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Background Methods Key Results Conclusions & Inferences Diabetic gastroenteropathy can cause significant diagnostic challenges. Still, it remains unknown if measures of extraintestinal autonomic function reflect diabetic gastroenteropathy. We aimed to assess the associations between (1) gastrointestinal symptoms and motility measures and (2) gastrointestinal symptoms/motility measures and extraintestinal autonomic markers.We included 81 persons with type 1 or type 2 diabetes (65% female, mean age 54) with gastrointestinal symptoms and autonomic neuropathy. The Gastroparesis Cardinal Symptom Index (GCSI) and the Gastrointestinal Symptom Rating Scale (GSRS) assessed gastrointestinal symptoms. The wireless motility capsule (Smartpill™) assessed panenteric transit times and motility indices. Cardiovascular reflex tests (VAGUS™) and cardiac vagal tone (eMotion Faros) estimated cardiovascular autonomic neuropathy, while the SUDOSCAN™ evaluated sudomotor function.Proximal gastrointestinal symptoms were positively associated with the gastric motility index (GCSI: 1.18 (1.04–1.35), p = 0.01; GSRS: 1.15 (1.03–1.29), p = 0.02; median ratio (95% CI)), while only satiety correlated with gastric emptying time (1.24 (1.03–1.49), p = 0.02). Diarrhea was associated with decreased small bowel transit time (0.93 (0.89–0.98), p = 0.005), while constipation were associated with prolonged colonic transit time (1.16 (1.03–1.31), p = 0.02). Gastrointestinal symptoms increased with the degree of abnormal cardiovascular reflex tests (GCSI: 0.67 (0.16–1.19), p = 0.03; GSRS: 0.87 (0.30–1.45), p = 0.01; mean difference (95% CI)) but not with motility measures. Cardiac vagal tone and sudomotor function were not associated with gastrointestinal markers.Gastrointestinal and extraintestinal autonomic measures were not associated. However, proximal gastrointestinal symptoms were associated with the gastric motility index and cardiovascular reflex tests. Hence, the latter may contribute to evaluating whether proximal gastrointestinal symptoms are autonomically derived. [ABSTRACT FROM AUTHOR]

Degeneration of dopaminergic neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinson's disease. In idiopathic cases, high levels of mitochondrial DNA alterations, leading to mitochondrial dysfunction, are a central feature of these vulnerable neurons. Here we present a mouse model expressing the K320E variant of the mitochondrial helicase Twinkle in dopaminergic neurons, leading to accelerated mitochondrial DNA mutations. These K320E-TwinkleDaN mice showed normal motor function at 20 months of age, although ∼70% of nigral dopaminergic neurons had perished. Remaining neurons still preserved ∼75% of axon terminals in the dorsal striatum and enabled normal dopamine release. Transcriptome analysis and viral tracing confirmed compensatory axonal sprouting of the surviving neurons. We conclude that a small population of substantia nigra dopaminergic neurons is able to adapt to the accumulation of mitochondrial DNA mutations and maintain motor control. [ABSTRACT FROM AUTHOR]

Aims: Impaired awareness of hypoglycaemia (IAH) increases the risk of severe hypoglycaemia in people with type 1 diabetes mellitus (T1DM). IAH can be reversed through meticulous avoidance of hypoglycaemia. Diabetic autonomic neuropathy (DAN) has been proposed as an underlying mechanism contributing to IAH; however, data are inconsistent. The aim of this study was to examine the effects of cardiac autonomic neuropathy (CAN) on IAH reversibility inT1DM. Methods: Participants with T1DM and IAH (Gold score ≥4) recruited to the HypoCOMPaSS (24‐week 2 × 2 factorial randomised controlled) trial were included. All underwent screening for cardiac autonomic function testing at baseline and received comparable education and support aimed at avoiding hypoglycaemia and improving hypoglycaemia awareness. Definite CAN was defined as the presence of ≥2 abnormal cardiac reflex tests. Participants were grouped according to their CAN status, and changes in Gold score were compared. Results: Eighty‐three participants (52 women [62.7%]) were included with mean age (SD) of 48 (12) years and mean HbA1c of 66 (13) mmol/mol (8.2 [3.3] %). The mean duration of T1DM was 29 (13) years. The prevalence of CAN was low with 5/83 (6%) participants having definite autonomic neuropathy with 11 (13%) classified with possible/early neuropathy. All participants, regardless of the autonomic function status, showed a mean improvement in Gold score of ≥1 (mean improvement −1.2 [95% CI −0.8, −1.6]; p < 0.001). Conclusions: IAH can be improved in people with T1DM, and a long duration of disease, with and without cardiac autonomic dysfunction. These data suggest that CAN is not a prime driver for modulating IAH reversibility. [ABSTRACT FROM AUTHOR]

Background and Aims: Cardiovascular autonomic neuropathy (CAN) in patients with diabetes is associated with poor prognosis. We aimed to assess signs of CAN and autonomic symptoms and to investigate the impact of sensorimotor neuropathy on CAN by examining type 2 diabetes patients with (DPN [distal sensorimotor polyneuropathy]) and without distal sensorimotor polyneuropathy (noDPN) and healthy controls (HC). Secondarily, we aimed to describe the characteristics of patients with CAN. Methods: A population of 374 subjects from a previously described cohort of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) were included. Subjects were examined with the Vagus™ device for the diagnosis of CAN, where two or more abnormal cardiovascular autonomic reflex tests indicate definite CAN. Autonomic symptoms were assessed with Composite Autonomic Symptom Score 31 (COMPASS 31) questionnaire. DPN was defined according to the Toronto consensus panel definition. Results: Definite CAN was present in 22% with DPN, 7% without DPN and 3% of HC, and 91% of patients with definite CAN had DPN. Patients with DPN and definite CAN reported higher COMPASS 31 scores compared to patients with noDPN (20.0 vs. 8.3, p < 0.001) and no CAN (22.1 vs. 12.3, p = 0.01). CAN was associated with HbA1c and age in a multivariate logistic regression analysis but was not associated with IEFND or triglycerides. Interpretation: One in five patients with DPN have CAN and specific CAN characteristics may help identify patients at risk for developing this severe diabetic complication. Autonomic symptoms were strongly associated with having both DPN and CAN, but too unspecific for diagnosing CAN. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic autonomic neuropathy (DAN), a serious complication of diabetes, is a significant contributor to increased morbidity and mortality. Although DAN often coexists with different peripheral neuropathies and other complications, it may also present in isolation. The present study aimed to understand the DAN status of a cohort of ambulatory type 2 diabetics in a tertiary care setting. Methods: A single-arm prospective observational study was carried out, where enrolled patients were interviewed for basic demographics and comorbidities, screened for symptoms of autonomic dysregulation, and other risk factors such as smoking and alcoholism. Based on the presence of overt symptoms, they were divided into two groups with or without any overt symptoms of autonomic neuropathy. Both groups were subjected to a battery of autonomic neuropathy tests, and their DAN status was characterized based on the observed scores. Results: The overall prevalence of DAN, as observed in our study, was 36%. Of 108 patients, 97 presented with one or more symptoms of autonomic dysregulation, whereas the rest, 10.1%, were without any symptoms. Among heart rate-based tests, a significant (P < 0.001) decrease followed by an increase in the Valsalva ratio was observed in 6 months and 12 months, respectively. A significant decrease (P < 0.001) in deep breathing test (E: I) values was observed in the 12th month. Most of the DAN patients presented with moderate autonomic dysfunction, followed by mild and severe, respectively. However, no significant change in DAN severity was noted with time. Conclusion: Using simple cardiovascular tests, DAN can be detected during the asymptomatic phase of the disease. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is one of the most debilitating diseases, diabetic neuropathy happens to be the most common and perhaps the most serious complication of diabetes mellitus, often leading to morbidity and mortality. A 60 year old female presented with disorientation, history of vomiting, shortness of breath, respiratory failure initially. Blood reports revealed that she was positive for ketone bodies with elevated HbA1c and general random blood sugar. Chest radiogram revealed atelectasis of the right lung with prominent involvement of right middle and lower lobes. High-resolution computed tomography of chest confirmed the findings and unilateral diaphragmatic paralysis due to phrenic nerve neuropathy due to undetected type 2 diabetes was diagnosed. Although phrenic nerve paralysis is a rare occurrence with diabetes, the possibility shouldn't be overlooked as a presentation of diabetes mellitus. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The manifestations of diabetic autonomic neuropathy (DAN) are protean and clinically involve multiple systems, including the cardiovascular system, the gastrointestinal system, the genitourinary system as well as the sweat glands (sudomotor dysfunction) and the gallbladder. In addition, cardiac autonomic neuropathy (CAN) is associated with a correctible inability to appreciate and correct hypoglycaemia. While not a clinical problem, pupillary involvement should be the clue and the catalyst to investigate for other manifestations of DAN. This review outlines a practical approach to detecting and investigating the manifestations of DAN. Of particular importance is early detection of cardiovascular involvement where prompt therapy through glycaemic control can decrease the severity of CAN and decelerate the frequency and severity of retinopathy and nephropathy in addition to decreasing cardiovascular events and mortality. CAN also plays a role in accelerating other diabetic complications such as acute ischaemic stroke, heart failure, medial artery calcinosis, foot ulcers, peripheral artery disease and Charcot joints. Many therapies of DAN are available, which should not only decrease morbidity and mortality from DAN, but also improve the patient's quality of life. However, the therapies available are largely symptomatic. [ABSTRACT FROM AUTHOR]

Background: Patients who suffer from diabetic peripheral neuropathy in the lower leg experience a greater risk of falls due to a decrease in strength of the lower extremities. Methods: Fourteen participants, diagnosed with diabetic peripheral neuropathy or nocturnal allodynia in either one or both extremities, volunteered to participate in this study. Participants were purposively selected from two private Podiatry practices based on their signs and symptoms, age, gender, and doctor's clearance to participate in any form of physical activity. Dependent variables included isometric muscle strength of the hip, knee and ankle, range of motion of the ankle in plantarflexion and dorsiflexion and an assessment of balance, which were measured pre- and post-intervention. The researcher developed a scientifically based exercise intervention program to target the entire kinetic chain, and to develop a standard isometric protocol for patients with DPN. The intervention program consisted of a combination of ankle, hip, and knee specific rehabilitation. The intervention took place 3 times a week for 45 min per session. Results: The Mann-Whitney test was used to evaluate the differences in dependent variables from pre- to post-intervention. The level of significance was set at p<0.05. Notable increases were observed in range of motion in ankle plantarflexion and in balance time in the intervention group, post-intervention. Conclusions: Although many of the changes noted were insignificant, the trends indicated an improvement in the intervention group over the 10-week intervention period. These improvements can be considered clinically important. [ABSTRACT FROM AUTHOR]

Background and Objectives: Cardiac autonomic neuropathy (CAN) encompasses damage to the autonomic nerve fibres that innervate the heart and blood vessels, resulting in abnormalities in heart rate control and vascular dynamics. The reported prevalence of CAN varies depending on the clinical setting, type and number of tests performed, different diagnostic methods applied, and selection criteria for the patients. Studies using different end points have reported prevalence estimates ranging from 1% to 90%. Hence we studied CAN in T2DM patients and attempted to see the correlation between the two along with glycaemic control and QT ratio in CAN. Materials and Methods: The study was conducted on 100 type2 diabetes subjects meeting inclusion and exclusion criteria. Subjects were tested for five cardiac autonomic neuropathy tests, HbA1c levels and ECG with reference to QT ratio. Results: In our study 60% were asymptomatic and 40% were symptomatic for diabetic autonomic neuropathy(DAN) symptoms. 32% of asymptomatic DAN patients had early CAN. Patients who had absent, early and definite CAN were 28%, 44% and 28% respectively. Majority of patients in absent CAN group (15%) were having DM less than 5yr duration. In definite CAN group (20%) were having above 10yr duration. Stages of CAN is directly associated with duration of diabetes which is statistically significant (P value: <0.001). Among 28 patients who had definite CAN, corrected QTc was prolonged in 22 patients. Conclusion: 32% of asymptomatic DAN patients had early CAN. Poorly controlled diabetic state group had CAN in 82% of the subjects concluding that stages of CAN is directly related to the duration of diabetes. QTc dispersion was significantly high in diabetics with autonomic neuropathy. [ABSTRACT FROM AUTHOR]

Neuropathy is a common complication of diabetes that can appear in the early stages of diabetes or even in the prediabetes stage. The relationship between autonomic neuropathy and cardiovascular disease (CVD) is well established. Resting tachycardia, exercise intolerance, and non-dipping/reverse dipping caused by the relative overactivity of the sympathetic nervous system are the main factors that lead to the increased risk of CVD and cardiovascular mortality. Little is known, however, about the cardiovascular consequences of peripheral neuropathy (PN). Two recent major studies suggested the possibility of a significant association between PN and CVD and mortality; thus, cardiovascular risk management for patients with PN may be necessary. Positive results on MNSI (Michigan Neuropathy Screening Instrument) questionnaires and 10-g monofilament test are convenient methods for early screening and management of PN that may also be useful in evaluating PN-related CVD risk. [ABSTRACT FROM AUTHOR]

Aims: Diabetic autonomic neuropathy is a severe complication of diabetes, estimated to affect up to 44% in type 1 diabetes (T1D) and 73% in type 2 diabetes (T2D) based on clinical studies. Currently, the assessment of diabetic autonomic neuropathy is not implemented in Denmark’s clinical guidelines, complicating the estimation of the true prevalence. Thus, this study investigated the prevalence of self-reported symptoms of autonomic dysfunction in people living with diabetes in the North Denmark Region using the Composite Autonomic Symptoms Score (COMPASS)-31 questionnaire.In 2022, all adults with T1D or T2D in the North Denmark Region (n = 29,155) were identified using The National Health Insurance Service Registry and invited to an online survey including the Danish version of COMPASS-31. The prevalence and associated 95% confidence intervals (CI) for symptomatic autonomic dysfunction were determined using a cut-off value of 16.In total, 7,377 completed COMPASS-31, of which 82.4% reported having T2D and 13.7% T1D. The prevalence of symptomatic autonomic dysfunction was 36.8% (95% CI: 34–40) after a median of 26 years with diabetes for T1D and 44.2% (95% CI: 43–45) after a median of 10 years for T2D. Pupillary and orthostatic intolerance were the most frequent moderate to severe symptoms, respectively (38.4% and 24.0% in T1D and 32.8% and 26.3% in T2D).Symptoms of autonomic dysfunction are very common in individuals with diabetes living in the North Denmark Region, emphasizing the unmet need for regular testing to increase awareness and allow for adequate management, ultimately reducing the morbidity of diabetes.Methods: Diabetic autonomic neuropathy is a severe complication of diabetes, estimated to affect up to 44% in type 1 diabetes (T1D) and 73% in type 2 diabetes (T2D) based on clinical studies. Currently, the assessment of diabetic autonomic neuropathy is not implemented in Denmark’s clinical guidelines, complicating the estimation of the true prevalence. Thus, this study investigated the prevalence of self-reported symptoms of autonomic dysfunction in people living with diabetes in the North Denmark Region using the Composite Autonomic Symptoms Score (COMPASS)-31 questionnaire.In 2022, all adults with T1D or T2D in the North Denmark Region (n = 29,155) were identified using The National Health Insurance Service Registry and invited to an online survey including the Danish version of COMPASS-31. The prevalence and associated 95% confidence intervals (CI) for symptomatic autonomic dysfunction were determined using a cut-off value of 16.In total, 7,377 completed COMPASS-31, of which 82.4% reported having T2D and 13.7% T1D. The prevalence of symptomatic autonomic dysfunction was 36.8% (95% CI: 34–40) after a median of 26 years with diabetes for T1D and 44.2% (95% CI: 43–45) after a median of 10 years for T2D. Pupillary and orthostatic intolerance were the most frequent moderate to severe symptoms, respectively (38.4% and 24.0% in T1D and 32.8% and 26.3% in T2D).Symptoms of autonomic dysfunction are very common in individuals with diabetes living in the North Denmark Region, emphasizing the unmet need for regular testing to increase awareness and allow for adequate management, ultimately reducing the morbidity of diabetes.Results: Diabetic autonomic neuropathy is a severe complication of diabetes, estimated to affect up to 44% in type 1 diabetes (T1D) and 73% in type 2 diabetes (T2D) based on clinical studies. Currently, the assessment of diabetic autonomic neuropathy is not implemented in Denmark’s clinical guidelines, complicating the estimation of the true prevalence. Thus, this study investigated the prevalence of self-reported symptoms of autonomic dysfunction in people living with diabetes in the North Denmark Region using the Composite Autonomic Symptoms Score (COMPASS)-31 questionnaire.In 2022, all adults with T1D or T2D in the North Denmark Region (n = 29,155) were identified using The National Health Insurance Service Registry and invited to an online survey including the Danish version of COMPASS-31. The prevalence and associated 95% confidence intervals (CI) for symptomatic autonomic dysfunction were determined using a cut-off value of 16.In total, 7,377 completed COMPASS-31, of which 82.4% reported having T2D and 13.7% T1D. The prevalence of symptomatic autonomic dysfunction was 36.8% (95% CI: 34–40) after a median of 26 years with diabetes for T1D and 44.2% (95% CI: 43–45) after a median of 10 years for T2D. Pupillary and orthostatic intolerance were the most frequent moderate to severe symptoms, respectively (38.4% and 24.0% in T1D and 32.8% and 26.3% in T2D).Symptoms of autonomic dysfunction are very common in individuals with diabetes living in the North Denmark Region, emphasizing the unmet need for regular testing to increase awareness and allow for adequate management, ultimately reducing the morbidity of diabetes.Conclusion: Diabetic autonomic neuropathy is a severe complication of diabetes, estimated to affect up to 44% in type 1 diabetes (T1D) and 73% in type 2 diabetes (T2D) based on clinical studies. Currently, the assessment of diabetic autonomic neuropathy is not implemented in Denmark’s clinical guidelines, complicating the estimation of the true prevalence. Thus, this study investigated the prevalence of self-reported symptoms of autonomic dysfunction in people living with diabetes in the North Denmark Region using the Composite Autonomic Symptoms Score (COMPASS)-31 questionnaire.In 2022, all adults with T1D or T2D in the North Denmark Region (n = 29,155) were identified using The National Health Insurance Service Registry and invited to an online survey including the Danish version of COMPASS-31. The prevalence and associated 95% confidence intervals (CI) for symptomatic autonomic dysfunction were determined using a cut-off value of 16.In total, 7,377 completed COMPASS-31, of which 82.4% reported having T2D and 13.7% T1D. The prevalence of symptomatic autonomic dysfunction was 36.8% (95% CI: 34–40) after a median of 26 years with diabetes for T1D and 44.2% (95% CI: 43–45) after a median of 10 years for T2D. Pupillary and orthostatic intolerance were the most frequent moderate to severe symptoms, respectively (38.4% and 24.0% in T1D and 32.8% and 26.3% in T2D).Symptoms of autonomic dysfunction are very common in individuals with diabetes living in the North Denmark Region, emphasizing the unmet need for regular testing to increase awareness and allow for adequate management, ultimately reducing the morbidity of diabetes. [ABSTRACT FROM AUTHOR]

Background: In general, hypoglycemia is more frequent among the young explaining the higher frequency of impaired awareness of hypoglycemia (IAH) among children and adolescents. Thus the aim of the current study was to assess the frequency of IAH among an Egyptian cohort of children and adolescents with type 1 diabetes and identify the possible association between impaired awareness of hypoglycemia and autonomic neuropathy. Patients and Methods: A cross sectional study recruiting 100 patients with type 1 diabetes for at least 6 months duration and aged less than 18 years old recruited from the Pediatric and Adolescent Diabetes Unit (PADU). Patients with other form of diabetes, cardiac disease, thyroid disease, anemia, other chronic disease, patients with intellectual disabilities or patients taking any medications were excluded from the study. The Gold and Clarke questionnaires were used to assess hypoglycemia awareness among the studied cohort. Cardiac autonomic neuropathy (CAN) was assessed using 15 minutes Holterelectrocardiography (ECG). Results: Among the studied cohort, 42% showed IAH using the Clarke's and Gold's Questionnaires. When assessing CAN, 46% of the studied cohort showed resting tachycardia and patients with resting tachycardia showed significantly longer disease duration. There were no normative heart rate variability parameters values for the Egyptian children that can be used as a reference for diagnosis of cardiac autonomic neuropathy. So we used sex and age matched control group to find specific cutoff values for heart rate variability parameters to diagnose CAN. The results showed that the prevalence of CAN among studied- patients was 88% and there were no significant correlation between CAN and both questionnaires score. 55.7% of CAN patients were aware while 44.3% were unaware. Thus, there were no association between impaired awareness of hypoglycemia and CAN. The results showed that there was significant positive correlation between cardiac autonomic neuropathy (CAN) and diabetic duration more than 5 years. Conclusion: Although there were no association between impaired awareness of hypoglycemia and cardiac autonomic neuropathy, it is important to screen for CAN in patients with IAH, especially that CAN is usually asymptomatic among children with type 1 diabetes. [ABSTRACT FROM AUTHOR]

• Sensitive, validated, noninvasive electrodiagnostic tests of autonomic function have been developed. • An international expert panel provides evidence-based recommendations to guide autonomic testing. • Recommendations allow for standardized assessment of severity and distribution of autonomic failure. 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. [ABSTRACT FROM AUTHOR]

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

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 < 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. [ABSTRACT FROM AUTHOR]

Cardiovascular autonomic neuropathy (CAN) is a major cause of morbidity and mortality in patients with diabetes as it is associated with a high risk of cardiac arrhythmias. Objectives: This prospective observational cross-sectional study was done to estimate the prevalence of CAN in patients with type 2 diabetes and to study its association with serum omentin and leptin levels. Methods: This study included 100 patients with type 2 diabetes mellitus attending the outpatient department of JIPMER Hospital, Pondicherry, India, from January 2017 to December 2018. CAN was assessed in all subjects using four cardiovascular autonomic function tests. Blood samples were collected and stored at - 80°C to estimate leptin and omentin levels. Comparison of leptin and omentin levels was done between diabetic patients with and without CAN. Results: CAN was present in 64% of the study subjects. Serum leptin levels were significantly higher in patients with CAN, whereas omentin levels, though elevated in those with CAN, were not statistically significant in diabetic patients without CAN. Conclusion: There is a high prevalence of CAN in patients with type 2 diabetes mellitus. Leptin levels were elevated in these patients, whereas omentin levels were not significantly different between diabetic patients with and without CAN. [ABSTRACT FROM AUTHOR]

This study aims to evaluate the feasibility of substituting electrochemical skin conductance measurement using SUDOSCAN for sudomotor function testing in the Composite Autonomic Scoring Scale (CASS) and to correlate the results with the Composite Autonomic Symptom Scale 31 (COMPASS 31) among patients with type 2 diabetes mellitus (T2DM). Fifty patients with T2DM underwent cardiovascular autonomic function testing and the SUDOSCAN test and completed the COMPASS 31 questionnaire. We developed a SUDOSCAN-based sudomotor subscore as a substitute for the original sudomotor subscore (based on the quantitative sudomotor axon reflex test [QSART]). The modified CASS score (SUDOSCAN-based sudomotor subscore combined with the adrenergic and cardiovagal subscores) and the original CASS score without suomotor assessment (sum of the adrenergic and cardiovagal subscores) were obtained according to the results of the cardiovascular autonomic function and SUDOSCAN tests. The total COMPASS 31 score was significantly correlated with the modified CASS score (p = 0.019 and 0.037 for the raw and weighted scores, respectively) but not with the CASS score without sudomotor assessment. After adding the SUDOSCAN-based sudomotor subscore, the number of patients identified as having diabetic autonomic neuropathy (DAN) increased from 24 (48 %, based on the CASS score without sudomotor assessment) to 35 (70 %, based on the modified CASS score). The modified CASS score enhances the accuracy of assessing autonomic function and improves the diagnosis of diabetic autonomic neuropathy (DAN) among patients with T2DM. In medical settings where QSART is not accessible, SUDOSCAN testing offers a practical and efficient alternative. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract 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. [ABSTRACT FROM AUTHOR]

Disorders of the autonomic nervous system are more com-mon in neurology practice than previously recognized in dia-gnostic conclusions. Besides the primary involvement of the autonomic nervous system, there are sympathetic or parasympathetic (especial-ly vagal) dysfunctions as-sociated with other dis-eases of the central or peripheral nervous system. The aim of this paper is to provide a short overview of the clinical symp-tomatology of autonomic dysfunctions, the examination methods of the autonomic nervous system, especial-ly those available and applicable in clinical neurology practice, and furthemore, the clinical pictures of generalized and localized autonomic dysfunctions. The most important autonomic examinations focus on the cardiovascular system, as-ses-s--ing both heart rate and blood pres-sure changes in appropriately selected autonomic tests. The cardiovascular autonomic reflex tests and the heart rate variability as-ses-sment are the most com-monly used dia-gnostic tools. The examination methods of the autonomic regulations 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 dis-eases and clinical symp-tomatology, among generalized (systematic) disorders of the autonomic nervous system, diabetic autonomic polyneuropathy and autonomic polyneuropathies of other causes which are discus-sed in greater detail. This is fol-lowed by an overview of autonomic disturbances and dysfunctions of central origin that may constitute either major or minor symp-toms of neurological dis-eases. The paper further describes clinical features of localized autonomic disturbances. A simple dia-gnostic scheme for basic evaluation of the autonomic functions in clinical neurology practice is proposed at the end of this paper. [ABSTRACT FROM AUTHOR]

Although diabetic autonomic neuropathy (DAN), a complication associated with diabetes, is increasing in prevalence, it is often overlooked. Knowledge regarding the development and progression of this complication is limited. NPs are in a key position to prevent complications of DAN, including sexual dysfunction, in this vulnerable population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: To assess gastrointestinal and cardiovascular diabetic autonomic neuropathy in patients with type 2 diabetes mellitus (DM). Materials and Methods: The study group composed of DM patients examined between March and September 2012. Age, body mass index (BMI), fasting blood glucose, HbA1c, C-peptide, duration of diabetes, electrocardiogram, blood pressure, heart rate were recorded. Patients were grouped as controlled and uncontrolled diabetics. Cardiac autonomic neuropathy (CAN) tests were done. Rectoanal inhibitory reflex, resting and squeeze pressures were measured by anal manometry. Results: A total of 50 DM patients were enrolled and the mean age of patients was 57.06±8.92 years, the mean resting anal pressure was 55.92±14.84 mmHg, and squeezing anal pressure was 83.15±31.00 mmHg. There was no significantly different resting anal pressure between mild and severe CAN groups (p=0.573), but maximum squeezing pressure was significantly different between mild and severe CAN groups (p=0.005). Anal manometric pressures were not different in patients with short or long duration of diabetes. BMI was not associated with CAN, whereas age was. Bad glycemic control was associtated with a decrease in resting pressures, but no significant difference between maximum squeeze pressures and insufficient glycemic control groups. Severity of CAN was associated with a decrease in maximum squeeze pressures. Conclusion: Cardiac and gastrointestinal autonomic dysfunction are important complications of DM. Anal manometric tests and CAN may show these complications of diabetes. [ABSTRACT FROM AUTHOR]

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. Participants with longstanding type 2 diabetes, newly onset, untreated diabetes <1 year, and matched controls, were included. Tests included cardiovascular reflex tests, orthostatic blood pressure, electrical skin conductance assessment, sural nerve testing and monofilament test. The rectal balloon distention pressure at earliest sensation and threshold of unpleasantness were identified and used to elicit mechanical EPs. 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. 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. • Gastrointestinal symptoms in diabetes may be due to autonomic dysfunction of the gut. • There is a lack of methods investigating gut autonomic nerve function. • We investigated evoked potentials following rapid balloon distention in the rectum. • People with both longstanding and early diabetes showed rectal hyposensitivity. • The test may be a promising research tool to evaluate gut autonomic nerve function. [ABSTRACT FROM AUTHOR]

Aims Heart rate corrected QT (QTc) interval prolongation is a risk factor associated with increased mortality. Hyperbaric oxygen therapy (HBO) has previously been shown to have acute beneficial effects on QTc dispersion. The aim of this study was to evaluate long-term effects of HBO on QTc time in diabetic patients with hard-to-heal foot ulcers. Methods In a prospective, double-blinded placebo-controlled study, patients were randomized to 40 treatment sessions with either HBO or air (placebo), at 2.5 ATA. Patients fulfilling > 35 completed treatment sessions were included in the evaluation. Results Of the initial 75 patients (38 HBO/37 placebo), two were excluded due to pacemaker use. Baseline characteristics were similar between groups. At the 2-year follow-up, QTc time was significantly shorter in the HBO compared to the placebo group (438 vs. 453 ms, p < 0.05). Further, fewer HBO treated patients had a QTc time > 450 ms (22 vs. 53 %, p < 0.02). This difference seemed to be caused by a significant prolongation of the QTc interval in the placebo group (427 (419–459) at baseline vs. 456 ms (424–469) after 2 years), whereas no significant change was seen in HBO treated patients. Conclusions HBO treatment might protect against QTc prolongation in this high-risk diabetic population. [ABSTRACT FROM AUTHOR]

Objective: To study the degree of pupillary impairment in diabetic and non-diabetic autonomic neuropathy. Methods: We retrospectively sampled from all patients who underwent comprehensive autonomic testing and infrared pupillometry at UT Southwestern Medical Center. Composite autonomic severity score (CASS) and pupillary indices from the average of at least three pupillary response curves were recorded. We randomly matched patients with diabetic autonomic neuropathy (DAN) and patients with autonomic impairment unrelated to diabetes (non-DAN) based on gender, age (±5 years), and CASS (±1 point). We used the paired t test to analyze differences between the groups. Results: We identified 40 patients with DAN and 40 matched controls with non-DAN. M:F ratio was 1:1. Mean CASS was 4.2 and mean age was 62.4 years. Six had type I and the rest had type II diabetes mellitus. Both absolute constriction amplitude (ACA) and maximum constriction velocity (MCV) were significantly lower in DAN compared to non-DAN; mean ACA was 0.9 mm vs. 1.17 mm ( p = 0.0077) and mean MCV was 2.8 vs. 3.6 mm/s ( p = 0.0039). Severely diminished MCV for age was noted in 48 % of diabetic and in only 28 % of non-DAN patients. The ACA-corrected time to 75 % re-dilation was significantly delayed in DAN vs. non-DAN [mean 3.2 vs. 1.7 s/mm ( p = 0.025)]. A statistically significant decline was noted for both the MCV and ACA with higher cardiovagal subscores among DAN patients. Conclusions: Parasympathetic and sympathetic pupillary dysfunction appears to be a common feature of autonomic impairment in diabetes compared to non-diabetic causes of autonomic impairment. [ABSTRACT FROM AUTHOR]

Introduction: Cardiac autonomic neuropathy (CAN) causes substantial morbidity and increased mortality in patients with diabetes mellitus (DM). Besides heart rate variability (HRV), heart rate turbulence (HRT) is an important method of assessment of cardiac autonomic regulation. The aim of the study was to assess the correlation between HRT and diabetic control. Material and methods: Fifty-nine patients met the inclusion criteria - 38 males and 21 females, age 64.4 ±7.6. The patients included had inadequately controlled DM type 2 defined as glycated haemoglobin (HbA1c) > 9% (mean 11.8 ±2.7%). In all patients, intensive insulin treatment had been applied for 6 months. After 6 months, HbA1c was measured. ECG Holter monitoring was performed before and after insulin treatment to evaluate the time domain HRV and HRT parameters (turbulence onset (TO) and turbulence slope (TS)). Results: After 6 months of intensive insulin treatment, HbA1c concentrations ranged from 6.3% (45 mmol/mol) to 11.2% (99 mmol/mol) - mean 8.5 ±3.8% (69 ±18 mmol/mol). Significant improvement of TO, TS and SDNN was observed. The TO and TS significantly correlated with HbA1c (r = 0.35, p = 0.006 and r = -0.31, p = 0.02 respectively). Among analyzed HRV time domain parameters such as SDNN, rMSSD and pNN50, only SDNN correlated with HbA1c (r = -0.41, p = 0.001). It was further concluded that intensive insulin therapy led to better glycemic control, resulting in improvement of HRT. Conclusions: Heart rate turbulence may be useful in monitoring changes of the autonomic nervous system functions in patients with DM, similarly to HRV parameters. [ABSTRACT FROM AUTHOR]

To determine the prevalence and the associated clinical characteristics of orthostatic hypotension and orthostatic hypertension in patients with diabetic sensorimotor polyneuropathy (DSP).Methods: A single-center retrospective cross-sectional study was conducted on 200 DSP patients who had 3-minute orthostatic measures as part of the standard clinic evaluation. We measured the heart rate (HR) and blood pressure (BP) supine and again after 3 min of standing.Results: The prevalence of orthostatic hypotension was 19.5% and that of orthostatic hypertension was 23%. Subjects with orthostatic hypotension had significantly longer diabetes duration than subjects who were normotensive and those with orthostatic hypertension. Quantitatively, BP changes from supine to standing correlated with diabetes duration (R = 0.306; P = 0.0582) and age (R = 0.434; P = 0.006) in subjects with orthostatic hypotension.Conclusions: Orthostatic hypertension and orthostatic hypotension are frequent in patients with DSP. Orthostatic hypertension is associated with shorter diabetes duration than orthostatic hypotension. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

QT Variability and Sympathetic Dysinnervation. Introduction: The mechanism of adverse prognosis attributable to proarrhythmic cardiac sympathetic dysinnervation in patients with type 2 diabetes is incompletely understood. This study sought the association of cardiac sympathetic dysinnervation with temporal instability of ventricular repolarization assessed by beat-to-beat QT interval variability. Methods and Results: 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy was analyzed in 31 type 2 diabetic patients for cardiac sympathetic dysinnervation (4-hour heart-to-mediastinum ratio <1.8) and regional sympathetic integrity and washout rate (from 15-minute 123I-MIBG uptake). Relative QT variability was defined from a continuous 5-minute ECG in the supine position (n = 31) and standing position (subgroup; n = 15) by the log ratio of absolute QT variability (QT variance divided by the mean QT interval squared) to heart rate (HR) variability (HR variance divided by the mean HR squared). Patients with (n = 16; 52%) versus without cardiac sympathetic dysinnervation demonstrated higher relative QT variability in the supine position (P < 0.001), owing to lower HR variability. However, on standing, absolute QT variability was significantly raised in these patients (P = 0.009) despite similar HR variability in the 2 groups. Correlations of heart-to-mediastinum ratio with standing QT variability (relative [r =−0.63, P = 0.013] and absolute [r =−0.79, P = 0.001]) were superior to corresponding supine measures (relative [r =−0.47, P = 0.008] and absolute [P = NS]). No associations of QT variability with washout rate or regional 123I-MIBG uptake were identified. Conclusion: Elevated QT variability is associated with cardiac sympathetic dysinnervation in type 2 diabetes and may contribute to adverse prognosis. Moreover, QT variability may be more specific for cardiac sympathetic innervation when measured in the context of sympathetic activation. (J Cardiovasc Electrophysiol, Vol. 24, pp. 305-313, March 2013) [ABSTRACT FROM AUTHOR]

Diabet. Med. 29, e312-e320 (2012) Abstract Aims Poor prognosis associated with blunted post-exercise heart-rate recovery may reflect autonomic dysfunction. This study sought the accuracy of post-exercise heart-rate recovery in the diagnosis of cardiac autonomic neuropathy, which represents a serious, but often unrecognized complication of Type 2 diabetes. Methods Clinical assessment of cardiac autonomic neuropathy and maximal treadmill exercise testing for heart-rate recovery were performed in 135 patients with Type 2 diabetes and negative exercise echocardiograms. Cardiac autonomic neuropathy was defined by abnormalities in ≥ 2 of 7 autonomic function markers, including four cardiac reflex tests and three indices of short-term (5-min) heart-rate variability. Heart-rate recovery was defined at 1-, 2- and 3-min post-exercise. Results Patients with cardiac autonomic neuropathy ( n = 27; 20%) had lower heart-rate recovery at 1-, 2- and 3-min post-exercise ( P < 0.01). Heart-rate recovery demonstrated univariate associations with autonomic function markers ( r-values 0.20-0.46, P < 0.05). Area under the receiver-operating characteristic curve revealed good diagnostic performance of all heart-rate recovery parameters (range 0.80-0.83, P < 0.001). Optimal cut-offs for heart-rate recovery at 1-, 2- and 3-min post-exercise were ≤ 28 beats/min (sensitivity 93%, specificity 69%), ≤ 50 beats/min (sensitivity 96%, specificity 63%) and ≤ 52 beats/min (sensitivity 70%, specificity 84%), respectively. These criteria predicted cardiac autonomic neuropathy independently of relevant clinical and exercise test information (adjusted odds ratios 7-28, P < 0.05). Conclusions Post-exercise heart-rate recovery provides an accurate diagnostic test for cardiac autonomic neuropathy in Type 2 diabetes. The high sensitivity and modest specificity suggests heart-rate recovery may be useful to screen for patients requiring clinical autonomic evaluation. [ABSTRACT FROM AUTHOR]

Heart rate is a non-stationary signal and provides a powerful interplay between the sympathetic and parasympathetic nervous systems. The heart rate variation signal can reveal disorders associated with how these nervous systems regulate the heart rate, and hence may contain indicators of this disease state, or warnings about impending or future cardiac diseases. These indicators may be present at all times or may occur at random during certain intervals in the time scale. It is difficult and time consuming to pinpoint these abnormalities in a huge cardiac data set. Heart rate variability (HRV) constitutes a tool for assessing the activities of the autonomic nervous system (ANS). In this work, we have proposed a computer based analytical system to determine the HRV, and analyzed it to obtain HRV Power-spectrum for normal, diabetes and diabetes with neuropathy subjects in deep breathing, standing and supine position. We have then designated indices based on the HRV power-spectra power values and frequency shift of these peaks from their normal frequency values. We have shown the efficacy and sensitivity of these indices, to differentiate between normals, diabetics and diabetics with ischemic heart disease. Thus we have demonstrated how effectively these HRV power-spectral indices can enable diagnosis of diabetic autonomic neuropathy. Finally, we have composed an integrated index made up of these power-spectral indices, to facilitate distinguishing and diagnosing diabetic autonomic neuropathy in terms of just one index or number. [ABSTRACT FROM AUTHOR]

Cardiac autonomic neuropathy is a serious complication among diabetic patients. It occurs in both type 1 and type 2 diabetes, and its progression results in poor prognosis and increased mortality. During its course, parasympathetic and sympathetic nerve fibers of the cardiovascular system are damaged, resulting in potentially serious cardiac complications and even death. Poor glycemic control is believed to play a pivotal role in the pathogenesis of cardiac autonomic neuropathy. Its underlying etiology is not well understood; however, several potential pathologic mechanisms have been identified. Several clinical manifestations of cardiac autonomic neuropathy have been reported, including resting tachycardia, exercise intolerance, loss of heart rate variability, orthostatic hypotension, prolonged QT interval, silent ischemia, and sudden death. Diabetic patients exhibiting these signs and symptoms are at greater risk of anesthesia-related complications. A series of noninvasive autonomic tests were developed for the diagnosis of cardiac autonomic neuropathy, improving the management of diabetic patients requiring general anesthesia. These patients often experience cardiovascular events that may increase perioperative morbidity and mortality. The presence of cardiac autonomic neuropathy alters the hemodynamic response to induction and tracheal intubation during general anesthesia, resulting in intraoperative hypotension. A thorough preoperative assessment and vigilant monitoring perioperatively ensure successful anesthesia management. [ABSTRACT FROM AUTHOR]

Background Heart rate variability (HRV) and heart rate turbulence (HRT) illustrate regulation of the heart by autonomic nervous system (ANS). The autonomic nervous system plays an important role not only in physiological situations, but also in various pathological settings such as diabetic neuropathy Diabetic autonomic neuropathy is a serious and common complication of diabetes. Objective To determine the association between HRT, HRV and diabetes control monitored by concentrations of HbA1c. Methods In 52 patients with diabetes mellitus type II of either sex attending Cardiac Care Unit (CCU) in Al-Kadhimya Hospital, 24-hour Holter ECG monitoring was performed to evaluate time domain HRV parameters (SDNN, SDNNI, SDANN, rMSSD, pNN50) and HRT parameters (TO and TS). HBA1c was measured in all patients. Regression analysis was performed to evaluate the association between tested parameters. Results Significant correlation has been observed between TO and SDNN, SDNNI and SDANN. TS correlated significantly with SDNN, SDNNI, SDANN, rMSSD, pNN50. We noted no correlation between HbA1c and HRV or HRT parameters. Conclusion We concluded that HRV time domain parameters correlate with HRT in patients with diabetes mellitus. Diabetes control estimated on basis of HbA1c value did not show correlation with HRV and HRT. [ABSTRACT FROM AUTHOR]

Objective: To study whether HR variability might be impaired before the clinician becomes aware for the presence of PNP and to defi ne the correlation between CAN and PNP in type 2 diabetes. Patients and method: 212 type 2 diabetic patients were examined by 5 autonomic refl ex tests: 1.deep breathing test 2.Valsalva test; 3.heart rate response during stand test; 4.orthostatic blood pressure response; 5. dyastolic blood pressure response during isometric exercise. PNP was diagnosed Michigan screening test. Results: More than half the patients without evidence of PNP were diagnosed as subclinical CAN and almost 3/4 of patients with evidence of PNP had autonomic impairment. We found a good correlation between CAN and PNP (p=0.0017). Conclusion: 1. CAN may develop fi rst and independent from PNP in type 2 diabetes. 2. Evidence of one type of neuropathy increases the risk for the other type of neuropathy. 3. Periodical survey of neurological involvement should include autonomic function testing besides the well known practice of screening for somatic neuropathy in diabetes. [ABSTRACT FROM AUTHOR]

Objective: To diagnose cardiovascular autonomic neuropathy in the general population of type 2 diabetes in our geographical area and determine its prevalence, severity and correlation with time, metabolic and vascular factors. Patients and method: 212 type 2 diabetic patients (49% men), ages 20-80 years (mean age: 52+-5.10 years) were examined by 5 autonomic reflex tests: 1. deep breathing test 2. Valsalva test; 3. heart rate response during stand test; 4. orthostatic blood pressure response; 5. dyastolic blood pressure response during isometric exercise. Cardiovascular autonomic neuropathy (CAN) was defined by at least 2 abnormal results. Total vegetative score was also calculated, associating to each test a conventional value of 0/0.5/1 and severity stages were defined. Results: The overall prevalence of CAN was high (62,26%). CAN was clinically evident in 3% of patients only. Early and mild forms were predominant. CAN correlated well with: age, disease duration, HbA1C, body mass index (BMI), systolic blood pressure and did not correlate with gender. Conclusion: Autonomic impairment is an early finding in type 2 diabetes which may go unnoticed long before clinical history is positive. Active diagnosing CAN by autonomic function tests in its subclinical phase would enable a closer metabolic control and prevent further deterioration. [ABSTRACT FROM AUTHOR]

Carotid sinus hypersensitivity is a common cause of fainting and falls in older adults and can be diagnosed by carotid sinus massage. We have presented a 67-year-old diabetic male patient who was admitted to our clinic because of hyperglycemia. In thyroid examination, clouding of consciousness occurred with unilateral palpation. Documented 4,8 seconds and undocumented 7 seconds of asystole were detected during the carotid sinus massage. An implantable cardioverter defibrillator was implanted in our patient. Carotid sinus hypersensitivity should be kept in mind in the examination of diabetic patients. [ABSTRACT FROM AUTHOR]

OBJECTIVES To provide sensitive physiological endpoints for the onset and long-term progression of deficits induced by diabetes mellitus (DM) in bladder and erectile function in male rats, and to evaluate parallel changes in urogenital and nerve function induced by hyperglycaemia over a protracted period as a model for chronic deficits in patients with diabetes. MATERIALS AND METHODS The study comprised in 877 male, 3-month-old, Fischer 344 rats; 666 were injected intraperitoneally with 35 mg/kg streptozotocin (STZ) and divided into insulin-treated and untreated diabetic groups. The rats were studied over 8 months and measurements made of both erectile and bladder function, as well as nerve conduction studies over the duration of the study. RESULTS There was an early (first month) abnormality of both erectile and bladder function that persisted through the 8 months of the study. The erectile dysfunction was manifest as reduced intracavernous pressure/blood pressure ratio, and the bladder dysfunction as a persistent increase in detrusor overactivity with no detrusor decompensation. Insulin treatment prevented or modified the abnormality in each organ. Hyperglycaemia caused a progressive decrease in caudal nerve conduction velocity. The mean digital sensory and tibial motor nerve conduction velocity did not deteriorate over time. Correlation measurements of nerve and organ function were not consistent. CONCLUSIONS The results of this extensive long-term study show early and profound effects of hyperglycaemia on the smooth muscle of the penis and bladder, that were persistent and stable in surviving rats over the 8 months. The physiological changes did not correlate well with neurological measurements of those organs. Significantly, diverse smooth-muscle cellular and subcellular events antedated the measured neurological manifestations of the hyperglycaemia by several months. Although autonomic diabetic neuropathy is a primary life-threatening complication of long-term diabetes in humans, this rat model of STZ-induced diabetes showed that the rapid onset of physiological manifestations was based on many molecular changes in the smooth muscle cells in this model of type 1 DM. [ABSTRACT FROM AUTHOR]

Abstract: Cerebrovascular disease (CeVD) represents a major cause of morbidity and mortality worldwide. Diabetes mellitus (DM) represents an independent risk factor for CeVD. The aim of the present review is to describe the epidemiology of CeVD in patients with DM and to explain how DM and diabetic autonomic neuropathy can increase the risk of CeVD. The prevention and management of CeVD in the diabetic population are also analyzed. [Copyright &y& Elsevier]

• NPY and CGRP were upregulated in choroids in patients with diabetes. • The key enzymes (TH, VMAT2) of epinephrine were decreased in the sympathetic nervous system in choroids in patients with diabetes. • nNOS and VAchT were increased in choroids in patients with diabetes. • For now, no studies are published with alteration of NPY and CGRP in choroid in patients with diabetes. We sought to evaluate alterations in markers of the autonomic nervous system in human diabetic choroid. Eighteen eyeballs from subjects with diabetes and 22 eyeballs from subjects without diabetes were evaluated in this study. Synaptophysin, tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DβH), neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), vesicular monoamine transporter II (VMAT-2), vesicular acetylcholine transporter (VAChT), vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), and calcitonin gene-related peptide (CGRP) levels were detected by western blot analysis and immunofluorescence was performed in some cases. Furthermore, differences in adrenergic (α1- and β2-subtypes) and cholinergic (M1 and M3) receptor levels between diabetic subjects and controls were noted. Decreased synaptophysin levels were found in diabetic choroids by western blot analysis and a reduction of synaptophysin-immunoreactive nerves was also found by immunofluorescence. Furthermore, a decrease of the levels of the key enzyme (TH) and transporter (VMAT2) of norepinephrine was evident both by western blot analysis and immunofluorescence. Additionally, increased NPY, VAChT, nNOS, and CGRP levels were observed in diabetic choroids. The levels of adrenergic (β2 subtype) and acetylcholine (M1 subtype) receptors decreased in diabetic choroids, as shown by western blotting and although the differences in α1 and M3 were not significant, there was a downward trend. In the diabetic choroid, the levels of neurotransmitters, enzymes, and receptors associated with choroidal blood flow regulation are altered. These changes may affect the regulation of choroidal blood flow and may be associated with impaired retinal function and retinal pathology. [ABSTRACT FROM AUTHOR]

Abstract: The present study explored parallel changes in the physiology and structure of myelinated (Aδ) and unmyelinated (C) small diameter axons in the cavernous nerve of rats associated with streptozotocin-induced hyperglycemia. Damage to these axons is thought to play a key role in diabetic autonomic neuropathy and erectile dysfunction, but their pathophysiology has been poorly studied. Velocities in slow conducting fibers were measured by applying multiple unit procedures; histopathology was evaluated with both light and electron microscopy. To our knowledge, these are the initial studies of slow nerve conduction velocities in the distal segments of the cavernous nerve. We report that hyperglycemia is associated with a substantial reduction in the amplitude of the slow conducting response, as well as a slowing of velocities within this very slow range (< 2.5m/s). Even with prolonged hyperglycemia (> 4months), histopathological abnormalities were mild and limited to the distal segments of the cavernous nerve. Structural findings included dystrophic changes in nerve terminals, abnormal accumulations of glycogen granules in unmyelinated and preterminal axons, and necrosis of scattered smooth muscle fibers. The onset of slowing of velocity in the distal cavernous nerve occurred subsequent to slowing in somatic nerves in the same rats. The functional changes in the cavernous nerve anticipated and exceeded the axonal degeneration detected by morphology. The physiologic techniques outlined in these studies are feasible in most electrophysiologic laboratories and could substantially enhance our sensitivity to the onset and progression of small fiber diabetic neuropathy. [Copyright &y& Elsevier]

Cerebral autoregulation (CA) was assessed by chaotic analysis based on mean arterial blood pressure (MABP) and mean cerebral blood flow velocity (MCBFV) in 19 diabetics with autonomic neuropathy (AN) and 11 age-matched normal subjects. MABP in diabetics dropped significantly in response to tilting (91.6 ± 14.9 vs. 74.1 ± 13.4 mmHg, P < 0.05). Valsalva ratio of heart rate was reduced in diabetics compared to normal (1.1 ± 0.1 vs. 1.5 ± 0.2, P < 0.05). It indicated AN affects the vasomotor tone of peripheral vessels and baroreflex. Nonlinear results showed higher correlation dimension values of MABP and MCBFV in diabetics compared to normal, especially MABP (3.7 ± 2.3 vs. 2.0 ± 0.8, P < 0.05). It indicated CA is more complicated in diabetics. The lower Lyapunov exponent and the higher Kolmogorov entropy values in diabetics indicated less predictable behavior and higher chaotic degree. This study suggests impaired autoregulation would be more chaotic and less predictable. [ABSTRACT FROM AUTHOR]

Abstract: Although the 13C-octanoic acid breath test (OBT) has been applied to diabetic patients for assessing gastric emptying, such studies are still limited. Gastric emptying was measured using solid meal containing 13C-octanoic acid in 52 patients with Type 2 diabetes mellitus and 4 diabetic patients with mitochondrial DNA (mitDNA) 3243 mutation. Delayed gastric emptying was detected in 29% of patients with Type 2 diabetes mellitus, and multiple regression analysis showed that gastric emptying was independently associated with gastrointestinal symptoms and cardiac autonomic neuropathy. Gastric emptying was not related to gastric dysrhythmia in cutaneous electrogastrography (EGG). Diabetic patients with mitDNA 3243 mutation showed delayed gastric emptying. Because the pathogenesis of delayed gastric emptying is multifactorial in diabetic patients, the recently developed OBT is useful for studying gastric emptying in various clinical settings of diabetic patients. [Copyright &y& Elsevier]

Diabetic autonomic neuropathy (DAN) is one of the most disabling complications of diabetes mellitus. This study aimed to evaluate a special pupillary analysis for the early diagnosis of DAN by investigating pupil responsiveness under different conditions. Images of the pupils of 40 type 2 diabetic patients, who were divided into two (subclinical and nonproliferative diabetic retinopathy [NPDR]) groups using the results of fundus fluorescein angiography, and 20 healthy subjects were taken under mesopic, photopic, and pharmacologically dilated conditions. The pupil diameters, constriction ratio (CR), and dilation ratio (DR) were computed and calculated from the images. The mean mesopic pupil diameters (D1) of the control group, the subclinical group, and the NPDR group were 6.02 ± 0.48, 5.87 ± 0.99, and 4.95 ± 1.12 mm, respectively. The mean photopic pupil diameters (D2) were 3.40 ± 0.33, 3.37 ± 0.31, and 3.25 ± 0.47 mm, respectively. The mean pharmacologically dilated pupil diameters (D3) were 7.37 ± 0.59, 6.91 ± 1.00, and 5.49 ± 1.24 mm, respectively. The mean CR of the three groups were 0.43 ± 0.07, 0.41 ± 0.10, and 0.32 ± 0.14, respectively, and the mean DR were 0.23 ± 0.08, 0.19 ± 0.13, and 0.11 ± 0.05, respectively. There were statistically significant differences between the three groups with regard to the data of dark-adapted pupil diameter, dilated pupil diameter, CR, and DR ( p [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the effect of angiotensin converting enzyme inhibition (ACE-I) or angiotensin receptor blockade (ARB), and their combination, on both diabetic autonomic neuropathy (DAN) and left ventricular (LV) diastolic dysfunction (LVDD) in asymptomatic patients with diabetes mellitus (DM). Materials and Methods: Sixty-two patients (34 women) with long-term DM (24 with Type 1) and DAN, aged 51.7±13.9 years, free of coronary artery disease (CAD) or arterial hypertension (HT) at baseline, were studied for a 12-month period. Diagnosis of DAN was established if two or more of the standard cardiovascular reflex tests (CRT) were abnormal. Patients were randomly allocated to quinapril (20 mg/day), losartan (100 mg/day), or quinapril plus losartan (20 mg/day+100 mg/day). LV systolic and diastolic function was assessed using radionuclide ventriculography (RNV) at baseline and after 12 months of treatment. Results: In all three treatment groups, abnormal CRT values were improved. In the quinapril group, the first third filling fraction (1/3FF, 48.9±17.8% vs. 39.2±12.9% at baseline, P=.005) was increased and the atrial contribution to ventricular filling (25.1±6.3 vs. 30.1±7.8, P=.027) was reduced in the losartan group; the peak filling rate (PFR) was improved (3.41±.62 vs. 3.11±.44 volumes/s, P=.05), and in the combination group, the 1/3FF (39.4±11.8% vs. 29.6±11.9%, P=.018) was markedly increased, while the time to peak filling (TPF; 147±42 vs. 184±33 ms, P=.02) and the TPF/filling time (TPF/FT; 32.5±6.2% vs. 38.2±5.7%, P=.016) were reduced. Conclusions: Early ACE-I or ARB improve both DAN and LVDD in asymptomatic patients with Type 1 or 2 DM, after 1 year of treatment. Their combination may be slightly better than monotherapies on DAN and LVDD. The clinical importance of these effects should be validated by larger studies. [Copyright &y& Elsevier]

Cardiovascular complications are the main cause of death in people with diabetes. Early, asymptomatic changes are due to autonomic nervous system dysfunction, which if identified can lead to improved health. This study used detrended fluctuation analysis to identify changes in heart rate variability (HRV) associated with short-time electrocardiograph (ECG) recordings. The aim of the study was to determine whether heart rate variability analysis on short ECG recordings has the potential to be a useful adjunct to clinical practice.Comparative design with three independent simple random samples.University-based research project.Forty-eight people with no diabetes or cardiovascular complications had a 20 min ECG recorded, which was subsequently analysed using mathematical procedures. All participants also had a lying-to-standing autonomic nervous system test. Data was analysed using a Studentt-test.Heart rate variability expressed as a numeric value (α1 ), is reduced in disease states. We found a significant difference inα1 (P = 0.03) between the ECG recordings of the diabetes and control groups. In addition lowerα1 values were obtained from people identified with autonomic dysfunction within the diabetes group.The importance of our findings is that abnormal HRV identifies people with cardiovascular disease, irrespective of diabetes status, that may have autonomic neuropathy. HRV analysis is easily implemented by primary health care providers and has the potential to lead to improved health care by reducing inequity in rural areas and specifically addressing cardiovascular complications associated with diabetes. [ABSTRACT FROM AUTHOR]

We measured sympathetic skin response (SSR), a measure of sympathetic sudomotor function, and compared SSR with other quantitative neurological tests including power spectral analysis (PSA) of heart rate variations in 60 type 2 diabetic subjects. SSR was detected in all 20 age-matched healthy subjects but was absent in 17 patients with type 2 diabetes (28%) (P<.01). Even after exclusion of diabetic patients with absent SSR, the SSR amplitude in diabetic patients was significantly lower than in healthy subjects (P<.05). Both the low frequency power of R-R intervals, which reflects both cardiac sympathetic and parasympathetic function, and the postural fall in systolic blood pressure were significantly lower in the diabetic patients with absent SSR than in those with present SSR (P<.05 and .001, respectively). However, we found no significant difference in the high frequency power of R-R intervals, which reflects accurately cardiac parasympathetic function, between the diabetic patients with absent SSR and those with present SSR. In the diabetic patients with present SSR, SSR amplitude was also positively correlated with the postural fall in systolic blood pressure, low-frequency (LF) power, and high-frequency (HF) power. These results suggest that SSR is a useful and sensitive method for evaluating diabetic autonomic neuropathy, and that sympathetic sudomotor neuropathy may be preceded by cardiac parasympathetic neuropathy in patients with type 2 diabetes. [Copyright &y& Elsevier]

Abstract Aim/hypothesis In the diagnosis of diabetic autonomic neuropathy (DAN) various autonomic tests are used. We took a novel statistical approach to find a combination of autonomic tests that best separates normal controls from patients with DAN. Methods Twenty-four patients with Type-1 diabetes mellitus considered as having mild to moderate DAN as well as 10 normal, nondiabetic control subjects were analysed, searching for a test or a combination of tests that would optimally discriminate Type-1 diabetes mellitus from controls. Variations of heart rate during deep breathing (ΔR6) and during a Valsalva manoeuvre (VR), the number of reactive sweat glands on the foot (testing sympathetic sudomotor function), and the response of human pancreatic polypeptide to hypoglycaemia [ln(ΔhPP + 1)] were evaluated. Results Respective values for respective sensitivity and specificity values were: ΔR6, 96 and 70%; VR, 96 and 60%; sweat gland function, 71 and 90%; and ln(ΔhPP + 1), 71 and 90%. In a multivariate analysis approach a single discriminant function separating patients with Type-1 diabetes mellitus from nondiabetic controls was generated {Logit P = 288·5 –[14·7 ΔR6]–[26·6 ln(ΔhPP + 1)]}. This function allowed complete separation of patients with Type-1 diabetes mellitus from normal controls. Conclusion/interpretation We conclude that the combined determination of ΔR6 and of ln (ΔhPP + 1) optimally separates subjects with parasympathetic impairment from normal subjects. In addition, this combination of tests may serve as a sensitive method for the assessment of DAN. [ABSTRACT FROM AUTHOR]