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Aims: To investigate the co-existence of diabetic peripheral neuropathy (DPN), painful diabetic peripheral neuropathy (PDPN), and cardiac autonomic neuropathy (CAN) and to establish a model to predict CAN based on peripheral measurements.Methods: Eighty participants (20 type 1 diabetes (T1DM) + PDPN, 20 T1DM + DPN, 20 T1DM-DPN (without DPN), and 20 healthy controls (HC)) underwent quantitative sensory testing, cardiac autonomic reflex tests (CARTs), and conventional nerve conduction. CAN was defined as ≥ 2 abnormal CARTs. After the initial analysis, the participants with diabetes were re-grouped based on the presence or absence of small (SFN) and large fibre neuropathy (LFN), respectively. A prediction model for CAN was made using logistic regression with backward elimination.Results: CAN was most prevalent in T1DM + PDPN (50%), followed by T1DM + DPN (25%) and T1DM-DPN and HC (0%). The differences in prevalence of CAN between T1DM + PDPN and T1DM-DPN/HC were significant (p < 0.001). When re-grouping, 58% had CAN in the SFN group and 55% in the LFN group, while no participants without either SFN or LFN had CAN. The prediction model had a sensitivity of 64%, a specificity of 67%, a positive predictive value of 30%, and a negative predictive value of 90%.Conclusion: This study suggests that CAN predominantly co-exists with concomitant DPN. Aims: To investigate the co-existence of diabetic peripheral neuropathy (DPN), painful diabetic peripheral neuropathy (PDPN), and cardiac autonomic neuropathy (CAN) and to establish a model to predict CAN based on peripheral measurements. Methods: Eighty participants (20 type 1 diabetes (T1DM) + PDPN, 20 T1DM + DPN, 20 T1DM-DPN (without DPN), and 20 healthy controls (HC)) underwent quantitative sensory testing, cardiac autonomic reflex tests (CARTs), and conventional nerve conduction. CAN was defined as ≥ 2 abnormal CARTs. After the initial analysis, the participants with diabetes were re-grouped based on the presence or absence of small (SFN) and large fibre neuropathy (LFN), respectively. A prediction model for CAN was made using logistic regression with backward elimination. Results: CAN was most prevalent in T1DM + PDPN (50%), followed by T1DM + DPN (25%) and T1DM-DPN and HC (0%). The differences in prevalence of CAN between T1DM + PDPN and T1DM-DPN/HC were significant (p < 0.001). When re-grouping, 58% had CAN in the SFN group and 55% in the LFN group, while no participants without either SFN or LFN had CAN. The prediction model had a sensitivity of 64%, a specificity of 67%, a positive predictive value of 30%, and a negative predictive value of 90%. Conclusion: This study suggests that CAN predominantly co-exists with concomitant DPN.

Yiying Liu,1,&ast; Xin Wang,2,&ast; Linying Wang,1 Wenwen Chen,3 Wenyue Liu,1 Tingting Ye,1 Jing Hong,1 Hong Zhu,1 Feixia Shen1 1Department of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Urology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, People’s Republic of China; 3Department of Senile Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feixia ShenDepartment of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaEmail shenfeixia@wmu.edu.cnPurpose: Diabetic neurogenic bladder (DNB) has been widely recognized in recent years. It is common in patients with long-term diabetes and may also lead to many severe complications. Although there has been widespread evidence that inflammation is involved in the development of some diabetic complications, there is little evidence that this can also occur in the bladder. In recent years, platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) have been viewed as potential novel markers of inflammatory responses. This study was designed to evaluate the relationship between the presence of DNB and the PLR and NLR.Patients and Methods: A total of 371 cases of T2DM patients were included in this retrospective study. Patients were divided into two groups, with 115 diabetic subjects diagnosed with diabetic neurogenic bladder and 256 control subjects without DNB. The independent predictors of DNB were analyzed using logistic regression.Results: Compared with patients without DNB, the mean PLR and NLR were significantly higher in those with DNB (p < 0.001). Based on the logistic regression, PLR was found to be an independent risk factor for DNB (odds ratio [OR]: 1.408, 95% confidence interval [CI]: 1.248– 1.617). From the receiver operating characteristic (ROC) curve, using PLR as indicative of DNB was expected to be 101.1949, and it generated a sensitivity and specificity value of 89.6% and 23.4%, respectively. The area under the curve (AUC) was also found to be 0.899 (95% CI: 0.865– 0.932).Conclusion: In our study, PLR and NLR were significantly higher for patients with DNB. The PLR was found to be a risk factor in the presence of DNB after correcting for possible confounding factors. Considering the severe complications associated with DNB, patients with elevated PLR should be seriously cared for in clinics.Keywords: diabetic autonomic neuropathy, neurogenic bladder, oxidative stress, inflammatory response

Yiying Liu,1,&ast; Xin Wang,2,&ast; Linying Wang,1 Wenwen Chen,3 Wenyue Liu,1 Tingting Ye,1 Jing Hong,1 Hong Zhu,1 Feixia Shen1 1Department of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Urology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, People’s Republic of China; 3Department of Senile Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feixia ShenDepartment of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaEmail shenfeixia@wmu.edu.cnPurpose: Diabetic neurogenic bladder (DNB) has been widely recognized in recent years. It is common in patients with long-term diabetes and may also lead to many severe complications. Although there has been widespread evidence that inflammation is involved in the development of some diabetic complications, there is little evidence that this can also occur in the bladder. In recent years, platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) have been viewed as potential novel markers of inflammatory responses. This study was designed to evaluate the relationship between the presence of DNB and the PLR and NLR.Patients and Methods: A total of 371 cases of T2DM patients were included in this retrospective study. Patients were divided into two groups, with 115 diabetic subjects diagnosed with diabetic neurogenic bladder and 256 control subjects without DNB. The independent predictors of DNB were analyzed using logistic regression.Results: Compared with patients without DNB, the mean PLR and NLR were significantly higher in those with DNB (p < 0.001). Based on the logistic regression, PLR was found to be an independent risk factor for DNB (odds ratio [OR]: 1.408, 95% confidence interval [CI]: 1.248– 1.617). From the receiver operating characteristic (ROC) curve, using PLR as indicative of DNB was expected to be 101.1949, and it generated a sensitivity and specificity value of 89.6% and 23.4%, respectively. The area under the curve (AUC) was also found to be 0.899 (95% CI: 0.865– 0.932).Conclusion: In our study, PLR and NLR were significantly higher for patients with DNB. The PLR was found to be a risk factor in the presence of DNB after correcting for possible confounding factors. Considering the severe complications associated with DNB, patients with elevated PLR should be seriously cared for in clinics.Keywords: diabetic autonomic neuropathy, neurogenic bladder, oxidative stress, inflammatory response

Background. The aim of the study is to evaluate the effectiveness of non-invasive research methods in the diagnosis of urinary disorders in patients with type 1 diabetes mellitus (DM). Materials and methods. In this work, we have examined 184 female patients with type 1 DM complicated by urogenital form of diabetic autonomic neuropathy and urinary disorders using non-invasive methods. These methods include surface electromyography and ultrasound of the bladder. Results. It is established that the study of the contractile ability of the pelvic floor muscles and the sphincter apparatus of the urethra makes it possible to determine the clinical form of urinary disorders. The study of the contractile ability of the pelvic floor muscles and the urethral sphincter apparatus allows, in addition to the results of the questionnaire scale in diabetes, to determine the possible clinical form of urinary disorders in patients with type 1 DM. The parameters of surface electromyography vary depending on the clinical form of urination disorders. In urinary retention, there is an increase in the muscle tone of the urogenital zone as a consequence of the formation of the phenomenon of denervation hypersensitivity. Conclusions. Urinary incontinence is accompanied by diffuse demyelination of sensory and motor nerve trunks, with a coarse axonal component as a result of increased vegetative-trophic disturbances of the muscular apparatus of the urogenital zone. The amount of residual urine, which is determined by ultrasound, in patients with retention grows with an increase in the degree of impaired urination.

Purpose of the review Pure autonomic failure (PAF) is a peripheral autonomic neurodegenerative disease caused by alpha-synuclein deposition that is predominantly confined to peripheral autonomic neurons. Patients present with insidious features of autonomic failure that have a chronic course.In this review, we highlight the features of PAF, the differentiating features from other autonomic neuropathies, the diagnostic tests, and the predictors for conversion to a central synucleinopathy. Recent findings Natural history studies have defined the predictors for and rate of conversion to a central alpha-synucleinopathy. Skin immunohistochemistry techniques and demonstration of length-dependent neuronal loss of both somatic and autonomic small fiber nerves, and intraneural phosphorylated synuclein deposition provide diagnostic biomarkers. In the future, diagnosis maybe supported by measuring cerebrospinal fluid alpha-synuclein oligomers using techniques, such as protein misfolding cyclic amplification assay and real-time quaking-induced conversion. Summary PAF is a sporadic peripheral autonomic neurodegenerative disease that belongs to the group of disorders known as alpha-synucleinopathies. Peripheral autonomic manifestations are similar to those seen in other autonomic neuropathies, particularly, diabetic autonomic neuropathy, amyloid polyneuropathy, and autoimmune autonomic neuropathies. Novel diagnostic procedures like skin immunohistochemistry for alpha-synuclein, and protein amplification techniques are being investigated to provide an earlier and more specific diagnosis. A substantial number of PAF patients' phenoconvert to a central alpha-synucleinopathy.

Introduction. Early diagnosis of cardiac autonomic neuropathy is the basis for the risk of heart disease and premature death in patients with type 2 diabetes mellitus (type 2 diabetes). All patients with type 2 diabetes and prediabetes should undergo annual screening, including history taking and neurophysiologic evaluation, for early diabetic autonomic neuropathy. This article describes a modern diagnostic technique based on changes in heart rate variability, which allows early detection of damage to the parasympathetic nervous system and timely prescribing disease-modifying treatment in patients with type 2 diabetes.Materials and methods. The study included 50 patients with type 2 diabetes (cf. Age 56.5 ± 13.5 years) and 30 healthy subjects (cf. Age 58 ± 10 years), matched by sex and age. according to the NSC questionnaire, the severity of neurological deficit - according to the NIS-LL scale, neuropathic pain syndrome - according to the TSS scale.Results. In the study group of patients with type 2 diabetes, severe CAN was detected in 13.3%, moderate CAN in 40% of patients, in 46.6% of patients, CAN was not detected. In the group of healthy volunteers, disorders of the autonomic nervous system of moderate were detected in 3.3%, in the remaining 96.7% of autonomic disorders were not accepted.Conclusion. The results of pulse oximetric tests with deep breathing are comparable to the results of the QAT device Case-4 (p < 0.001). The method of pulse oximetric diagnostics is more practical to use in comparison with the hardware QAT.

The progression of autonomic dysfunction from peripheral autonomic neuropathy (PAN) to cardiovascular autonomic neuropathy, including diabetic autonomic neuropathy and advanced autonomic dysfunction, increases morbidity and mortality risks. PAN is the earliest stage of autonomic neuropathy. It typically involves small fiber disorder and often is an early component. Small fiber disorder (SFD) is an inflammation of the C-nerve fibers. Currently, the most universally utilized diagnostic test for SFD as an indicator of PAN is galvanic skin response (GSR), as it is less invasive than skin biopsy. It is important to correlate a patient’s symptoms with several autonomic diagnostic tests so as not to treat patients with normal findings unnecessarily. At a large suburban northeastern United States (Sicklerville, NJ) autonomic clinic, 340 consecutive patients were tested with parasympathetic and sympathetic (P&S) monitoring (P&S Monitor 4.0; Physio PS, Inc., Atlanta, GA, USA) with cardiorespiratory analyses, and TMFlow (Omron Corp., Hoffman Estates, Chicago, IL, USA) with LD Technology sudomotor test (SweatC™). This is a prospective, nonrandomized, observational, population study. All patients were less than 60 y/o and were consecutively tested, analyzed and followed from February 2018 through May 2020. P&S Monitoring is based on cardiorespiratory analyses and SweatC™ sudomotor testing is based on GSR. Overall, regardless of the stage of autonomic neuropathy, SweatC™ and P&S Monitoring are in concordance for 306/340 (90.0%) of patients from this cohort. The result is an 89.4% negative predictive value of any P&S disorder if the sudomotor GSR test is negative and a positive predictive value of 90.4% if the sudomotor testing is positive. In detecting early stages of autonomic neuropathy, P&S Monitoring was equivalent to sudomotor testing with high sensitivity and specificity and high negative and positive predictive values. Therefore, either testing modality may be used to risk stratify patients with suspected autonomic dysfunction, including the earliest stages of PAN and SFD. Moreover, when these testing modalities were normal, their high negative predictive values aid in excluding an underlying autonomic nervous system dysfunction.

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.

Aim: There is a lack of methods for investigating the autonomic nerves of the gastrointestinal tract. Our aim was to explore a novel test measuring visceral sensory evoked potentials (EPs) in response to rapid balloon distention in the rectum and compare it to established tests for diabetic neuropathy.Method: Participants with longstanding type 2 diabetes, newly onset, untreated diabetes Results: The pressure at earliest sensation was higher in people with diabetes, 0.038 (0.012) bar vs. controls 0.030 (0.009) bar, p = 0.002, and in people with signs of peripheral neuropathy, 0.045 (0.014) bar, p < 0.01. Clinical correlations between EP amplitude and latency, and other tests were found.Conclusions: Rectal hyposensitivity was associated with both longstanding and early diabetes, indicating enteric sensory dysfunction already in early stages of diabetes. Correlation analyses may indicate that central afferent processing is affected in parallel with peripheral neuronal function. Aim: There is a lack of methods for investigating the autonomic nerves of the gastrointestinal tract. Our aim was to explore a novel test measuring visceral sensory evoked potentials (EPs) in response to rapid balloon distention in the rectum and compare it to established tests for diabetic neuropathy. Method: Participants with longstanding type 2 diabetes, newly onset, untreated diabetes

Objective The aim: Is to determine the peculiarities of changes in the gastric acid secretion against the background of diabetic autonomic neuropathy and autonomic dysfunction in patients with chronic pancreatitis (CP) and type 2 diabetes (T2DM). Patients and methods Materials and methods: We investigated 64 patients with CP and T2DM, who were included in the first group of the patients examined; Group II consisted of 40 patients with T2DM; and Group III of the patients examined consisted of 34 patients with CP. Results Results: Differences were found in assessing the degree of autonomic nervous system (ANS) dysfunction in the examined patients, namely - the most pronounced ANS dysfunction according to the Wayne questionnaire was diagnosed in patients Group I, while patients of Group III. Analysis of gastric acid secretion indicates that no patients of Group III had normal acidity. Normal acidity is more often found in the second group of subjects. Both in patients with CP and T2DM, and in isolation with CP, moderate hyperacidity was more often determined. Conclusion Conclusions: The predominance of the parasympathetic division of the ANS, as well as manifestations of severe ANS dysfunction, are observed in patients with CP and T2DM. The prevalence of gastric hyperacidity on the background of DAN was established in patients with CP and T2DM. In this case, the absence of clinical symptoms or their minimal severity is determined, which indicates the lesion of the digestive tract in these patients.

Purpose Autonomic dysfunction may precede the microvascular changes that characterise diabetic retinopathy. The aim of this pilot study was to measure and compare pupillometry indices in type 2 diabetes (T2DM) patients - with and without diabetic retinopathy - and in healthy, age-matched controls. Methods Two hundred and eleven participants with T2DM aged 45-80 years were recruited from Dunedin Hospital Eye Department, Dunedin, New Zealand. They were categorised into three groups - no, mild/moderate, or severe diabetic retinopathy. Seventy age-matched, diabetes screen negative control participants were recruited from the Dunedin city community. Dynamic pupillometry was performed using an infrared pupillometer. The main outcome measures were maximum constriction velocity, average constriction velocity, absolute constriction amplitude, relative reflex amplitude, average dilation velocity and 75% re-dilation (recovery) time. Outcome measures were compared between study groups using the Kruskal-Wallis nonparametric test (with Dunn's multiple comparison post-test). Results Pupillary parasympathetic function differed between groups. Maximum constriction velocity (p

Samyukta Bista Karki,1 Kirsten J Coppell,2 Logan V Mitchell,2 Kelechi C Ogbuehi2 1Drishti Eye Care Center, Kathmandu 44600, Nepal; 2Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin 9054, New ZealandCorrespondence: Kelechi C OgbuehiDepartment of Medicine, Dunedin School of Medicine, University of Otago, 201 Great King Street, Dunedin 9054, New ZealandTel +64 3 474 0999 Ext 58308Email kelechi.ogbuehi@otago.ac.nzPurpose: Autonomic dysfunction may precede the microvascular changes that characterise diabetic retinopathy. The aim of this pilot study was to measure and compare pupillometry indices in type 2 diabetes (T2DM) patients – with and without diabetic retinopathy – and in healthy, age-matched controls.Methods: Two hundred and eleven participants with T2DM aged 45– 80 years were recruited from Dunedin Hospital Eye Department, Dunedin, New Zealand. They were categorised into three groups – no, mild/moderate, or severe diabetic retinopathy. Seventy age-matched, diabetes screen negative control participants were recruited from the Dunedin city community. Dynamic pupillometry was performed using an infrared pupillometer. The main outcome measures were maximum constriction velocity, average constriction velocity, absolute constriction amplitude, relative reflex amplitude, average dilation velocity and 75% re-dilation (recovery) time. Outcome measures were compared between study groups using the Kruskal–Wallis nonparametric test (with Dunn’s multiple comparison post-test).Results: Pupillary parasympathetic function differed between groups. Maximum constriction velocity (p < 0.001) and average constriction velocity (p < 0.001) were slower, and absolute constriction amplitude (p < 0.001) and relative reflex amplitude (p < 0.05) were lower in the three diabetes groups compared with controls. There were no significant differences in pupillary sympathetic function between the four groups for re-dilation time, but the diabetes groups had significantly slower average dilation velocity times.Conclusion: Pupillary light reflex is significantly impaired with diabetic retinal neuropathy, before clinically observable signs of diabetic retinopathy. Dynamic pupillometry may be a cheap, clinically relevant test, but sensitivity and specificity need to be determined before utilising as a screening tool for diabetic retinopathy.Keywords: diabetic autonomic neuropathy, diabetic retinopathy, diabetic macular oedema, pupillary reflex, parasympathetic nervous system, type 2 diabetes mellitus

This study aimed to compare static and dynamic pupil responses of diabetic patients with and without nonproliferative diabetic retinopathy (DR) and normal healthy individuals under different lighting conditions via quantitative automated pupillometry. Forty patients with DM with nonproliferative DR (group 1), 40 patients with DM without DR (group 2), and 40 healthy controls (group 3) underwent a complete ophthalmologic examination. Static pupillometry [scotopic pupil diameter (PD), mesopic PD, low photopic PD, and high photopic PD] and dynamic pupillometry (resting PD, contraction amplitude, latency, duration, velocity of contraction, dilatation latency, and duration and velocity at rest) were measured via automatic quantitative pupillometry. Analysis of variance revealed that scotopic PD [F(2, 117) = 6.42; p = 0.02], mesopic PD [F(2, 117) = 3.20; p = 0.04], and low photopic PD [F(2, 117) = 4.86; p = 0.009] were significantly different among the groups. Scotopic PD and low photopic PD were significantly lower in group 1 than in group 2 (p = 0.03 and p = 0.03, respectively). Meanwhile, the resting diameter, velocity of pupil contraction, and velocity of pupil dilatation were found to be significantly lower (p = 0.02, p = 0.01, and p = 0.008, respectively), and the duration of pupil contraction was significantly higher in group 1 than in group 3 (p = 0.03). Both DM patients with and without nonproliferative DR exhibited pupillary involvement. Automated pupillometry may be an easily applicable, noninvasive screening option for reducing mortality and morbidity rates associated with diabetic autonomic neuropathy.

Diabetic autonomic neuropathy is the second most common form of damage to the nervous system in diabetes mellitus as a result of disorders of the central and/or peripheral parts of the autonomic nervous system. On average, its frequency of occurrence is about 40%, and 60% or more with an increase in the duration of diabetes over than 10 years. Diabetic autonomic neuropathy is characterized by polysyndromism of clinical manifestations. In this regard, a number of forms of diabetic autonomic neuropathy are distinguished both in the form of an isolated violation of the function of organs and systems, and with their combined defeat. In the pathogenesis of autonomic neuropathy, vascular and metabolic changes common to the development of diabetic polyneuropathy play an important role. The most significant risk factors for the development of diabetic autonomic neuropathy are the patient's age, duration of diabetes mellitus, and a higher average HbA1c. The development and progression of diabetic autonomic neuropathy depends on glycemic control, but its forms such as gastrointestinal and impaired recognition of hypoglycemia (asymptomatic hypoglycemia) can cause poor compensation for diabetes. This article discusses the various clinical manifestations of gastrointestinal autonomic neuropathy. Attention is drawn to the fact that the clinical picture is often nonspecific and asymptomatic, which complicates timely diagnosis. The gastrointestinal form of diabetic autonomic neuropathy leads to limited performance, social maladaptation of patients, dramatically reduces the quality of life of patients with diabetes mellitus. In clinical practice, the doctor must remember that it can significantly affect the achievement of glycemic control, as a result of a violation of the digestion and passage of food, as well as a violation of the pharmacokinetics of hypoglycemic drugs. Impaired recognition of hypoglycemia also makes it difficult to compensate well. These complications require a personalized approach to the patient from the doctor, and strict and frequent self-control of glycemia with the help of a modern glucometer from the patient to maintain optimal glycemic control and prevent possible hypoglycemic conditions.

Hintergrund und Ziel: Die Erkrankung Diabetes mellitus 2 zeigt aufgrund der älter werdenden Bevölkerung ein steigendes Wachstum und ist mit Zusatzerkrankungen verbunden. Eine dieser Zusatzerkrankungen ist die kardiovaskuläre autonome Neuropathie. Da die Bewegungstherapie generell einen wichtigen Teil der Behandlung darstellt, sollen in dieser Literaturarbeit die Auswirkungen unterschiedlicher Trainingstherapien untersucht werden. In weiterer Folge werden aus den Ergebnissen physiotherapeutische Behandlungsempfehlungen abgeleitet, welche Physiotherapeut*innen dabei unterstützen können, einen geeigneten Trainingsplan zu erstellen. Dabei lautet die zentrale Frage: Welchen Einfluss haben physiotherapeutische Interventionen auf das autonome Nervensystem bei Diabetes mellitus 2 Patient*innen? Methodik: Diese Arbeit basiert auf einer systematischen Literaturrecherche, welche in medizinischen Datenbanken durchgeführt wurde. Im Rahmen der Einleitung wurden bereits bestehende systematische Reviews, welche sich mit dem Thema befassen, analysiert und die Schlagwörter für die Recherche anhand deren Empfehlungen erweitert. Der Fokus liegt dabei nach wie vor auf der aktiven Trainingstherapie. Als autonome Parameter wurden bei der Suche die Herzratenvariabilität, Ruheherzrate, Baroreflexsensitivität und Herzratenerholung herangezogen. Aufgrund zu weniger Ergebnisse wurden in weiterer Folge nur die Herzratenvariabilität und Baroreflexsensitivität untersucht. Hauptergebnisse: Prinzipiell kann bei Diabetes Mellitus 2 Patient*innen durch körperliches Training Einfluss auf die autonomen Parameter der Herzratenvariabilität und Baroreflexsensitivität genommen werden. Die Ergebnisse zeigen allerdings unterschiedlich starke Effekte und eine große Bandbreite an unterschiedlichen Analyseverfahren. Dies macht einen direkten Vergleich der Studien schwierig. Schlussfolgerung: In der Behandlung sollte eine interdisziplinäre Zusammenarbeit angestrebt werden und ein Trainingsprogramm erstellt werden, welches zumindest in 90 Minuten/Woche absolviert werden kann und eine möglichst hohe Adhärenz der Patient*innen aufweist. Das Ziel sollte nicht eine einmalige Intervention sein, sondern ein Bewegungsprogramm, welches über mehrere Monate und Jahre hinweg selbstständig absolviert werden kann. Context and aim: The disease diabetes mellitus 2 shows an increasing growth due to the aging population and is associated with additional diseases. One of these is cardiovascular autonomic neuropathy. Since exercise therapy is generally an important part of treatment, this literature review will research the effects of different exercise therapies. Furthermore, treatment recommendations will be derived from the results, which can support physiotherapists in creating a suitable training plan. The central question is: What influence do active physiotherapeutic interventions have on the autonomic nervous system to prevent or counteract cardiovascular autonomic neuropathy in patients with diabetes mellitus? Method: This work is based on a systematic literature search, which was conducted in medical databases. In the introduction, already existing systematic reviews were analysed, and the search keywords were expanded based on their recommendations given. The focus is still on active training therapy. The autonomic parameters used in the search were heart rate variability, resting heart rate, baroreflex sensitivity and heart rate recovery. Due to too few results, only heart rate variability and baroreflex sensitivity were subsequently investigated. Results: In principle, physical training can influence the autonomic parameters of heart rate variability and baroreflex sensitivity in diabetes mellitus 2 patients. However, the results show different strong effects and a wide range of different analysis methods. This makes a direct comparison difficult. Conclusion: In treatment, interdisciplinary cooperation should be an aim and a training program should be created, which can be completed for at least 90 min/week and has the highest possible adherence of the patients. The goal should not be a one-time intervention, but an exercise program that can be done independently over several months and years.

Background The exocrine function of the pancreas is controlled by the autonomic nervous system (ANS), and autonomic neuropathy is a common and serious complication of diabetes. There are many factors contributing to the development of autonomic neuropathy in diabetic patients. Cardiovascular tests have been developed to evaluate the function of the ANS. This study investigated the relationship between cardiovascular autonomic neuropathy (CAN) and pancreas exocrine insufficiency (PEI) in diabetic patients. Methods This study evaluated 110 individuals with type 2 diabetes mellitus (T2DM) and 40 healthy volunteers. Autonomous neuropathy tests were utilized to diagnose patients, and Ewing and Clarke's criteria were employed to assess the severity of autonomous dysfunction. Stool samples were also collected from patients to measure fecal elastase-1 (FE-1). Results A 65.5% incidence of PEI was observed in DM patients. There was no significant correlation among the duration of disease, C-peptide, HbA1c, and PEI, respectively (P = .782, P = .521, P = .580). However, a significant difference between DM patients and controls in terms of cardiac dysautonomia (P = .001) was seen. Moreover, a statistically significant correlation between the degree of cardiac dysautonomia and FE-1 level was observed within the patient group (P =.001). Conclusion It is possible that the disruption of exocrine hormone secretion in the pancreas due to the impairment of enteropancreatic reflexes is secondary to diabetic autonomic neuropathy and resulting in PEI. This study also showed that autonomic neuropathy might develop and cause PEI in diabetic patients without known added confounding factors.

This study proposed a pupillary light reflex (PLR) inherent model based on the system identification method to demonstrate the dynamic physiological mechanism of the PLR, in which pupillary constriction and dilation are controlled by the sympathetic and parasympathetic nervous system. This model was constructed and verified by comparing the simulated and predicted PLR response with that of healthy participants. The least root-mean-square error (RMSE) of simulated PLR response was less than 0.7% when stimulus duration was under 3 ms. The RMSE of predicted PLR response increased by approximately 6.76%/s from the stimulus duration of 1 ms to 3 s, when the model directly used the parameters extracted from the PLR at the stimulus duration of 10 ms. When model parameters were derived from the regression by the measured PLR response, the RMSE kept under 8.5%. The model was applied to explore the PLR abnormalities of the people with Diabetic Mellitus (DM) by extracting the model parameters from 42 people with DM and comparing these parameters with those of 42 healthy participants. The parameter in the first-order term of the elastic force of the participants with DM was significantly lower than that of the healthy participants (p &lt, 0.05). The sympathetic force and sympathetic action delay of the participants with DM were significantly larger (p &lt, 0.05) and longer (p &lt, 0.0001) than that of the healthy ones, respectively. The reason might be that the sympathetic nervous system, which controls the dilator muscle, degenerated in diabetic patients.

Diabetic autonomic neuropathy has been proved to be associated with onset of heart failure in patients with diabetes. However, relationship between sudomotor dysfunction, the early manifestation of autonomic neuropathy, and cardiac diastolic function has not yet been investigated. This study aimed to explore the association between sudomotor function and cardiac diastolic function in patients with type 2 diabetes mellitus (T2DM). A total of 63 patients (65% male, 50±13 years old) with T2DM were enrolled and divided into two groups according to mean feet electrochemical skin conductance (ESC) assessed by sudoscan device: sudomotor dysfunction group(SDF group: ESC≤60 μS) and normal sudomotor function group (NSF group: ESC>60 μS). Impaired cardiac diastolic function detected by tissue Doppler imaging echocardiography manifested as elevations of late atrial (A) transmitral peak flow velocity (LgA) and the early (E) transmitral peak flow velocity/early diastolic velocity (e’) (E/e’ratio). The prevalence of sudomotor dysfunction was 30.2%. In SDF group, LgA and E/e’ ratio were significantly higher than those in NSF group (-0.2±0.2 m/s vs. -0.4±0.3 m/s, P=0.011 and 11.0±3.8 vs. 8.8±2.7, P=0.013, respectively). Pearson correlation analysis revealed that LgA was negatively correlated with mean feet ESC(r=-0.3, P=0.017). In logistic regression analyse, LgA (OR=0.05, 95%CI 0.004-0.585, P=0.017) and E/e‘ ratio (OR=0.79, 95%CI 0.641-0.970, P=0.025) were found to be independently associated with presence of sudomotor dysfunction. Cardiac diastolic function significantly decreased in type 2 diabetic patients with sudomotor dysfunction. Disclosure X. Chen: None. X. Yang: None. W. Xu: None. H. Deng: None. J. Wu: None. J. Yan: None. B. Yao: None. Funding Natural Science Foundation of Guangdong Province (2018A030313915); Medical Scientific Research Foundation of Guangdong Province (A2018286)

Diabetic neuropathies are a group of heterogeneous peripheral neuropathies and are roughly classified into polyneuropathy and focal neuropathy. Diabetes-specific neuropathy is polyneuropathy, which is pathophysiologically associated with metabolic disorders due to hyperglycemia and microangiopathy. Recently, classification1,2) of the spectrum of diabetic polyneuropathy based on the different type of nerve fiber involved is growing (e.g. myelinated, unmyelinated, autonomic, somatic). Diabetic polyneuropathy (DPN) is divided into diabetic distal sensory neuropathy (DSN), diabetic small fiber neuropathy (DSFN) and diabetic autonomic neuropathy (DAN)2) .

Purpose Diabetic autonomic neuropathy (DAN) is a common and disabling complication of diabetes, with cardiac autonomic neuropathy (CAN) being a major cause of mortality and morbidity. Standard autonomic function tests (AFT) are cumbersome and time consuming to conduct in OPD setting. Objective To evaluate the diagnostic accuracy of composite autonomic symptom scale 31 (COMPASS-31) as a screening test for DAN. Patients and methods A cross-sectional study which enrolled 60 type 2 diabetes individuals was conducted at a tertiary care center. Autonomic functions were evaluated by COMPASS-31 questionnaire as well as by standard Ewing's battery of tests; short-term heart rate variability; sympathetic skin response along with nerve conduction studies. Results Thirty males and 24 females completed the study. Forty-nine (89%) participants had CAN, of which, 9 (17%) had definite CAN. Peripheral neuropathy was present in 20 (37%). COMPASS-31 scores showed no difference between "No CAN" and "Early CAN". "Definite CAN" individuals differed significantly from "No and Early CAN" on COMPASS-31 scores and its gastrointestinal sub-domain. Receiver operating characteristic between "Definite CAN" and "No and Early CAN" showed fair accuracy with AUC of 0.731 (95% CI 0.561-0.901), sensitivity 77.8%, specificity 71.7% at a cut-off of 28.67 of COMPASS-31 score. Gastrointestinal sub-domain, at a cut-off score of 5.8, had 77.8% sensitivity, 60% specificity, and AUC was 0.748 (95% CI 0.603-0.894). Conclusion COMPASS-31, a self-administered tool, requiring less time, qualifies as an acceptable screening tool, especially for definite CAN. However, individuals scoring low on COMPASS-31 are still required to be evaluated by Ewing's battery to differentiate between "Early CAN" and "No CAN".

Diabetic peripheral polyneuropathy (DPN) is one of the most frequent and serious complications of diabetes mellitus (DM). Appearing at any stage of the evolution of diabetes, polyneuropathy determines the severity of the underlying disease and often leads to disability of patients. Among the lesions of the peripheral nervous system in diabetes, as a rule, diabetic sensorimotor polyneuropathy and autonomic neuropathy are distinguished. Of great practical importance is diabetic autonomic neuropathy (DAN), the development of which has a significant effect not only on the course of diabetes, increasing metabolic disturbances, but also on the psycho-emotional state of patients, their social adaptation, restricts professional activity and often has a traumatic effect with appropriate psycho-emotional consequences up to the development of mental disorders. The most common form of DPN is recognized as chronic symmetric sensorimotor polyneuropathy (CSSMPN), which is manifested by sensations of numbness, chilliness, tingling and/or pain in the extremities, symmetric disturbances of all types of sensitivity (pain, temperature, tactile and vibration) are also observed — in areas of type of «socks» and «gloves». The overwhelming majority of patients with CSSMPN note emotional discomfort, communication problems, including in the family, and, in general, show lower quality of life indicators than patients with diabetes in the absence of DPN. In case of violation of the sensitivity of the fingers and the occurrence of other neuropathic manifestations, the use of portable glucometers and thin test-strips during self-monitoring can cause certain difficulties in patients. For people with impaired finger sensitivity, it is advisable to use BIONIME Rightesttm test-strips, the design of which provides convenience when using them.

BACKGROUND: Diabetic peripheral neuropathy (DPN) means the presence of symptoms and/or signs of peripheral nerve damage that occur to people with diabetes, excluding all other causes of neuropathy. Chronic hyperglycaemia leads to increased secretion of tumour necrotic factor-alpha (TNF-α), with the development of micro and macroangiopathy, damage to nerve fibres and local demyelination. AIM: To determine the role of inflammation in the peripheral nerve damage process concerning people suffering from type II diabetes mellitus. MATERIAL AND METHODS: The study included a total of 80 subjects, men and women, divided into two groups: an examined group (n = 50) consisting of subjects with DPN at the age from 30 to 80 years and a control group (n = 30) of healthy subjects aged from 18 to 45. In the investigated group, a neurological examination was performed using the Diabetic Neuropathy Symptoms (DNS) Score and Electroneurography. All the subjects had the blood plasma concentration of TNF-α by ELISA technique. RESULTS: The average value of TNF-α in the test group was 8.24 ± 2.899 pg/ml, while the control group was 4.36 ± 2.622 pg/ml (p < 0.0001). The average value of TNF-α was correlated with the achieved DNS score in the investigated group (p = 0.005). Concerning the linear association of the concentration of TNF-α with the peripheral nerve velocity in the investigated group, no statistical significance was detected. CONCLUSION: Inflammation can play a role in the pathogenesis of diabetic autonomic neuropathy and cranial neuritis.

Introduction. Diabetic neuropathy is the most wide-spread complication of diabetes mellitus and neuropathy is steadily progressing even with compensation of the underlying disease. The search of the new methods of treatment and diagnosis of neuropathy is required. Diabetic autonomic neuropathy lies in the base of early morbidity and mortality of diabetic patients.We estimated the potential of High-frequency Ultrasonic Dopplerography for diagnosis of autonomic neuropathy. Material and methods. 26 diabetic patients with sensorimotor neuropathy were examined. Microvascular blood flow of finger skin was assessed at rest as well as in functional tests: with cold impact and occlusion (cuff). Cardiac autonomic neuropathy was assessed using several cardiovascular autonomic reflex tests as a gold standard of diagnosis. Diagnostic values of microvascular blood flow test in detecting of cardiac autonomic neuropathy staging were evaluated in comparing with traditional modalities.Results. Cardiac autonomic neuropathy was found for all patients and definite/confirmed staging in 61.5 % cases. Initial parameters of microvascular blood flow velocity were significantly decreased in all patients in comparing with control (Vam= = (1.9±0.22); (1.7±0.51) and (6.7±0.51) sm/s in patients with early cardiac autonomic neuropathy, definite/confirmed staging and control subjects respectively, pConclusions. High-frequency Ultrasonic Dopplerography allowed to separate of cardiac autonomic neuropathy stages. This study is necessary to continue for revealing of all method possibilities.

Two diabetic women (case 1, 75 years old; case 2, 49 years old) being treated with glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) showed no suppression of cortisol secretion on a dexamethasone suppression test (DST). However, its secretion was suppressed after switching from GLP-1 RAs to insulin. We also checked the cortisol secretion by a DST in five consecutive inpatients (case 3-7) being treated with GLP-1 RAs. The coefficients of R-R interval variation at rest and during deep breathing were lower in the two false-positive cases (case 1 and 2) than in the five true-negative cases (case 3-6). GLP-1 RAs can be switched to insulin in order to eliminate the slow absorption effect of dexamethasone by GLP-1 RAs if a DST is planned in diabetic patients receiving GLP-1 RAs.

Maryam Vasheghani,1 Farzaneh Sarvghadi,2 Mohammad Reza Beyranvand31Endocrinology & Metabolism Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2Endocrinology & Metabolism Department, Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 3Interventional Cardiology, Department of Cardiology, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, IranIntroduction: Cardiac autonomic neuropathy (CAN) is one of major complications of diabetes mellitus (DM) that increases the risk of cardiovascular disorders, abnormal ventricular depolarization with poor prognosis as well as increased mortality and morbidity. Indeed, CAN has close relation with blood glucose level in diabetic patients. We investigated the relation of CAN with diabetes control.Materials and methods: Totally, 115 diabetic patients (mean age 50.87±13.90 years old; 78 females) underwent study. All patients had DM and cardiac sinus rhythm. Nobody had sickness affecting cardiac rhythm and blood pressure. In addition, they did not take drugs that had effect on blood pressure, cardiac rhythm, and QT interval. Forty-six patients had tight and 69 patients had uncontrolled DM according to American Diabetes Association (ADA) criteria. The CAN was assessed based on heart rate variation during physical examination (at rest tachycardia and orthostatic hypotension) and standard Ewing’s tests (deep-breathing and laying-to-standing tests) with bedside continuous ECG recording. The P-value

Introduction: Cardiac autonomic neuropathy (CAN) is one of major complications of diabetes mellitus (DM) that increases the risk of cardiovascular disorders, abnormal ventricular depolarization with poor prognosis as well as increased mortality and morbidity. Indeed, CAN has close relation with blood glucose level in diabetic patients. We investigated the relation of CAN with diabetes control. Materials and methods: Totally, 115 diabetic patients (mean age 50.87±13.90 years old; 78 females) underwent study. All patients had DM and cardiac sinus rhythm. Nobody had sickness affecting cardiac rhythm and blood pressure. In addition, they did not take drugs that had effect on blood pressure, cardiac rhythm, and QT interval. Forty-six patients had tight and 69 patients had uncontrolled DM according to American Diabetes Association (ADA) criteria. The CAN was assessed based on heart rate variation during physical examination (at rest tachycardia and orthostatic hypotension) and standard Ewing's tests (deep-breathing and laying-to-standing tests) with bedside continuous ECG recording. The P-value

Diabetic polyneuropathy affects 30–50% of patients with diabetes mellitus. It encompasses several neuropathic syndromes, the commonest being distal symmetrical polyneuropathy or ‘diabetic peripheral neuropathy’ (DPN). Risk factors for DPN include poor glycaemic control and drivers of macrovascular disease including hypertension. Strong evidence in humans and animals implicates nerve ischaemia as the cause of DPN. Despite several well-designed recent trials, no novel approved treatment with unequivocal effects on the decline in nerve function in DPN has emerged. Painful DPN affects 15–26% of those with diabetes, produces considerable disability, and is challenging to assess and manage. First-line therapies are tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors (e.g. duloxetine) or anticonvulsants (e.g. pregabalin, gabapentin). Second-line drugs include opioids. Diabetic autonomic neuropathy also results in considerable morbidity, reduced quality of life and increased mortality. It may involve cardiovascular, gastrointestinal, urogenital, pupillomotor, thermoregulatory and sudomotor function. Although counselling and non-pharmacological interventions are of some use, more severely afflicted patients require pharmacological intervention.

Introduction/Objective. Cardiovascular diabetic autonomic neuropathy (CDAN) mainly affects heart rhythm through sympathovagal imbalance. The objective of the study is to determine CDAN risk potential regarding electrical complications of acute myocardial ischemia (AMI), including admission glucose profile levels (AGP). Methods. Seventy-six patients suffering from type 2 diabetes mellitus were divided into two age-matched groups related to the presence of CDAN, and the influence of AGP on electrical complications was estimated. Ewing?s tests were used for diagnosis of CDAN. Results. Patients without CDAN have 42.86% risk for developing electrical complication into early post-AMI period. If it is a pre-existing condition, the risk is 63.64%, which is obvious, but not statistically significant. Considering the AGP, levels above 12.25 mmol/L as predictive for post-AMI electrical complications, in CDAN-positive patients with AGP levels above that cut-off value, the risk for electrical complications is raising up to 73.68%. The patients with CDAN who have AGP levels above the cut-off value have statistically higher risk for development electrical complications than those with lower levels (Z = 2.58, p < 0.01). On the other side, those without CDAN and with level of AGP lower than 12.25 mmol/L, the risk for electrical complications developing is as low as 23.08%. Conclusion. CDAN may be an important independent risk factor for electrical complications in postmyocardial ischemia period.

Purpose: To investigate the relation between erectile dysfunction (ED) severity and pupillary functions in patients with diabetes mellitus (DM). Methods: This prospective and observational study included 90 patients with type 2 DM and ED. Patients divided into three subgroups according to severity of ED: (i) Mild ED, (ii) Moderate ED and (iii) Severe ED groups. Thirty age-matched healthy subjects formed the control group. Main outcome measures were pupil diameter and average speed of pupil dilation. Static and dynamic pupillometry analysis was performed using the Sirius Topographer (CSO, Firenze, Italy). Results: Mean pupil diameter during static and dynamic pupillometry analysis were significantly greater in the control group than in the all study groups (P < 0.05). Mean pupil diameter in static pupillometry analysis was significantly different in each study group and pupil was more miotic in the Severe ED group than in the both Moderate and Mild ED groups (P < 0.05 for each). Dynamic pupillometry analysis revealed that mean pupil diameter and mean average dilation speed were significantly different in each study group throughout measurement period and the highest speed was observed in the Mild ED group and the lowest speed was observed in the severe ED group (P < 0.005 for each). Conclusion: Our study results suggest that abnormal pupil functions due to diabetic autonomic neuropathy may indicate the associated ED in patients with DM.

Diabetic autonomic neuropathy (DAN) is one of the least understood and attended complications which affects the quality of life. Increased oxidative stress, advanced glycation end products (AGEs), overactivation of protein kinase C (PKC) and reduced myoinositol content in autonomic nerves are major pathological conditions responsible for DAN. Limited treatment options appeal researchers to search for alternative treatments for DAN. Natural polyphenols are potent antioxidants and have been reported to have beneficial effects in above mentioned pathological conditions. Diabetes was induced in male Sprague Dawley rats weighing between 190-220 g with streptozotocin (55 mg/kg, i.p.). After 6 weeks of diabetes induction, animals were treated with catechin at dose 25 and 50 mg/kg for the next 28 days. Catechin treatment at dose 25 and 50 mg/kg showed significant improvement in body weight. The treatment with catechin at dose 50 mg/kg; significantly reduced heart hypertrophy (p 0.001) and plasma glucose levels (p 0.01). At dose 50 mg/kg catechin significantly improved hemodynamic parameters like heart rate, mean atrial pressure and left ventricular systolic pressure. Catechin also improved oxidative stress parameters in the nerves. Circulatory MMP-9 levels were significantly decreased (p 0.001) in catechin treated animals at a dose of 50 mg/kg. The histopathology results showed a significant reduction in neuronal damage due to catechin treatment for 28 days. The results of the study showed that catechin has a beneficial effect in the management of diabetic autonomic neuropathy in rats.

Background: There are many methods to diagnose diabetic autonomic neuropathy (DAN); however, often, the various methods do not provide consistent results. Even the two methods recommended by the American Diabetes Association (ADA) guidelines, Ewing's test and heart rate variability (HRV), sometimes give conflicting results. The purpose of this study was to evaluate the degree of agreement of the results of the Composite Autonomic Symptom Score 31 (COMPASS-31), skin sympathetic reaction (SSR) test, Ewing's test, and HRV in diagnosing DAN.Methods: Patients with type 2 diabetes were recruited and each received the COMPASS-31, SSR, Ewing's test, and HRV for the diagnosis of DAN. Patients were categorized as DAN(+) and DAN(–) by each of the tests. Kappa consistency tests were used to evaluate the agreement of diagnosing DAN between any two methods. Spearman's correlation test was used to evaluate the correlations of the severity of DAN between any two methods. Receiver operating characteristic (ROC) analyses were used to evaluate the diagnostic value and the cutoff value of each method.Results: A total of 126 type 2 diabetic patients were included in the study. The percentages of DAN(+) results by HRV, Ewing's test, COMPASS-31, and SSR were 61, 40, 35, and 33%, respectively. COMPASS-31 and Ewing's test had the best agreement for diagnosing DAN (κ = 0.512, p < 0.001). COMPASS-31 and Ewing's test also had the best correlation with respect to the severity of DAN (r = 0.587, p < 0.001). Ewing's test and COMPASS-31 had relatively good diagnostic values (AUC = 0.703 and 0.630, respectively) in the ROC analyses.Conclusions: COMPASS-31 and Ewing's test exhibit good diagnostic consistency and severity correlation for the diagnosis of DAN. Either test is suitable for the diagnosis of DAN and treatment follow-up.

Diabetic neuropathy is a neurodegenerative disorder that may alter both the somatic and autonomic peripheral nervous systems in the context of diabetes mellitus (DM). It is a prevalent and burdensome chronic complication of DM, that requires timely management. Optimized glycemic control (mainly for type 1 DM), multifactorial intervention (mainly for type 2 DM), with lifestyle intervention/physical exercise, and weight loss represent the basis of management for diabetic distal symmetrical polyneuropathy, and should be implemented early in the disease course. Despite better understanding of the pathogenetic mechanisms of diabetic peripheral neuropathy, there is still a stringent need for more pathogenetic-based agents that would significantly modify the natural history of the disease. The paper reviews the available drugs and current recommendations for the management of distal symmetrical polyneuropathy, including pain management, and for diabetic autonomic neuropathy. Evaluation of drug combinations that would perhaps be more efficient in slowing the progression of the disease or even reversing it, and that would provide a better pain management is still needed.

IntroductionA high proportion of people with diabetes experience gastrointestinal (GI) symptoms, which may be manifestations of diabetic autonomic neuropathy (DAN). The current treatment regime is ineffective and associated with major side effects. Transcutaneous vagal nerve stimulation (tVNS) is a new therapeutic option, which has been shown to increase GI motility and reduce inflammatory responses. As vagus is the main neuronal pathway for extrinsic coordination of GI secretion and motility, we hypothesise that tVNS will improve DAN-induced GI symptoms in subjects with diabetes.Methods and analysisThe DAN-VNS study is a randomised multicentre clinical trial investigating the effect of short-term, high intensity as well as long-term, medium-intensity tVNS on GI symptom alleviation in 120 subjects with diabetes. The primary outcome consists of changes from baseline in subjective ratings of symptom severity. Secondary outcomes include changes in gastric motility and GI transit time measured by MRI and wireless motility capsule. Moreover, cardiovascular and sudomotor function, glycaemic control, brain sensory processing and presence of low-grade inflammation will be investigated as secondary outcome measures. Lastly, 15 responders of tVNS treatment will be included in an explorative, randomised, cross-over study, in which the acute endocrine and metabolic response to short-term tVNS will be investigated.Ethics and disseminationThe study has been approved by the North Denmark Region Committee on Health Research Ethics (N-20190020). Results will be published in relevant international peer-reviewed journals.Trial registration numberNCT04143269.

Diabetic autonomic neuropathy (DAN) is a common microvascular complication of diabetes mellitus (DM). The main clinical manifestations of DAN result from involvement of cardiac, gastrointestinal, and urogenital systems; sudomotor and ocular dysfunction are also common. Cardiac autonomic neuropathy (CAN) manifests with resting tachycardia, exercise intolerance, abnormal blood pressure regulation, and orthostatic hypotension; the Ewing tests are the proposed method for the assessment of CAN. The presence of CAN is associated with increased cardiovascular mortality. Optimization of glycemic control and symptomatic treatment are essential for the management of CAN. DAN can affect the gastrointestinal tract causing esophageal dysfunction, gastroparesis, and enteropathy. Exclusion of gastric obstruction is needed before testing for gastroparesis, while radiolabeled scintigraphy is the gold standard method for the diagnosis of gastroparesis. Dietary management and glycemic control are essential for the management of gastroparesis, while metoclopramide is the only FDA-approved medical drug for this disorder. Involvement of the urogenital tract manifests with bladder and sexual dysfunction in both genders. Phosphodiesterase type 5 inhibitors are the first-line treatment option for males with erectile dysfunction. Sudomotor dysfunction leads to dry skin, itching, anhidrosis, and gustatory sweating and is associated with the development of diabetic foot ulcers. Ocular dysfunction results in pupillomotor function impairment, reduced corneal sensation, and dry eyes.

Evaluation of disorders of the autonomic nervous system is both an art and a science, calling upon the physician's most astute clinical skills as well as knowledge of autonomic neurology and physiology. Over the last three decades, the development of noninvasive clinical tests that assess the function of autonomic nerves, the validation and standardization of these tests, and the growth of a large body of literature characterizing test results in patients with autonomic disorders have equipped clinical practice further with a valuable set of objective tools to assist diagnosis and prognosis. This review, based on current evidence, outlines an international expert consensus set of recommendations to guide clinical electrodiagnostic autonomic testing. Grading and localization of autonomic deficits incorporates scores from sympathetic cardiovascular adrenergic, parasympathetic cardiovagal, and sudomotor testing, as no single test alone is sufficient to diagnose the degree or distribution of autonomic failure. The composite autonomic severity score (CASS) is a useful score of autonomic failure that is normalized for age and gender. Valid indications for autonomic testing include generalized autonomic failure, regional or selective system syndromes of autonomic impairment, peripheral autonomic neuropathy and ganglionopathy, small fiber neuropathy, orthostatic hypotension, orthostatic intolerance, syncope, neurodegenerative disorders, autonomic hyperactivity, and anhidrosis.

Gastroparesis and other gastrointestinal motility diseases can be associated with various autonomic neuropathies. The gastrointestinal tract has its own enteric nervous system, a branch of the autonomic nervous system (ANS), and exchanges modulatory signals with the extrinsic autonomic systems. Autonomic neuropathies impairing functions of the extrinsic autonomic pathways can contribute to gastroparesis. Neurological evaluation is needed in patients with gastroparesis to assess systemic or extra-intestinal autonomic involvements as well as to identify an underlying neurological etiology. Self-assessed autonomic questionnaires such as composite autonomic symptom score (COMPASS) are feasible tools for such purposes. Autonomic reflex tests can localize impaired branches of the ANS and to support a diagnosis of autonomic neuropathy. Because autonomic reflex tests clinically available at most autonomic laboratories are relevant to cardiovascular and sudomotor (sweating) autonomic systems, findings of tests do not always have a strong association with the presence and severity of gastroparesis or other localized autonomic/neurological conditions. Skin biopsy to estimate sensory small-fibers in the epidermal layers and autonomic fibers innervating sweat glands is a pathological diagnostic method for small-fiber neuropathy. Autonomic neuropathies associated with gastroparesis include diabetic autonomic neuropathy, Guillain-Barre syndrome, autoimmune autonomic ganglionopathy, paraneoplastic autonomic neuropathy, hereditary amyloid neuropathy. Other autonomic disorders with or without evidence of peripheral autonomic nerve involvements such as postural orthostatic tachycardia syndrome are discussed. Ehlers-Danlos Syndrome is a hereditary connective tissue disorder with multiple subtypes but it is worth mentioning due to its high association with postural orthostatic tachycardia syndrome.

Diabetic autonomic neuropathy is an under-recognised complication of diabetes and the prediabetic state. A wide range of manifestations can be seen due to involvement of cardiovascular, gastrointestinal, genitourinary, sudomotor and neuroendocrine systems. Cardiac autonomic neuropathy is the most dreaded complication carrying significant mortality and morbidity. Early detection and control of diabetes and other cardiovascular risk factors is the key to treat and prevent progression of autonomic neuropathy. Recently, a new entity of treatment-induced neuropathy (TIND) of diabetes mellitus causing autonomic neuropathy is being increasingly recognised.

Purpose Autonomic dysfunction may precede the microvascular changes that characterise diabetic retinopathy. The aim of this pilot study was to measure and compare pupillometry indices in type 2 diabetes (T2DM) patients – with and without diabetic retinopathy – and in healthy, age-matched controls. Methods Two hundred and eleven participants with T2DM aged 45–80 years were recruited from Dunedin Hospital Eye Department, Dunedin, New Zealand. They were categorised into three groups – no, mild/moderate, or severe diabetic retinopathy. Seventy age-matched, diabetes screen negative control participants were recruited from the Dunedin city community. Dynamic pupillometry was performed using an infrared pupillometer. The main outcome measures were maximum constriction velocity, average constriction velocity, absolute constriction amplitude, relative reflex amplitude, average dilation velocity and 75% re-dilation (recovery) time. Outcome measures were compared between study groups using the Kruskal–Wallis nonparametric test (with Dunn’s multiple comparison post-test). Results Pupillary parasympathetic function differed between groups. Maximum constriction velocity (p

PURPOSE: Cardiovascular autonomic neuropathy (CAN) is one of the most common and serious complications associated with diabetes and is defined as the impairment of the autonomic control of the cardiovascular system, whose prevalence in Indian population has been reported to be > 50%. The risk factors associated with CAN include hyperglycemia, duration of diabetes, hypertension, dyslipidemia, and obesity. This study was conducted to examine the association of CAN with its determinants among diabetics. METHODS: Socio-demographic characteristics were noted alongwith performance of biochemical analyses of blood samples according to standard hospital pathology laboratory protocols. Clinical assessment of CAN comprised a of 5 indexes, including 3 heart rate variability parameters (resting tachycardia, Qtc interval > 440 msec, exercise intolerance) and 2 blood pressure parameters (orthostatic hypotension, abnormal hand gripping test). RESULTS: The odds of CAN increased with poor glycemic control (FBS ≥ 126 mg/dL (OR = 1.17 (1.02–10.68); 2 hr PPBS ≥ 200 mg/dL (OR 1.63 (1.26–8.82) and HbA1c ≥ 6.5% (OR = 10.68 (1.54–208.02). Significant difference was also found in relation to duration of diabetes, weight and body mass index of the participants with various grades of CAN. CONCLUSIONS: CAN is associated strongly with poor glycemic control. Obesity seems to be involved in the impairments of the cardiac autonomic function and this factor must therefore be taken into account in future studies when interpreting the results. Body mass control and glycemic control could provide an important approach to reducing CAN.

Background Autonomic neuropathy (AN) commonly arises as a long‐term complication in diabetes mellitus and can be diagnosed from heart rate variability (HRV), calculated from electrocardiogram recordings. Psychosocial stress also affects HRV and could be one of several confounders for cardiac AN. The present work investigated the impact of psychosocial stress on HRV in individuals with type 1 diabetes mellitus (T1DM) and assessed the use of salivary cortisol as a biomarker for psychosocial stress in this context. Methods A total of 167 individuals 6–60 years old (113 with T1DM and 54 healthy controls) underwent 24‐hr ECG recordings with HRV analysis. Salivary cortisol was sampled thrice during the registration day. Perceived psychosocial stress along with other factors of possible importance for the interpretation of HRV was documented in a diary. Results Heart rate variability (high‐frequency power during sleep) was reduced (p

Background involvement of central and peripheral nervous systems are well-documented in SLE but literature on prevalence and pattern of autonomic neuropathy are few. Women with SLE have been found to have 5-8 fold increased risk of coronary heart disease. Autonomic dysfunction in the presence of structural cardiovascular disease is associated with adverse prognosis. Aim of the Work the purpose of this study is to evaluate the cardiovascular autonomic function in patients with Systemic lupus erythematosus, and to correlate it with SLE clinical features. Patients and Methods we conducted our study on one-hundred Egyptian SLE patients diagnosed according to SLICC classification criteria for SLE recruited from rheumatology outpatient clinic and inpatient department at Ain Shams University Hospitals. All the studied patients were subjected to history taking, clinical examination, and laboratory and radiological investigations related to SLE diagnosis and activity. SLE disease activity was assessed by SLE disease activity index-2000 (SLEDAI-2K).Tilt table test was used to assess for presence of cardiovascular autonomic neuropathy. Results we found that fifty (50%) of our SLE patients had symptoms suggestive for autonomic dysfunction, including orthostatic hypotension, palpitation and or Raynaud’s phenomenon. Regarding the result of tilt table test, sixty eight (68%) of the studied SLE patients were found to have positive tilt table responses. By doing the uni-variate analysis for predictors of SLE patients with positive tilt table test, we found that vasculitis, proteinuria, DNA, low TLC and complement levels, high SLEDAI, ESR and urinary P/C all were predictors for positivity of tilt table testing. Conclusion The prevalence of autonomic dysfunction was high among SLE patients.

Gastrointestinal autonomic neuropathy represents an important and diverse, but poorly appreciated, manifestation of diabetic autonomic neuropathy that impacts negatively on quality of life. There is no test to assess gastrointestinal autonomic nerve damage directly in humans; cardiovascular autonomic reflex tests are often used as a surrogate, but are suboptimal. Gastrointestinal symptoms are common in diabetes, but usually correlate only weakly with disordered motility. Diabetic gastroparesis, or abnormally delayed gastric emptying, occurs frequently and is the best characterized manifestation of gastrointestinal autonomic neuropathy. There is a bi-directional relationship between postprandial glycaemia and the rate of gastric emptying. However, autonomic neuropathy can affect the function of any gut segment from the esophagus to the anus. Current management options for gastrointestinal autonomic neuropathy are, for the main part, empirical and sub-optimal.

Diabetes mellitus has multiple negative effects on regenerative processes, especially on wound and fracture healing. Despite the well-known negative effects of diabetes on the autonomous nervous system, only little is known about the role in bone regeneration within this context. Subsequently, we investigated diabetic bone regeneration in db−/db− mice with a special emphasis on the sympathetic nervous system of the bone in a monocortical tibia defect model. Moreover, the effect of pharmacological sympathectomy via administration of 6-OHDA was evaluated in C57Bl6 wildtype mice. Diabetic animals as well as wildtype mice received a treatment of BRL37344, a β3-adrenergic agonist. Bones of animals were examined via µCT, aniline-blue and Masson–Goldner staining for new bone formation, TRAP staining for bone turnover and immunoflourescence staining against tyrosinhydroxylase and stromal cell-derived factor 1 (SDF-1). Sympathectomized wildtype mice showed a significantly decreased bone regeneration, just comparable to db−/db− mice. New bone formation of BRL37344 treated db−/db− and sympathectomized wildtype mice was markedly improved in histology and µCT. Immunoflourescence stainings revealed significantly increased SDF-1 due to BRL37344 treatment in diabetic animals and sympathectomized wildtypes. This study depicts the important role of the sympathetic nervous system for bone regenerative processes using the clinical example of diabetes mellitus type 2. In order to improve and gain further insights into diabetic fracture healing, β3-agonist BRL37344 proved to be a potent treatment option, restoring impaired diabetic bone regeneration.

Disorders of the autonomic nervous system are more common in neurologic practice than previously recognized in diagnostic conclusions. Besides the primary involvement of the autonomic nervous system, there are sympathetic or parasympathetic (especially vagal) dysfunctions associated with other diseases of the peripheral and central nervous system. The aim of this paper is to provide a short overview of the symptomatology of autonomic dysfunctions, the examination methods of the autonomic nervous system, especially those available and applicable in clinical neurological practice, and furthemore, the clinical pictures of generalized and localized autonomic dysfunctions. The most important autonomic examinations focus on the cardiovascular system, assessing both heart rate and blood pressure changes in appropriately selected autonomic tests. The cardiovascular autonomic reflex tests and the heart rate variability assessment are here the most commonly used diagnostic tools. The examination methods of the autonomic nervous system in other systems of the human body are described in this paper in a brief overview. The latter part of this article is dedicated to selected diseases and clinical symptomatology. Among generalized (systematic) disorders of the autonomic nervous system, diabetic autonomic neuropathy and autonomic polyneuropathies of other causes are discussed in greater detail. This is followed by an overview of autonomic disturbances and dysfunctions of central origin, that may constitute either major, or minor symptoms of neurological diseases. The paper further describes clinical features of localized autonomic disturbances. A simple diagnostic scheme for basic evaluation of the autonomic functions in clinical neurological practice is proposed at the end of this paper.

Background Disordered sleep breathing is a common complication of diabetic peripheral neuropathy (DPN) manifested by excessive daytime sleepiness, morning headache, morning dizziness, cognitive decline, and mood changes. Methods This study was performed on 30 non-obese type 2 diabetic patients; 20 with clinically evident DPN and 10 without. Ten age-, sex-, and body mass index-matched healthy control subjects were also included. Patients and control were subjected to history taking, neurological examination, glycated hemoglobin, and clinical assessment of the sensori-motor manifestations by the neuropathy symptom score and neuropathy disability score. The autonomic nervous system was evaluated clinically by the systolic blood pressure response to standing and heart rate response to each of standing, Valsalva, and deep breath. Finally, sleep was assessed by one-night polysomnogram (PSG) followed by multiple sleep latency test in the next day. Results The study showed significant increase in sleep apnea syndromes in diabetic peripheral neuropathy patients compared to diabetic neuropathy free patients and healthy control (p

Aim This study evaluated the association of Heart rate variability (HRV) measurements with diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes. Methods This study included 102 Korean subjects with type 2 diabetes. The Michigan neuropathy screening instrument (MNSI) questionnaire score, the MNSI examination score (MNSIES) and the total symptom score were examined for DPN evaluation. Noninvasive HRV measurements were performed using photoelectric plethysmography. Patients with a MNSIES > 2 were considered to have DPN. Results The MNSIES showed significant negative associations with the high frequency (HF) (r = −0.212, p = 0.033) and low frequency (LF) (r = −0.286, p = 0.004) powers. Multiple linear regression analysis revealed that only HF power maintained a significant negative association with the MNSIES (β = −0.184; 95% CI −0.365 to −0.003; p = 0.047), after controlling for significant related confounders, with HRV parameters in male patients with type 2 diabetes. The HF (p = 0.010) and LF (p = 0.025) powers differed significantly between male patients without and those with DPN according to the MNSIES. Conclusions This study revealed a negative association of DPN, as assessed by the MNSIES, with HF power in male patients with type 2 diabetes. DPN defined by foot examination was predictive of cardiac autonomic neuropathy.