Gastrointestinal symptom burden in diabetic autonomic and peripheral neuropathy - A Danes cohort study.

OBJECTIVE: We investigated associations between gastrointestinal symptoms - evaluated as a combined weighted symptom score (CWSS) - Diabetic autonomic neuropathy (DAN), and distal symmetrical polyneuropathy (DSPN) in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Cross-sectional study in a tertiary outpatient clinic. CWSS was calculated based on questionnaires: gastroparesis composite symptom index (GCSI) and gastrointestinal symptom rating score (GSRS). DAN and DSPN were addressed using the composite autonomic symptom score 31 (COMPASS-31) questionnaire, cardiac autonomic reflex tests (CARTs), electrochemical skin conductance (ESC), vibration perception threshold (VPT), Michigan Neuropathy Screening Instrument (MNSI), pain- and thermal sensation. Analyses were adjusted for age, sex, diabetes duration, smoking, LDL-cholesterol, HbA1C and systolic blood pressure. Type 1 and type 2 diabetes were evaluated separately. RESULTS: We included 566 with type 1 diabetes and 377 with type 2 diabetes. Mean ± SD age was 58 ± 15 years and 565 (59.9 %) were women. A high CWSS was present in 143 (25 %) with type 1 and 142 (38 %) with type 2 diabetes. The odds of DAN by COMPASS-31 (p < 0.001) were higher in the high score group. For type 1 diabetes, odds of cardiac autonomic neuropathy were higher in the high CWSS group. The odds of DSPN by VPT and MNSI in type 1 diabetes, and by ESC, VPT and pain sensation in type 2 diabetes were higher in the high CWSS group. CONCLUSIONS: A high symptom score was associated with neuropathy by COMPASS-31 and vibration perception. Gastrointestinal symptom burden associated inconsistently with other neuropathy tests between diabetes types.

Which scale is more useful to detect diabetic neuropathic pain?: A cross-sectional study.

BACKGROUND: Diabetic neuropathy is one of the most common causes of neuropathic pain. LANSS, sLANSS, DN4 and painDETECT are scales which are commonly used worldwide. There are not many studies comparing these screening tools in specific neuropathic pain subgroups. The aim of this study is to compare the utilities of LANSS, sLANSS, DN4 and PainDETECT for the diagnosis of diabetic neuropathic pain. METHODS: One hundred-one individuals without diabetic neuropathic pain were included in control group, 102 patients with diabetic neuropathic pain to DNP group. LANSS, sLANSS, DN4 and painDETECT scores of the groups were compared. RESULTS: The difference between the groups was significant for all questionnaires and for all questions/titles they included. DN4 had the highest sensitivity and painDETECT had the highest specificity. CONCLUSIONS: All questionnaires seemed to be useful for detecting diabetic neuropathic pain. DN4 had a high specificity and sensitivity. PainDETECT, also had a high sensitivity and specificity when cut off value was accepted more than 12.

The neuro-restorative effect of adipose-derived mesenchymal stem cell transplantation on a mouse model of diabetic neuropathy.

Diabetic neuropathy (DN) is the most common degenerative complication associated with Diabetes Mellitus. Despite widespread awareness about DN, the only effective treatments are blood glucose control and pain management. The aim of the current study was to determine the effect of intramuscular adipose-derived mesenchymal stem cell (AMSC) transplantation on sciatic nerves in DN using EMG and histological analyses. A total of 27 mice were randomly divided into three groups: control group, DN group and AMSC group. In EMG, CMAP amplitude in the sciatic nerves was lower, but distal latency was higher in the DN group compared with the control group. CMAP amplitude in the sciatic nerves was higher in the AMSC group compared with the DN group. Distal latency in the sciatic nerve was lower in the AMSC group compared with the DN group. Histologic examination of the tissues in the animals treated with AMSC showed a remarkable improvement in microscopic morphology. Fluorescence microscopy analyses demonstrated that intramuscularly transplanted AMSC was selectively localized in the sciatic nerves. Transplantation of AMSC increased protein expression of S100, cdk2, NGF and DHH, all of which, interfered with DN onset in sciatic nerves. The findings of the present study suggest that AMSC transplantation improved DN through a signal-regulatory effect on Schwann cells, neurotrophic actions and restoration of myelination.

Tocotrienol-Rich Vitamin E (Tocovid) Improved Nerve Conduction Velocity in Type 2 Diabetes Mellitus Patients in a Phase II Double-Blind, Randomized Controlled Clinical Trial.

Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of diabetes that affects approximately half of the diabetic population. Up to 53% of DPN patients experience neuropathic pain, which leads to a reduction in the quality of life and work productivity. Tocotrienols have been shown to possess antioxidant, anti-inflammatory, and neuroprotective properties in preclinical and clinical studies. This study aimed to investigate the effects of tocotrienol-rich vitamin E (Tocovid SuprabioTM) on nerve conduction parameters and serum biomarkers among patients with type 2 diabetes mellitus (T2DM). A total of 88 patients were randomized to receive 200 mg of Tocovid twice daily, or a matching placebo for 12 months. Fasting blood samples were collected for measurements of HbA1c, renal profile, lipid profile, and biomarkers. A nerve conduction study (NCS) was performed on all patients at baseline and subsequently at 2, 6, 12 months. Patients were reassessed after 6 months of washout. After 12 months of supplementation, patients in the Tocovid group exhibited highly significant improvements in conduction velocity (CV) of both median and sural sensory nerves as compared to those in the placebo group. The between-intervention-group differences (treatment effects) in CV were 1.60 m/s (95% CI: 0.70, 2.40) for the median nerve and 2.10 m/s (95% CI: 1.50, 2.90) for the sural nerve. A significant difference in peak velocity (PV) was also observed in the sural nerve (2.10 m/s; 95% CI: 1.00, 3.20) after 12 months. Significant improvements in CV were only observed up to 6 months in the tibial motor nerve, 1.30 m/s (95% CI: 0.60, 2.20). There were no significant changes in serum biomarkers, transforming growth factor beta-1 (TGFß-1), or vascular endothelial growth factor A (VEGF-A). After 6 months of washout, there were no significant differences from baseline between groups in nerve conduction parameters of all three nerves. Tocovid at 400 mg/day significantly improve tibial motor nerve CV up to 6 months, but median and sural sensory nerve CV in up to 12 months of supplementation. All improvements diminished after 6 months of washout.

Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy.

Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage. KEY MESSAGES: • In diabetic painful neuropathy in rats: • Blood nerve barrier and blood DRG barrier are leaky for micromolecules. • Perineurial Cldn1 sealing the blood nerve barrier is specifically downregulated. • Endoneurial vessel-associated macrophages are also decreased. • These changes occur after onset of hyperalgesia thereby maintaining rather than inducing pain.

Impaired hypoxic ventilatory drive induced by diabetic autonomic neuropathy, a cause of misdiagnosed severe cardiac events: brief report of two cases.

BACKGROUND: Sudden cardiac deaths are twice more frequent in diabetic patients with cardiac autonomic neuropathy. Sudden cardiac death etiologies remain unclear and no recommendations are made to identify factors associated with cardiorespiratory arrest in diabetic patients. We hypothesized, from two clinical cases, that impaired hypoxic ventilatory drive, induced by diabetic autonomic neuropathy, is a cause of misdiagnosed severe cardiac events. CASE PRESENTATION: We describe the cases of two patients with isolated low blood saturation on pulse oximeter during the systematic nurse check-up (77% and 85% respectively) contrasting with the absence of any complaint such as dyspnea, polypnea or other respiratory insufficiency signs observed during the clinical examination. Arterial blood gas measurements subsequently confirmed that blood oxygen saturation was low and both patients were indeed hypoxemic. Patient 1 suffered from vascular overload complicated by cardiac arrest caused by hypoxemia in light of the quick recovery observed after ventilation. Pulmonary edema was diagnosed in patient 2. The common denominator of these 2 cases described in this brief report is the absence of respiratory failure clinical signs contrasting with the presence of confirmed hypoxemia. Also, in both cases, such absence of precursory signs seems to be induced by an impaired ventilatory drive to hypoxemia. This appears to be related to the autonomic diabetic neuropathy encountered in those 2 patients. CONCLUSIONS: Therefore, we describe, in this brief report, cardiac autonomic neuropathy as a cause of impaired hypoxic ventilatory drive involved in severe acute cardiorespiratory events in two type 1 diabetic patients. We assume that altered response to hypoxemia due to cardiac autonomic neuropathy and non-functional central neurological breathing command could play a key role in sudden deaths among diabetic patients. An important point is that hypoxemia can be easily missed since no clinical signs of respiratory failure are reported in these two clinical cases. Systematic screening of cardiac autonomic neuropathy in diabetic patients and proactive detection of impaired hypoxic ventilatory drive for early management (e.g. treatment of hypoxemia) should be systematically undertaken in diabetic patients to prevent its dramatic consequences such as cardiorespiratory arrest and death.

cAMP-PKA signaling is involved in regulation of spinal HCN channels function in diabetic neuropathic pain.

The cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling acts a pivotal part in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels-mediated neuropathic and inflammatory pain. However, there has been no evidence of cAMP-PKA signaling is involved in regulation of spinal HCN channels function in the occurrence of diabetic neuropathic pain (DNP). The study aimed to elucidate the impact of HCN channels on neuropathic pain in a rat model of diabetes induced by streptozotocin, and whether cAMP-PKA signaling is involved in regulation of HCN channels function. In this report, we evaluated the effect of intrathecal administration of HCN channel blockers ZD7288, cAMP inhibitor SQ22536 and PKA inhibitor H-89 on nociceptive behavior in DNP rats. The mechanical withdrawal threshold (MWT) was measured to evaluate pain behavior in rats. Protein expression levels of HCN2, HCN4 channels and PKA in the spinal dorsal horn of rats were assessed. Furthermore, the levels of cAMP in rat spinal dorsal horn was analyzed. We discovered that DNP rats showed significant mechanical allodynia and are related to the increased HCN2 and HCN4 channels expression, enhanced cAMP production and elevated the expression of PKA protein in the spinal dorsal horn, which were attenuated by intrathecal ZD7288. Furthermore, intrathecal injection of SQ22536 and H-89 significantly reduced the HCN2 and HCN4 channels expression in the spinal dorsal horn of DNP rats. Our findings indicate that HCN channels of the spinal dorsal horn participate in the pathogenesis of allodynia in rats with DNP, which could be regulated by cAMP-PKA signaling. Therefore, HCN channels and cAMP-PKA signaling are potential targets for hyperalgesia treatment in DNP patients.

Metabolic syndrome and peripheral neuropathy.

Diabetic peripheral neuropathy and metabolic syndrome (MetS) are both global health challenges with well-established diagnostic criteria and significant impacts on quality of life. Clinical observations, epidemiologic evidence, and animal models of disease have strongly suggested MetS is associated with an elevated risk for cryptogenic sensory peripheral neuropathy (CSPN). MetS neuropathy preferentially affects small unmyelinated axons early in its course, and it may also affect autonomic and large fibers. CSPN risk is linked to MetS and several of its components including obesity, dyslipidemia, and prediabetes. MetS also increases neuropathy risk in patients with established type 1 and type 2 diabetes. In this review we present animal data regarding the role of inflammation and dyslipidemia in MetS neuropathy pathogenesis. Several studies suggest exercise-based lifestyle modification is a promising treatment approach for MetS neuropathy.

Treatable, motor-sensory, axonal neuropathies with C5b-9 complement on endoneurial microvessels.

INTRODUCTION: Identification and treatment of immune-mediated polyneuropathies may lead to improved strength and function. We studied the clinical and laboratory features, and treatment response, in patients with motor-sensory axonal polyneuropathies who were found to have C5b-9 complement staining on endoneurial microvessels. METHODS: Retrospective review of 16 consecutive adults with motor-sensory axonal polyneuropathies who were then found to have C5b-9 staining of endoneurial microvessels on nerve biopsy, and subsequently treated with intravenous corticosteroids (1 g methylprednisolone for 5 consecutive days, and then weekly). Strength measurements were done using quantitative handheld dynamometry. Nerve biopsy analysis included frozen and fixed tissue. RESULTS: Patients (mean onset age, 59 ± 4 years; range, 34-83 years; 12 of 16 were males; 9 of 16 had diabetes) had progressive (median duration, 2 years), asymmetric, distal weakness, in the lower extremities (16 of 16) and/or upper extremities (7 of 16), and panmodal sensory loss. Electrodiagnostic studies showed axon loss. Nerve pathology showed abnormal C5b-9 staining on endoneurial microvessels. Axon loss was present in all nerves, often varied among fascicles. Inflammation was uncommon. Distal strength usually improved (mean improvement of 34 ± 6% of normal strength; P = .0003) with corticosteroid treatment. DISCUSSION: Motor-sensory axonal polyneuropathies having noninflammatory, humoral immune pathology with C5b-9 staining of endoneurial microvessels (HIEM) frequently manifest progressive asymmetric, distal, lower extremity with or without upper extremity weakness that improves rapidly during corticosteroid treatment. HIEM may represent a new class of noninflammatory-vasculopathic, treatable axonal motor-sensory neuropathies.

Risk of cardiac autonomic neuropathy in latent autoimmune diabetes in adults is similar to type 1 diabetes and lower compared to type 2 diabetes: A cross-sectional study.

AIMS: Microvascular complications' risk differs between people with latent autoimmune diabetes in adults (LADA) and people with type 2 diabetes. We aimed to investigate whether the prevalence of cardiac autonomic neuropathy, a life-threatening complication of diabetes, also varies depending on diabetes type. METHODS: In this cross-sectional study, 43 adults with LADA, 80 with type 1 diabetes and 61 with type 2 diabetes were screened for cardiac autonomic neuropathy with recommended tests. Logistic regression models were used to test differences between diabetes types adjusting for confounders. RESULTS: Cardiac autonomic neuropathy was diagnosed in 17 (40%) participants with LADA, 21 (26%) participants with type 1 diabetes and 39 (64%) participants with type 2 diabetes (p < 0.001). The odds ratio (OR) for cardiac autonomic neuropathy in type 1 diabetes and in type 2 diabetes compared to LADA were 0.54 (95% CI: 0.25-1.20, p-value: 0.13) and 2.71 (95% CI: 1.21-6.06, p-value 0.015) respectively. Smoking (adj OR 3.09, 95% CI: 1.40-6.82, p-value: 0.005), HDL cholesterol (adj OR 0.29, 95% CI: 0.09-0.93, p-value: 0.037) and hypertension (adj OR 2.11, 95% CI: 1.05-4.24, p-value: 0.037) were independent modifiable risk factors for cardiac autonomic neuropathy. Differences among diabetes types did not change after correction for confounders. CONCLUSIONS: This is the first study offering a comparative evaluation of cardiac autonomic neuropathy among LADA, type 1 and type 2 diabetes, showing a lower risk of cardiac autonomic neuropathy in LADA compared to type 2 diabetes and similar compared to type 1 diabetes. This disparity was not due to differences in age, metabolic control or cardiovascular risk factors.

Cardiac vagal tone as a novel screening tool to recognize asymptomatic cardiovascular autonomic neuropathy: Aspects of utility in type 1 diabetes.

AIMS: To test the performance of the cardiac vagal tone (CVT) derived from a 5-minute ECG recording compared with the standardized cardiovascular autonomic reflex tests (CARTs). METHODS: Cross-sectional study included 56 well-phenotyped adults with type 1 diabetes (19-71 years, 2-54 years disease-duration). Autonomic testing included: standardized CARTs obtained with the VAGUS™, CVT, and indices of heart rate variability (HRV) obtained at 24- and 120-hour, and electrochemical skin conductance assessed with SUDOSCAN®. ROC AUC and cut-off values were calculated for CVT to recognize CAN based on ≥ 2 (established CAN, n = 7) or 1 (borderline CAN, n = 9) abnormal CARTs and compared to HRV indices and electrochemical skin conductance. RESULTS: Established CAN: The cut-off CVT value of 3.2LVS showed 67% sensitivity and 87% specificity (p = 0.01). Indices of HRV at either 24-hour (AUC > 0.90) and 120-hour (AUC > 0.88) performed better than CVT. Borderline CAN: The cut-off CVT value of 5.2LVS indicated 88% sensitivity and 63% specificity (p = 0.07). CVT performed better than HRV indices (AUC < 0.72). Electrochemical skin conductance (AUC:0.63-0.72) had lower sensitivity and specificity compared with CVT. CONCLUSIONS: Implementation of CVT with a clinically applicable cut-off value may be considered a quicker and accessible screening tool which could ultimately decrease the number of unrecognized CAN and initiate earlier prevention initiatives.

Glucokinase in stellate ganglia cooperates with P2X3 receptor to develop cardiac sympathetic neuropathy in type 2 diabetes rats.

Glucokinase (GCK) may be involved in inflammatory pathological changes, while the P2X3 receptor in the stellate ganglia (SG) is related to diabetic cardiac autonomic neuropathy. In this study, we explored the relationship between the upregulated GCK in SG and diabetic cardiac sympathy. The expression and location of GCK and P2X3 in SG of type 2 diabetes mellitus (T2DM) rats were assessed. Changes in cardiac function were determined by measuring blood pressure, sympathetic nerve activity, heart rate, and heart rate variability. P2X3 agonist-activated currents in isolated stellate ganglion neurons and cultured human embryonic kidney 293 (HEK293) cells were recorded using whole-cell patch clamp techniques. The upregulated expression of GCK in SG of T2DM rats was decreased after treatment with GCK short hairpin RNA (shRNA). GCK shRNA treatment also improved the blood pressure, sympathetic nerve activity, heart rate, and heart rate variability in T2DM rats. By contrast, the expression of P2X3 and tumor necrosis factor α (TNF-α) was lessened by GCK shRNA treatment. In addition, adenosine triphosphate (ATP)-activated currents in stellate ganglion neurons and HEK293 cells co-transfected with GCK and P2X3 receptor plasmids were reduced after GCK shRNA treatment. In T2DM rats, knockdown of GCK relieved the diabetic cardiac sympathy mediated by P2X3 receptor-involved upregulation of GCK in SG.

High-Dose Vitamin D Supplementation Improves Microcirculation and Reduces Inflammation in Diabetic Neuropathy Patients.

We assessed the effect of different doses of vitamin D supplementation on microcirculation, signs and symptoms of peripheral neuropathy and inflammatory markers in patients with type 2 diabetes (T2DM). Sixty-seven patients with T2DM and peripheral neuropathy (34 females) were randomized into two treatment groups: Cholecalciferol 5000 IU and 40,000 IU once/week orally for 24 weeks. Severity of neuropathy (NSS, NDS scores, visual analogue scale), cutaneous microcirculation (MC) parameters and inflammatory markers (ILs, CRP, TNFα) were assessed before and after treatment. Vitamin D deficiency/insufficiency was detected in 78% of the 62 completed subjects. Following treatment with cholecalciferol 40,000 IU/week, a significant decrease in neuropathy severity (NSS, p = 0.001; NDS, p = 0.001; VAS, p = 0.001) and improvement of cutaneous MC were observed (p < 0.05). Also, we found a decrease in IL-6 level (2.5 pg/mL vs. 0.6 pg/mL, p < 0.001) and an increase in IL-10 level (2.5 pg/mL vs. 4.5 pg/mL, p < 0.001) after 24 weeks of vitamin D supplementation in this group. No changes were detected in the cholecalciferol 5000 IU/week group. High-dose cholecalciferol supplementation of 40,000 IU/week for 24 weeks was associated with improvement in clinical manifestation, cutaneous microcirculation and inflammatory markers in patients with T2DM and peripheral neuropathy.

Chronic hyperglycemia impairs mitochondrial unfolded protein response and precipitates proteotoxicity in experimental diabetic neuropathy: focus on LonP1 mediated mitochondrial regulation.

BACKGROUND: Disturbed mitochondrial homeostasis has been identified to contribute to the pathogenesis of diabetic neuropathy (DN). However, the role of Mitochondrial Lon peptidase 1 (Lonp1) and Heat shock proteins (HSP's) in DN remains elusive. Here we studied the role of these proteins in experimental DN. METHODS: Rats were injected with STZ (55 mg/kg, ip) to induce diabetes. After confirmation of diabetes, animals were maintained for 8 weeks to develop neuropathy. Resveratrol was administered at two dose levels 10 and 20 mg/kg for last 2 weeks. Neuronal PC12 cells was challenged with 30 mM of ß-D glucose to evaluate the molecular changes. RESULTS: Diabetic rats showed reduced expression of various mitochondrial proteases in dorsal root ganglions (DRG). This effect may increase proteotoxicity and diminish electron transport chain (ETC) activity as evident by increased protein oxidation and reduced ETC complexes activities under diabetic condition. In particular, we focused on our efforts to characterize the expression pattern of Lonp1 which was found to be significantly (p < 0.01 vs. control group) under expressed in DRG of diabetic rats. We used Resveratrol to characterize the importance of Lonp1 in regulation of mitochondrial function. High glucose (HG) (30 mM) exposed PC12 cells suggested that Resveratrol treatment attenuated the HG induced mitochondrial damage via induction of mitochondrial proteases. Moreover, siRNA directed against Lonp1 has impaired the activity of Resveratrol in attenuating the HG induced mitochondrial dysfunction. CONCLUSION: These results would signify the importance of modulating mitochondrial proteases for the therapeutic management of DN.

Increased NRSF/REST in anterior cingulate cortex contributes to diabetes-related neuropathic pain.

Diabetic neuropathic pain is one of the most common complications of diabetes. Mechanisms underlying the central modulation are still unclear. Here, we investigated the role of the neuron-restricted silencing factor (NRSF/REST) in diabetic-related neuropathic pain. Mechanical allodynia and thermal hyperalgesia were assessed to evaluate painful behaviors. Our results found that in the anterior cingulate cortex (ACC) of db/db mice, NRSF/REST levels increased significantly. Reduction of NRSF/REST improved the painful sensation. Meanwhile, in vitro study found that high glucose and high palmitic acid treatment induced elevation of NRSF/REST and its cofactors (mSin3A, CoREST and HDAC1), whereas downregulation of GluR2 and NMDAR2B. Knockdown of NRSF/REST could attenuate the LDH release and partially reversed the expression changes of HDAC1 and NMDAR2B. Our results suggested that the elevation of NRSF/REST in the ACC area of db/db mice is one of the key mediators of diabetic neuropathic pain.

(Cost-)effectiveness of lower extremity nerve decompression surgery in subjects with diabetes: the DeCompression (DECO) trial-study protocol for a randomised controlled trial.

INTRODUCTION: The peripheral nerves of patients with diabetes are often pathologically swollen, which results in entrapment at places of anatomical narrowing. This results in nerve dysfunction. Surgical treatment of compression neuropathies in the lower extremities (lower extremity nerve decompression (LEND)) results in relief of symptoms and gain in peripheral nerve function, which may lead to less sensory loss (short term) and less associated detrimental effects including foot ulceration and amputations, and lower costs (long term). The aim of the DeCompression trial is to evaluate the effectiveness and (cost-)effectiveness of surgical decompression of compressed lower extremity nerves (LEND surgery) compared with patients treated with conventional (non-surgical) care. METHODS AND ANALYSIS: A stratified randomised (1 to 1) controlled trial comparing LEND surgery (intervention) with conventional non-surgical care (control strategy) in subjects with diabetes with problems of neuropathy due to compression neuropathies in the lower extremity. Randomisation is stratified for participating hospital (n=11) and gender. Patients and controls have the same follow-up at 1.5, 3, 6, 9, 12, 18, 24 and 48 months. Participants (n=344) will be recruited in 12 months and enrolled in all affiliated hospitals in which they receive both the intervention or conventional non-surgical care and follow-up. Outcome assessors are blinded to group assignment. PRIMARY OUTCOME: disease-specific quality of life (Norfolk Quality of Life Questionnaire-Diabetic Neuropathy). SECONDARY OUTCOMES: health-related quality of life (EuroQoL 5-dimension 5-level (EQ-5D5L), 36-item Short Form (SF-36)), plantar sensation (Rotterdam Diabetic Foot Test Battery), incidence of ulcerations/amputations, resource use and productivity loss (Medical Cost Questionnaire, Productivity Cost Questionnaire) during follow-up. The incremental cost-effectiveness ratio will be estimated on the basis of the collected empirical data and a cost-utility model. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Medical Research Ethics Committee of Utrecht University Medical Center (reference: NL68312.041.19v5, protocol number: 19-335/M). Dissemination of results will be via journal articles and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: NetherlandsTrial Registry NL7664.

A novel method to quantify cutaneous vascular innervation.

INTRODUCTION: To develop a new method to quantify the density of nerves, vessels, and the neurovascular contacts, we studied skin biopsies in diabetes and control subjects. METHODS: Skin biopsies with dual immunofluorescent staining were used to visualize nerves and blood vessels. The density of nerves, vessels, and their neurovascular contacts were quantified with unbiased stereology. Results were compared with examination findings, validated questionnaires, and autonomic function. RESULTS: In tissue from 19 controls and 20 patients with diabetes, inter-rater and intra-rater intraclass correlation coefficients were high (>0.85; P < .001) for all quantitative methods. In diabetes, the nerve densities (P < .05), vessel densities (P < .01), and the neurovascular densities (P < .01) were lower compared with 20 controls. Results correlated with autonomic function, examination and symptom scores. DISCUSSION: We report an unbiased, stereological method to quantify the cutaneous nerve, vessel and neurovascular density and offer new avenues of investigation into cutaneous neurovascular innervation in health and disease.

Clinical Examination and Self-Reported Upper Extremity Impairments in Patients with Long-Standing Type 1 Diabetes Mellitus.

AIM: The aims of the current study were (1) to determine the prevalence of upper extremity impairments (UEIs) in patients with type 1 diabetes by clinical investigation; (2) to investigate if self-reported impairments were concordant with clinical findings and if key questions could be identified; and (3) to investigate if answers to our self-reported questionnaire regarding UEIs are reliable. METHODS: Patients with type 1 diabetes were invited to participate in a cross-sectional study of clinical and self-reported (12 items) UEIs in adjunction to ordinary scheduled clinical visit. Before the visit, a questionnaire on UEIs was filled in twice (test-retest) followed by clinical testing at the planned visit. RESULTS: In total, 69 patients aged 45 ± 14 years and with diabetes duration 26 ± 15 were included in the study. In the clinical examination, two-thirds (65%) of the patients showed one or more UEI, with failure to perform hand against back as the most common clinical finding (40%) followed by positive Phalen's test (27%), Tinel's test (26%), and Prayer's sign (24%). UEIs observed by clinical examination were often bilateral, and multiple impairments often coexisted. Self-reported shoulder stiffness was associated with impaired shoulder mobility and with Prayer's sign. Self-reported reduced hand strength was associated to lower grip force, Prayer's sign, trigger finger, fibrosis string structures, and reduced thenar strength as well as reduced shoulder mobility. In addition, self-reporting previous surgery of carpal tunnel and trigger finger was associated with several clinical UEIs including shoulder, hand, and finger. The test-retest of the questionnaire showed a high agreement of 80-98% for reported shoulder, hand, and finger impairments. CONCLUSION: UEIs are common in type 1 diabetes. Self-reported shoulder stiffness and reduced hand strength might be used to capture patients with UEIs in need of clinical investigation and enhanced preventive and therapeutic strategies, as well as rehabilitative interventions.

Chronic Diabetes Complications: The Need to Move beyond Classical Concepts.

Chronic-diabetes-related complications simultaneously compromise both the micro- and macrovascular trees, with target organs considered as the paradigm of large vessel injury also entailing microangiopathic changes. However, complications independent or partially independent from vascular damage are often overlooked. This includes neuronal dysfunction (e.g., retinal neurodegeneration), interstitial injury (e.g., tubulointerstitial disease), metabolic damage (e.g., in the heart and liver), and nonclassical conditions such as cognitive decline, impaired pulmonary function, or increased risk of cancer. In this scenario, researchers, endocrinologists and primary care physicians should have a holistic view of the disease and pay further attention to all organs and all potential clinical repercussions, which would certainly contribute to a more rational and integrated patient health care.

Skeletal Muscle Regeneration in Advanced Diabetic Peripheral Neuropathy.

BACKGROUND: Decreased lean muscle mass in the lower extremity in diabetic peripheral neuropathy (DPN) is thought to contribute to altered joint loading, immobility, and disability. However, the mechanism behind this loss is unknown and could derive from a reduction in size of myofibers (atrophy), destruction of myofibers (degeneration), or both. Degenerative changes require participation of muscle stem (satellite) cells to regenerate lost myofibers and restore lean mass. Determining the degenerative state and residual regenerative capacity of DPN muscle will inform the utility of regeneration-targeted therapeutic strategies. METHODS: Biopsies were acquired from 2 muscles in 12 individuals with and without diabetic neuropathy undergoing below-knee amputation surgery. Biopsies were subdivided for histological analysis, transcriptional profiling, and satellite cell isolation and culture. RESULTS: Histological analysis revealed evidence of ongoing degeneration and regeneration in DPN muscles. Transcriptional profiling supports these findings, indicating significant upregulation of regeneration-related pathways. However, regeneration appeared to be limited in samples exhibiting the most severe structural pathology as only extremely small, immature regenerated myofibers were found. Immunostaining for satellite cells revealed a significant decrease in their relative frequency only in the subset with severe pathology. Similarly, a reduction in fusion in cultured satellite cells in this group suggests impairment in regenerative capacity in severe DPN pathology. CONCLUSION: DPN muscle exhibited features of degeneration with attempted regeneration. In the most severely pathological muscle samples, regeneration appeared to be stymied and our data suggest that this may be partly due to intrinsic dysfunction of the satellite cell pool in addition to extrinsic structural pathology (eg, nerve damage). CLINICAL RELEVANCE: Restoration of DPN muscle function for improved mobility and physical activity is a goal of surgical and rehabilitation clinicians. Identifying myofiber degeneration and compromised regeneration as contributors to dysfunction suggests that adjuvant cell-based therapies may improve clinical outcomes.