. Two independent reviewers assessed the risk of bias of controlled studies and extracted data. Meta-analysis (using Mantel-Haenszel's statistical method and random effect models) was performed when >2 RCTs were available that met our criteria. Evidence statements, including the certainty of evidence, were formulated according to GRADE. RESULTS: We included a total of 29 studies, of which 16 were RCTs. A foot-ankle exercise programme of 8-12 weeks duration for people at risk of foot ulceration results in: (a) no increase or decrease risk of foot ulceration or pre-ulcerative lesion (Risk Ratio (RR): 0.56 (95% CI: 0.20-1.57)); (b) no increase or decrease risk of adverse events (RR: 1.04 (95% CI: 0.65-1.67)); (c) not increase or decrease barefoot peak plantar pressure during walking (Mean Difference (MD): -6.28 kPa (95% CI: -69.90-57.34)); (d) no increase or decrease health-related quality of life (no meta-analysis possible). Likely results in increases in ankle joint and first metatarsalphalangeal joint range of motion (MD: 1.49° (95% CI: -0.28-3.26)) may result in improvements in neuropathy signs and symptoms (MD: -1.42 (95% CI: -2.95-0.12)), may result in a small increase in daily steps in some people (MD: 131 steps (95% CI: -492-754)), and may not increase or decrease foot and ankle muscle strength and function (no meta-analysis was possible). CONCLUSIONS: In people at risk of foot ulceration, a foot-ankle exercise programme of 8-12 weeks duration may not prevent or cause diabetes-related foot ulceration. However, such a programme likely improves the ankle joint and first metatarsalphalangeal joint range of motion and neuropathy signs and symptoms. Further research is needed to strengthen the evidence base, and should also focus on the effects of specific components of foot-ankle exercise programs.

Gastroparesis might not be uncommon in patients with diabetes mellitus in a real-world clinical setting: a cohort study.

BACKGROUND: This study investigated the frequency of diabetic gastroparesis and associated risk factors in a real-world clinical setting. METHODS: This retrospective cross-sectional study included patients who underwent assessments of solid gastric emptying time (GET) by technetium-99 m scintigraphy between May 2019 and December 2020. We categorized patients into three groups according to gastric retention of technetium-99 m: rapid (< 65% at 1 h or < 20% at 2 h), normal (≤60% at 2 h and/or ≤ 10% at 4 h), and delayed (> 60% at 2 h and/or > 10% at 4 h). RESULTS: Patients with diabetes mellitus (DM) were more likely to show abnormal GET than those without DM (119 [70.8%] vs. 16 [44.4%]). The mean glycated A1c was 10.3% in DM patients. DM patients with normal GET were significantly younger (57.2 years, P = 0.044) than those with delayed (65.0 years) or rapid GET (60.2 years). Fasting glucose levels were the lowest in the normal GET group and the highest in the rapid GET group (delayed: 176.3 mg/dL, normal: 151.2 mg/dL, rapid: 181.0 mg/dL, P = 0.030). However, glycated A1c was not significantly different among the delayed, normal, and rapid GET groups in patients with DM. Patients with delayed and rapid GET showed a higher frequency of retinopathy (6.0 vs. 15.5%, P = 0.001) and peripheral neuropathy (11.3 vs. 24.4%, P = 0.001) than those with normal GET. In the multinomial logistic regression analysis, retinopathy demonstrated a positive association with delayed GET, while nephropathy showed a significant negative correlation. CONCLUSION: DM gastroparesis in the clinical setting was not uncommon. Abnormal GET, including delayed and rapid GET, was associated with DM retinopathy or peripheral neuropathy.

The Effect of Resistance Exercises Using an Elastic Band on Balance and Fear of Falling in Older Adults With Diabetic Peripheral Neuropathy: A 16-week Randomized Controlled Trial.

OBJECTIVE: The current study aimed to investigate the effect of resistance training using an elastic band on balance and fear of falling in older adults with diabetic peripheral neuropathy. DESIGN: The study was a clinical controlled trial with a repeated measure design. SETTING: Iranian Diabetes Foundation of Mashhad. PARTICIPANTS: The participants were 51 older adults with diabetic peripheral neuropathy and balance impairment (N=51). INTERVENTIONS: Participants were randomly assigned to 2 groups; 1 group received balance training using an elastic band and the other group just received balance training. MAIN OUTCOME MEASURES: The main outcomes were balance and fear of falling that were measured using Berg Balance Scale and a short version of the Fall Efficiency Scale-International, respectively. RESULTS: The results showed that balance resistance training with and without using an elastic band significantly enhances balance and reduces fear of falling in diabetic older adults suffering from balance issues. However, balance resistance training using an elastic band had a significantly better effect on the balance and fear of falling in the participants. The best results were obtained after week 12 (48 sessions of balance training). CONCLUSION: Balance rehabilitation programs may include an elastic band in balance resistance training for 12 weeks (3-4 sessions a week) for enhancing balance in diabetic older adults suffering from balance impairment.

Apolipoprotein-CIII O-Glycosylation Is Associated with Micro- and Macrovascular Complications of Type 2 Diabetes.

Apolipoprotein-CIII (apo-CIII) inhibits the clearance of triglycerides from circulation and is associated with an increased risk of diabetes complications. It exists in four main proteoforms: O-glycosylated variants containing either zero, one, or two sialic acids and a non-glycosylated variant. O-glycosylation may affect the metabolic functions of apo-CIII. We investigated the associations of apo-CIII glycosylation in blood plasma, measured by mass spectrometry of the intact protein, and genetic variants with micro- and macrovascular complications (retinopathy, nephropathy, neuropathy, cardiovascular disease) of type 2 diabetes in a DiaGene study (n = 1571) and the Hoorn DCS cohort (n = 5409). Mono-sialylated apolipoprotein-CIII (apo-CIII1) was associated with a reduced risk of retinopathy (ß = -7.215, 95% CI -11.137 to -3.294) whereas disialylated apolipoprotein-CIII (apo-CIII2) was associated with an increased risk (ß = 5.309, 95% CI 2.279 to 8.339). A variant of the GALNT2-gene (rs4846913), previously linked to lower apo-CIII0a, was associated with a decreased prevalence of retinopathy (OR = 0.739, 95% CI 0.575 to 0.951). Higher apo-CIII1 levels were associated with neuropathy (ß = 7.706, 95% CI 2.317 to 13.095) and lower apo-CIII0a with macrovascular complications (ß = -9.195, 95% CI -15.847 to -2.543). In conclusion, apo-CIII glycosylation was associated with the prevalence of micro- and macrovascular complications of diabetes. Moreover, a variant in the GALNT2-gene was associated with apo-CIII glycosylation and retinopathy, suggesting a causal effect. The findings facilitate a molecular understanding of the pathophysiology of diabetes complications and warrant consideration of apo-CIII glycosylation as a potential target in the prevention of diabetes complications.

A comprehensive review of the typical and atypical side effects of gabapentin.

BACKGROUND: Gabapentin, a widely prescribed medication for various neuropathic pain conditions, has demonstrated efficacy in managing diverse neurological disorders. While conventional side effects are well-documented, a growing body of evidence suggests the existence of atypical side effects, necessitating comprehensive exploration. This paper aims to systematically review and summarize the literature on the atypical side effects of gabapentin, shedding light on manifestations beyond the conventional spectrum. METHODS: A systematic review was conducted, encompassing peer-reviewed articles published up to the knowledge cutoff date in November 2023. Databases, specifically PubMed, were searched for relevant studies, focusing on atypical side effects such as myoclonus, ataxia, pediatric aggression, respiratory depression, pneumonia, pregnancy complications, sleep interference, encephalopathy, peripheral edema, suicidal ideation, dyskinesia, anorgasmia, and myopathy. Inclusion criteria comprised studies with a focus on gabapentin-related atypical side effects, published in recognized journals and involving human subjects. RESULTS: The review identified a spectrum of atypical side effects associated with gabapentin use, ranging from neurological manifestations like myoclonus and ataxia to behavioral changes such as pediatric aggression and suicidal ideation. Additionally, respiratory complications, pregnancy-related issues, sleep disturbances, and rare complications like encephalopathy and myopathy were observed. Literature synthesis provided insights into the incidence, clinical presentation, and potential mechanisms underlying these atypical side effects. CONCLUSION: This comprehensive review highlights the diverse range of atypical side effects associated with gabapentin use, expanding beyond conventional knowledge. Healthcare practitioners must be cognizant of these manifestations, recognizing their potential impact on patient well-being. As clinical decision-making relies on a thorough understanding of a medication's side effect profile, this review contributes to enhancing awareness and fostering informed practices in the prescription and management of gabapentin. Further research is warranted to elucidate the mechanisms and risk factors associated with these atypical side effects, refining our understanding of gabapentin's safety profile.

Diffusion-weighted MR imaging and utility of ADC measurements in characterizing nerve and muscle changes in diabetic patients on ankle DWI studies: a cross-sectional study.

OBJECTIVE: To evaluate the utility of apparent diffusion coefficient (ADC) measurements from ankle MRI diffusion-weighted imaging (DWI) studies in identifying neuropathic changes in diabetic patients. METHODS: In total, 109 consecutive ankle MRI scans (n = 101 patients) at a single tertiary care county hospital from November 1, 2019, to July 11, 2021, who met the inclusion criteria were identified. Patients were divided into 2 cohorts: diabetic (n = 62) and non-diabetic (n = 39). Demographics, HgbA1c, neuropathy diagnosis, and image quality data were collected. Abductor hallucis (AH) ADC mean and minimum (min) values and posterior tibial nerve (PTN) ADC mean and minimum values were measured. Student t-test and Pearson's correlation coefficient analysis were performed using R. RESULTS: Diabetic patients had significantly higher mean and min ADC values (× 10-3 mm2/s) of the AH muscle (mean: 1.77 vs 1.39, p < 0.001; min: 1.51 vs 1.06, p < 0.001) and PTN (mean: 1.65 vs 1.18, p < 0.001; min: 1.33 vs 0.95, p < 0.001) compared to non-diabetic patients. HgbA1c positively correlated with AH and PTN ADC mean values (AH: p = 0.036; PTN: p = 0.004). CONCLUSION: Our data suggests that an increasing diffusivity of water as quantified by ADC across neuronal and muscular membranes is a consequence of the pathophysiology of the disease. Thus, ankle MRI-DWI studies are useful in identifying neuropathic changes in diabetic patients and quantifying the severity noninvasively. KEY POINTS: • Diabetic patients had significantly higher mean and minimum ADC values of the abductor hallucis muscle and posterior tibial nerve compared to non-diabetic patients. • HgbA1c positively correlated with ADC mean values (AH: p = 0.036; PTN: p = 0.004) suggesting that an increasing diffusivity of water across neuronal and muscular membranes is a consequence of the pathophysiology of diabetic neuropathy. • Ankle MRI DWI can be used clinically to non-invasively identify neuropathic changes due to diabetes mellitus.

Nicotinamide Riboside Improves Enteric Neuropathy in Streptozocin-Induced Diabetic Rats Through Myenteric Plexus Neuroprotection.

BACKGROUND: Diabetes Mellitus causes a systemic oxidative stress due in part to the hyperglycemia and the reactive oxygen species generated. Up to 75% of diabetic patients present with an autonomic neuropathy affecting the Enteric Nervous System. Deficits in the human population are chronic dysmotilities with either increased (i.e., constipation) or decreased (i.e., diarrhea) total gastrointestinal transit times. These are recapitulated in the streptozocin-induced diabetic rat, which is a model of Type I Diabetes Mellitus. AIMS: Examine the effects that a precursor of nicotinamide adenosine dinucleotide (NAD), nicotinamide riboside (NR), had on the development of dysmotility in induced diabetic rats and if fecal microbiota transplant (FMT) could produce the same results. MATERIALS AND METHODS: Utilizing a 6-week treatment paradigm, NR was administered intraperitoneally every 48 h. Total gastrointestinal transit time was assessed weekly utilizing the carmine red method. Three weeks following hyperglycemic induction, FMT was performed between NR-treated animals and untreated animals. SIGNIFICANT RESULTS: There is improvement in overall gastrointestinal transit time with the use of NR. 16S microbiome sequencing demonstrated decreased alpha and beta diversity in induced diabetic rats without change in animals receiving FMT. Improvements in myenteric plexus ganglia density in small and large intestines in diabetic animals treated with NR were seen. CONCLUSIONS: NR treatment led to functional improvement in total gastrointestinal transit time in induced diabetic animals. This was associated with neuroprotection in the myenteric plexuses of both small and large intestines of induced diabetic rats. This represents an important first step in showing NR's benefit as a treatment for diabetic enteric neuropathy. Streptozocin-induced diabetic rats have improved transit times and increased myenteric plexus ganglia density when treated with intraperitoneal nicotinamide riboside.

Potential predictive effect of mechanical properties of the plantar skin and superficial soft tissue, and vibration perception on plantar loading during gait in individuals with diabetes.

BACKGROUND: This exploratory study aimed to investigate the extent to which mechanical properties of the plantar skin and superficial soft tissue (hardness, stiffness, and thickness) and vibration perception thresholds (VPTs) predict plantar pressure loading during gait in people with diabetes compared to healthy controls. METHODS: Mechanical properties, VPTs, and plantar loadings during gait at the heel and first metatarsal head (MTH) of 20 subjects with diabetes, 13 with DPN, and 33 healthy controls were acquired. Multiple regression analyses were used to predict plantar pressure peaks and pressure-time integrals at both locations based on the mechanical properties of the skin and superficial soft tissues and VPTs. RESULTS: In the diabetes group at the MTH, skin hardness associated with 30-Hz (R2 = 0.343) and 200-Hz (R2 = 0.314) VPTs predicted peak pressure at the forefoot. In the controls at the heel, peak pressure was predicted by the skin thickness, hardness, and stiffness associated with 30-Hz (R2 = 0.269, 0.268, and 0.267, respectively) and 200-Hz (R2 = 0.214, 0.247, and 0.265, respectively) VPTs. CONCLUSION: The forefoot loading of people with diabetes can be predicted by the hardness of the skin when combined with loss of vibration perception at low (30-Hz) and high (200-Hz) frequencies. Further data from larger sample sizes are needed to confirm the current findings.

Spinal Cord Stimulation Alleviates Pain Hypersensitivity by Attenuating Neuroinflammation in a Model of Painful Diabetic Neuropathy.

INTRODUCTION: Painful diabetic neuropathy (PDN) is an intractable chronic pain condition affecting a growing number of adults in China. Spinal cord stimulation (SCS) has been employed in the treatment of PDN for several decades. However, the efficacy and underlying mechanisms of SCS are still inconclusive. METHODS: In this study, we adopted an implantable pulse generator to deliver electrical stimulation (50 Hz, 200 us pulse width, 12 hours/day in 5 weeks) via a quadripolar electrode in the lumbar epidural space to treat pain hypersensitivity in the rat model of PDN. Electronic von Frey and Hargreaves tests were used to measure the responses to mechanical and heat stimuli, respectively. Quantitative PCR, western blotting, and enzyme-linked immunosorbent assay (ELISA) were adopted to explore the changes in neuroinflammation after SCS. RESULTS: SCS alleviated mechanical allodynia and heat hyperalgesia over a period of 3 weeks in diabetic rats. SCS completely suppressed neuropathy-induced Tlr4 and NFκB p65 elevation, resulting in the reduction of pain-promoting Il1ß, Il6, and Tnfα proteins in the spinal cord dorsal horn. CONCLUSIONS: SCS may alleviate diabetic neuropathy-induced pain hypersensitivity via attenuating neuroinflammation in the spinal cord dorsal horn.

A comparison of hyperspectral imaging with routine vascular noninvasive techniques to assess the healing prognosis in patients with diabetic foot ulcers.

OBJECTIVE: To compare the potential healing prognosis of the different routine noninvasive techniques implemented in the International Working Group Diabetic Foot Guidelines with the novel use of hyperspectral imaging (HSI) in patients with diabetic foot ulcers (DFUs). METHODS: Twenty-one patients with active DFUs participated in this 1-year prospective study in a specialized diabetic foot unit between December 2018 and January 2020. HSI was performed at baseline to quantify tissue oxygenation and should be presented on an anatomical map by analyzing the following parameters: (1) oxygen saturation of the hemoglobin, (2) tissue hemoglobin index, (3) the near-infrared perfusion index, and (4) tissue water index. In addition, transcutaneous oxygen pressure (TcpO2), systolic toe and ankle pressures, ankle-brachial index, and toe-brachial index values were calculated for the ulcerated limb. The primary outcome measure was wound healing, defined as complete epithelization without any drainage confirmed for at least 10 days after closure was first documented at 24 weeks. RESULTS: During the follow-up period 14 patients (66.66 %) healed and 7 patients did not heal (33.3%) by 24 weeks. The TcpO2 optimal cut-off point as determined by a balance of sensitivity and specificity of 28.5 mm Hg that yielded a sensitivity of 91% and a specificity of 100%, and area under the curve of 0.989 (P = .005; 95% confidence interval [CI], 0.945-1.000). Followed by the oxygen saturation of the hemoglobin optimal cut-off point as determined by a balance of sensitivity and specificity of 48.5 mm Hg that yielded a sensitivity of 93% and a specificity of 0.71%, and area under the curve of 0.932 (P = .013; 95% CI, 0.787-1.000). The logistic regression analyses showed that TcpO2 was the only variable associated with wound healing at 24 weeks (P < .001; 95% CI, 0.046-0.642). CONCLUSIONS: The HSI was shown to be effective in the prognosis of DFU healing compared with other noninvasive test; only TcpO2 values resulted in better diagnosis potential in wound healing.

Biomechanical and musculoskeletal changes after flexor tenotomy to reduce the risk of diabetic neuropathic toe ulcer recurrence.

OBJECTIVE: To assess the effect of flexor tenotomy in patients with diabetes on barefoot plantar pressure, toe joint angles and ulcer recurrence during patient follow-up. METHODS: Patients with a history of ulceration on the toe apex were included. They underwent minimally invasive needle flexor tenotomy by an experienced musculoskeletal surgeon. Dynamic barefoot plantar pressure measurements and static weight-bearing radiographs were taken before and 2-4 weeks after the procedure. RESULTS: A total of 14 patients underwent flexor tenotomy on 50 toes in 19 feet. There was a mean follow-up time of 11.4 months. No ulcer recurrence occurred during follow-up. Mean barefoot plantar pressure was assessed on 34 toes and decreased significantly after the procedure by a mean 279 kPa (95% CI: 204-353; p < 0.001). Metatarsophalangeal, proximal interphalangeal and distal interphalangeal joint angles were assessed on nine toes and all decreased significantly (by 7° [95% CI: 4-9; p < 0.001], 19° [95% CI: 11-26; p < 0.001] and 28° [95% CI: 13-44; p = 0.003], respectively). CONCLUSION: These observations show a beneficial effect of flexor tenotomy on biomechanical and musculoskeletal outcomes in the toes, without ulcer recurrence.

Antidiabetic and neuroprotective effects of a novel repaglinide analog.

Repaglinide (RPG) is an oral insulin secretagogue used in the treatment of diabetes. In this study, a new RPG analog was synthesized. Its antidiabetic and neuroprotective effects on dorsal root ganglions (DRG) in streptozotocin (STZ)-induced diabetic rats were examined compared to RPG. To assess the effects of 2-methoxy-4-(2-((3-methyl-1-(2-(piperidin-1-yl)phenyl)butyl)amino)-2-oxoethoxy)benzoic acid (OXR), the impact of OXR on oxidative stress biomarkers, motor function, and the expression of the glutamate dehydrogenase 1 (GLUD1), SLC2A2/glucose transporter 2 (GLUT2), and glucokinase (GCK) genes in STZ-induced diabetic rats were assessed. DRGs were examined histologically using hemotoxylin and eosin staining. Molecular docking was used to investigate the interactions between OXR and the binding site of RPG, the ATP-sensitive potassium (KATP) channel. Following 5 weeks of treatment, OXR significantly increased the level of total antioxidant power, decreased reactive oxygen species, and lipid peroxidation in the DRGs of diabetic rats. OXR restored STZ-induced pathophysiological damages in DRG tissues. Administration of OXR improved motor function of rats with diabetic neuropathy. Administration of 0.5 mg/kg OXR reduced blood glucose while promoting insulin, mainly through upregulation of messenger RNA expression of GLUD1, GLUT2, and GCK in the pancreas. Molecular docking revealed a favorable binding mode of OXR to the KATP channel. In conclusion, OXR has neuroprotective effects in diabetic rats by lowering oxidative stress, lowering blood glucose, and stimulating insulin secretion. We report that 0.5 mg/kg OXR administration was the most effective concentration of the compound in this study. OXR may be a promising target for further research on neuroprotective antidiabetic molecules.

American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update.

OBJECTIVE: The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS: The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS: This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS: This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.

Could an Internet-Based Foot-Ankle Therapeutic Exercise Program Modify Clinical Outcomes and Gait Biomechanics in People with Diabetic Neuropathy? A Clinical Proof-of-Concept Study.

Previous studies have shown the efficacy of foot-ankle exercises in people with diabetic peripheral neuropathy (DPN), but the quality of evidence is still low. This proof-of-concept study pursues preliminary evidence for potential clinical and gait biomechanical benefits from an internet-based foot-ankle therapeutic exercise program for people with DPN. We randomized 30 individuals with DPN (IWGDF risk category 1 or 2) into either the control group (CG) receiving the usual care or the intervention group (IG) receiving the usual care plus an internet-based foot-ankle exercise program, fully guided by the Sistema de Orientação ao Pé Diabético (SOPeD; translation: Diabetic Foot Guidance System) three times per week for 12 weeks. We assessed face-to-face clinical and biomechanical outcomes at baseline, 12 weeks, and 24 weeks (follow up). Participants had good adherence to the proposed intervention and it led to only mild adverse events. The IG showed improvements in the ankle and first metatarsophalangeal joint motion after 12 and 24 weeks, changed forefoot load absorption during foot rollover during gait after 24 weeks, reduced foot pain after 12 weeks, and improved foot function after 24 weeks. A 12-week internet-based foot-ankle exercise program using the SOPeD software (version 1.0) has the potential to reduce foot pain, improve foot function, and modify some important foot-ankle kinematic outcomes in people with DPN.

Digital Biomarkers of Gait and Balance in Diabetic Foot, Measurable by Wearable Inertial Measurement Units: A Mini Review.

People with diabetic foot frequently exhibit gait and balance dysfunction. Recent advances in wearable inertial measurement units (IMUs) enable to assess some of the gait and balance dysfunction associated with diabetic foot (i.e., digital biomarkers of gait and balance). However, there is no review to inform digital biomarkers of gait and balance dysfunction related to diabetic foot, measurable by wearable IMUs (e.g., what gait and balance parameters can wearable IMUs collect? Are the measurements repeatable?). Accordingly, we conducted a web-based, mini review using PubMed. Our search was limited to human subjects and English-written papers published in peer-reviewed journals. We identified 20 papers in this mini review. We found preliminary evidence of digital biomarkers of gait and balance dysfunction in people with diabetic foot, such as slow gait speed, large gait variability, unstable gait initiation, and large body sway. However, due to heterogeneities in included papers in terms of study design, movement tasks, and small sample size, more studies are recommended to confirm this preliminary evidence. Additionally, based on our mini review, we recommend establishing appropriate strategies to successfully incorporate wearable-based assessment into clinical practice for diabetic foot care.

Severe burn injury from the common Asian practice of heat application in patients with diabetic neuropathy.

This was the first study to analyse patients who sustained severe self-induced burns from this common Asian practice. There is a need to raise public awareness and physician attention about the consequences of preventable burn injuries and the importance of first aid in patients with diabetic neuropathy. Retrospective data on 16 consecutive patients who had diabetes and neuropathy admitted to the plastic surgery ward at the Tri-Service General Hospital from January 1, 2015, to February 2, 2021 with burn injuries because of heat applications were collected and analysed for this study. Age, gender, season, first aid adequacy, comorbidity, interventions, total body surface area (TBSA), degree of burn, aetiology, length of stay (LOS), and status at discharge were reviewed. The mean age of the 16 patients was 65.13 years. The most common burn aetiology was contact (50%), followed by scald (37.5%) and radiation burns (12.5%). TBSA burn averaged ± standard deviation 1.54 ± 1.22. Seven patients (44%) had wound infections, and three patients underwent amputations. The average LOS was 28.2 days. Asian practice of heat application is the common aetiology of severe and preventable burn injuries. Education about neuropathy and the consequences of a burn injury should be provided to patients with diabetes.

Diurnal efficacy of alpha-lipoic acid/nifedipine/glimepiride combination mitigates diabetic neuropathies in rats.

OBJECTIVES: Time-dependent effects of alpha-lipoic acid/nifedipine/glimepiride combination on diabetic neuropathies were investigated in rats. 7 groups (n=9) of rats were used. MATERIALS AND METHODS: First and second groups were apparently normal and diabetic rats respectively, and were administered 1mL/kg distilled water. The rest of the groups were diabetic and administered 10mg/kg glimepiride at night-time (8:00 pm). Groups 4-7 were administered additional 20mg/kg nifedipine at morning-time (8:00 am), while groups 5-7 were also administered 100mg/kg alpha-lipoic acid (ALA) in the morning, afternoon and night-time respectively (8:00 am, 2:00 pm and 8:00 pm). During the 28 days of oral treatment, paw pressure, tail immersion and motor coordination tests were conducted. The rats were euthanized on the 29th day after a charcoal meal. The small intestines were excised to determine intestinal transit while the brain was collected, homogenised and used to determine levels of oxidative stress. RESULTS: Data show that treatment with ALA at 8:00 am or 2:00 pm significantly (P≤0.01) produced a delay in the onset and improved prognosis of neuropathies. Treatment with ALA at 8:00 pm prevented manifestation of neuropathies throughout the study with positive antioxidant effects. CONCLUSION: Time-dependent ALA treatment in combination with nifedipine and glimepiride should be studied in humans with an approximately similar circadian timing. This may provide additional clinical therapeutic options for diabetic neuropathies.

Quantitative proteomic analysis of human peripheral nerves from subjects with type 2 diabetes.

AIMS: Diabetic peripheral neuropathy (DPN) is a common and severe complication to type 2 diabetes. The pathogenesis of DPN is not fully known, but several pathways and gene polymorphisms contributing to DPN are described. DPN can be studied using nerve biopsies, but studies on the proteome of the nerve itself, and its surrounding tissue as a whole, are lacking. Studies on the posterior interosseous nerve (PIN) have proposed PIN a useful indicator of DPN. METHODS: A quantitative mass spectrometry-based proteomics analysis was made of peripheral nerves from age- and gender-matched living human male tissue donors; nine type 2 diabetes subjects, with decreased sural nerve action potentials indicating DPN, and six controls without type 2 diabetes, with normal electrophysiology results. RESULTS: A total of 2617 proteins were identified. Linear regression was used to discover which proteins were differentially expressed between type 2 diabetes and controls. Only soft signals were found. Therefore, clustering of the 500 most variable proteins was made to find clusters of similar proteins in type 2 diabetes subjects and healthy controls. CONCLUSIONS: This feasibility study shows, for the first time, that the use of quantitative mass spectrometry enables quantification of proteins from nerve biopsies from subjects with and without type 2 diabetes, which may aid in finding biomarkers of importance to DPN development.

Diabetic neuropathies.

Diabetic neuropathies are the most common type of neuropathies seen in clinical practice. These neuropathies can range clinically from asymptomatic to manifesting symptoms caused by motor, sensory, and autonomic nerve dysfunction. These neuropathies can affect the peripheral nervous system, pain receptors, cardiovascular, urogenital, and gastrointestinal systems. This monograph presents an overview of the different types of diabetic neuropathies, their presentations, diagnostic tools, and strategies for management.

Progressive Response to Repeat Application of Capsaicin 179 mg (8% w/w) Cutaneous Patch in Peripheral Neuropathic Pain: Comprehensive New Analysis and Clinical Implications.

OBJECTIVE: To investigate the efficacy of repeated application of capsaicin 179 mg cutaneous patch in nonresponders to the first application. DESIGN: Post hoc, as-treated analysis of two prospective trials (STRIDE and PACE) with 52-week follow-up. BLINDING: Open-label. SETTING: Multicenter clinical trial. SUBJECTS: STRIDE: nondiabetic neuropathic pain; PACE: painful diabetic peripheral neuropathy. METHODS: Patients were divided according to number of applications needed before attainment of a ≥30% reduction in average pain intensity (question 5 of the Brief Pain Inventory [BPI-Q5]). We assessed the change from baseline in average pain intensity (BPI-Q5), mean "interference with sleep" score, Patient Global Impression of Change, quality of life (QOL) via the EuroQol 5-dimension, and Self-Assessment of Treatment. RESULTS: In STRIDE and PACE, respectively, n = 306 and n = 313 received the capsaicin patch; n = 60 and n = 96 had a response after the first application, n = 33 and n = 68 after the second, and n = 11 and n = 43 after the third. Among patients without a ≥30% reduction in pain intensity at 3 months, in STRIDE and PACE, respectively, 23.3% and 28.1% achieved a ≥30% reduction at 6 months, increasing to 33.9% and 45.7% at 12 months. Similar results were obtained when a decrease of ≥50% was used as the responder definition. Progressive improvements in pain intensity in slower responders reached levels similar to those in early responders at month 12 and were accompanied by improvements in sleep, QOL, and patient satisfaction. CONCLUSIONS: Although some patients with peripheral neuropathic pain experience rapid improvements with a single treatment of capsaicin 179 mg patch, some may require two or three treatments before an initial response is observed. Similar benefits for pain, sleep, and QOL can be achieved in early and late responders.