Autonomic and Peripheral Nerve Function in Early Diabetic Neuropathy

ABSTRACT. Sundkvist G, Lilja B, Rosén I, Agardh C-D (Departments of Internal Medicine and Clinical Physiology, Malmö General Hospital, and Departments of Clinical Neurophysiology and Internal Medicine, University Hospital, University of Lund, Lund, Sweden). Autonomic and peripheral nerve function in early diabetic neuropathy. Possible influence of a novel aldose reductase inhibitor on autonomic function. Acta Med Scand 1987; 221:445–53. Autonomic and peripheral nerve functions as well as the possible short-term effect of a novel aldose reductase inhibitor (ARI) on neuropathy were evaluated in 30 male type I diabetics (age 25–44 years, mean 34; duration of diabetes 10–20 years, mean 34) with neurographic signs of peripheral neuropathy (PN). Autonomic neuropathy (AN) was established by the heart rate reactions to deep breathing (E/I ratio = vagal function) and to tilt (acceleration index = sympathetic and vagal functions; the brake index = vagal function). Twenty-nine patients, 13 with AN, completed the study. Among neurographic variables, only sural nerve function tests correlated with autonomic functions. Patients with AN showed significantly lower mean sensory action potential amplitudes (SAPA) sural, indicating axonal losses, than patients without AN (3.58±0.79 μV vs. 7.34±1.12 μV; p<0.01). PN as measured by neurography did not improve during ARI treatment. On the other hand, vagal function (brake indices) improved (p<0.05) during ARI in AN patients.     

A Novel Quantitative Method for Diabetic Cardiac Autonomic Neuropathy Assessment in Type 1 Diabetic Mice

In this work, we used a sensitive and noninvasive computational method to assess diabetic cardiovascular autonomic neuropathy (DCAN) from pulse oximeter (photoplethysmographic; PPG) recordings from mice. The method, which could be easily applied to humans, is based on principal dynamic mode (PDM) analysis of heart rate variability (HRV). Unlike the power spectral density, PDM has been shown to be able to separately identify the activities of the parasympathetic and sympathetic nervous systems without pharmacological intervention. HRV parameters were measured by processing PPG signals from conscious 1.5- to 5-month-old C57/BL6 control mice and in Akita mice, a model of insulin-dependent type 1 diabetes, and compared with the gold-standard Western blot and immunohistochemical analyses. The PDM results indicate significant cardiac autonomic impairment in the diabetic mice in comparison to the controls. When tail-cuff PPG recordings were collected and analyzed starting from 1.5 months of age in both C57/Bl6 controls and Akita mice, onset of DCAN was seen at 3 months in the Akita mice, which persisted up to the termination of the recording at 5 months. Western blot and immunohistochemical analyses also showed a reduction in nerve density in Akita mice at 3 and 4 months as compared to the control mice, thus, corroborating our PDM data analysis of HRV records. Western blot analysis of autonomic nerve proteins corroborated the PPG-based HRV analysis via the PDM approach. In contrast, traditional HRV analysis (based on either the power spectral density or time-domain measures) failed to detect the nerve rarefaction.     

通心络胶囊对糖尿病自主神经病变的影响

目的观察通心络胶囊联合甲钴胺片对糖尿病自主神经病变（DAN）患者的影响。方法48例DAN患者均予通心络胶囊4老V次口服,3次／d,甲钴胺片500μg／次口服,3次／d,共2个月。观察服药前后患者心率变异性（HRV）的变化,并记录患者症状的积分情况。结果通心络胶囊治疗后患者多汗、腹泻、便秘、排尿障碍、直立性低血压症状减轻或消失,5项症状的积分均较治疗前减少达50％以上,与治疗前比较差异有统计学意义（P〈0．05）;HRV各指标中低频范围内的功率（LF）降低（32．8±11．4）ms^2,LF／高频范围内的功率（HF）降低（1．8±0．6）ms^2,余指标均增高,差异有统计学意义（P〈0．01）,且未见明显不良反应。结论通心络胶囊联合甲钴胺片对糖尿病自主神经病变有改善交感、迷走神经平衡失调的作用,是治疗DAN安全、有效的药物。     

Postural Hypotension in Diabetic Autonomic Neuropathy: a Review

Postural hypotension is uncommon in diabetes but can occur secondary to autonomic neuropathy. Symptoms are rare and include dizziness, weakness, blurred vision, tiredness, and loss of consciousness. The pathophysiology of postural hypotension is not clear, but changes in intravascular volume, heart rate, cardiac output, and splanchnic vascular resistance are similar in patients and controls. The main factors producing hypotension are a blunted catecholamine response to standing, and failure of lower limb vascular resistance to increase adequately. Treatment for symptomatic postural hypotension includes avoidance of dehydration, adequate salt intake, and fludrocortisone. Other treatments are reviewed but are less helpful. Patients with postural hypotension have intermittent symptoms over the years but rarely become severely disabled. They have a poorer prognosis than patients with symptomatic autonomic neuropathy without postural hypotension.     

Mortality in Diabetic Patients with Cardiovascular Autonomic Neuropathy

Cardiovascular autonomic diabetic neuropathy (CADN) may carry an increased risk of mortality. However, in previous studies the prognosis of patients with CADN seemed to be influenced by life-threatening macro- and microvascular complications which had already been present at the start of the study period. Between 1981 and 1983, 1015 diabetic patients have been examined for CADN (abnormal heart rate variation at rest and during deep respiration) at the Diabetes Research Institute, Düsseldorf. Thirty-five patients (28 with Type 1 diabetes, 7 with Type 2 diabetes) with CADN have been retrospectively recruited and reviewed 8 years later and compared with 35 patients without CADN who were matched for sex, age, and duration of diabetes. Exclusion criteria for entry into the study included severe micro- or macrovascular complications, such as proliferative retinopathy, proteinuria or symptomatic coronary artery disease. During the 8-year observation period, 8 patients with CADN and 1 patient without CADN died. The survival rate estimates steadily declined in patients with CADN over the whole period studied. The 8-year survival rate estimate in patients with CADN was 77 % compared with 97 % in those with normal autonomic function (p < 0.05). Deaths were mainly due to macrovascular diseases (n = 3) and sudden unexpected deaths (n = 3). One patient with CADN died after an episode of severe hypoglycaemia. Among the deceased patients, coefficient of variation of R-R intervals during deep breathing was significantly reduced when compared with those who survived (1.04 ± 0.5 % vs 1.87 ± 1.0 %; p < 0.05), and symptoms of autonomic neuropathy (orthostatic hypotension, gastroparesis, gustatory sweating) were more frequent (7/8 vs 10/27 patients). The mean QTc interval was not different between the groups. These results suggest a relatively poor prognosis of patients with CADN in the absence of clinically detectable micro- and macrovascular complications.     

Relationship between Pancreas Exocrine Insufficiency and Cardiac Autonomic Neuropathy in Patients with Type 2 Diabetes Mellitus

BackgroundThe 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.     

Does Abnormal QT Interval Prolongation Reflect Autonomic Dysfunction in Diabetic Patients? QTc Interval Measure Versus Standardized Tests in Diabetic Autonomic Neuropathy

The question as to whether the QTc interval correlates with five cardiovascular tests (deep breathing test, 30/15 ratio test, lying to standing test, cough test, and postural blood pressure test) for the diagnosis of diabetic autonomic neuropathy (DAN) was investigated in 168 (38 Type 1, 130 Type 2) consecutive outpatients (mean age 54.9 ± 11.2 years). QT interval was measured on an ECG recorded at rest and QTc calculated according to Bazett's formula. The percentage of patients with a QTc greater than 0.440 s was: absent DAN = 11% (n = 7), probable DAN = 7% (n = 4), definite DAN = 23% (n = 12) (p < 0.05), and the mean (± SD) QTc values were 0.403 ± 0.028 s, 0.405 ± 0.023 s, and 0.421 ± 0.026 s, respectively. A significant correlation between QTc duration and DAN score of autonomic cardiovascular test results (r = 0.34, p < 0.0001) was observed. The calculated specificity, sensitivity, positive and negative predictive values were 89%, 15%, 70% and 37%, respectively. In conclusion, QTc can be considered as an additional specific test in the assessment of diabetic autonomic neuropathy, but cannot replace the standard battery of cardiovascular tests.     

Prospective Study of Autonomic Nerve Function in Type 1 and Type 2 Diabetic Patients: 24 Hour Heart Rate Variation and Plasma Motilin Levels Disturbed in Parasympathetic Neuropathy

To clarify the impact of autonomic neuropathy in diabetic patients, we have conducted a prospective study of 58 Type 1 and 51 Type 2 diabetic patients (investigated at baseline, after 4, and after 7 years). In Type 1 diabetic patients, the sympathetic nerve function (orthostatic acceleration and brake indices) and in Type 2 patients, parasympathetic nerve function (R-R interval variation; E/I ratio) deteriorated during 7 years of prospective observation. Symptoms of autonomic neuropathy were associated with signs of autonomic neuropathy (low brake indices) in Type 1 but not in Type 2 diabetic patients. In the latest assessment 24 h ECG recording was performed and blood samples assayed for neuropeptide Y (NPY) and motilin were obtained. Type 1 diabetic patients with parasympathetic neuropathy (abnormal E/I ratio) showed significantly lower SD value (less variation in the R-R intervals; 29 [17] vs 50 [16], [mean {interquartile range}]; p = 0.001) and higher postprandial plasma motilin values (70 [20] pmol I^?1 vs 50 [15] pmol I^?1; p< 0.01) than patients with normal parasympathetic nerve function. In Type 2 diabetic patients, sympathetic neuropathy (low brake indices) was associated with an increased frequency of ventricular extra systolic beats during 24 h ECG recording (r_s = 0.65; p<0.01). Postprandial plasma NPY levels were not associated with disturbed autonomic nerve function.     

The Splanchnic Circulation and Postural Hypotension in Diabetic Autonomic Neuropathy

Postural hypotension results from sympathetic failure to cause superior peripheral vasoconstriction. The importance of the splanchnic circulation was studied by measuring mesenteric artery blood flow with duplex Doppler scanning. Nine normal and 9 Type 1 diabetic controls were compared to 8 Type 1 patients with autonomic neuropathy whose pressure fell 40–113 mmHg (range) on tilting. Measurements were made supine and after vertical tilt, fasting without insulin and after a 550 kcal meal. Superior mesenteric artery diameter decreased on tilting in normal controls but not in diabetic control or neuropathy groups (supine vs tilted: controls. 6.3 ± 0.9 to 5 ± 0.9 mm, p = 0.004, diabetic controls: 6.0 ± 0.6 to 6.0 ± 1.0 mm, and neuropathy group: 6.4 ± 0.9 to 5.6 ± 0.9 mm), but proportional blood flow changes were similar in all subjects (controls: 407 ± 154 to 255 ± 67 ml min^?1 (-31%, p = 0.03), diabetic controls: 379 ± 140 to 306 ± 149 ml min^?1 (-8%, p = 0.28), neuropathy group: 639 ± 371 to 435 ± 142 ml min^?1 (-23%, p = 0.10). Postprandially supine superior mesenteric artery flow increased in all subjects but this did not affect the degree of systolic blood pressure drop on tilting (fasting vs postprandial blood flow: controls: 407 ± 154 to 775 ± 400 ml min^?1 (p = 0.04), diabetic controls: 379 ± 140 to 691 ± 262 ml min^?1 (p = 0.01), neuropathy group: 639 ± 371 to 943 ± 468 ml min^?1 (p < 0.06)). The similarity of superior mesenteric artery responses to tilting in the three groups, and the lack of exacerbation of postural hypotension in the presence of postprandial hyperaemia indicates that control of splanchnic blood flow is less important in the aetiology of diabetic autonomic postural hypotension than previously thought.     

Autonomic Neuropathy and Toe Circulation

ABSTRACT. Ankle and toe pressure ratios and toe temperature reactions to cold followed by indirect heating were evaluated in 23 diabetic patients with and without autonomic neuropathy (AN) in a first and in a second follow-up study after 5–7 years. In the first study, despite normal blood pressure ratios, AN patients, all with parasympathetic neuropathy, showed a markedly delayed increase in toe temperature after cooling followed by indirect heating. In the second study, most AN patients showed sympathetic neuropathy and had higher toe temperatures before cooling than those without AN. Parasympathetic neuropathy leads to increased sensitivity to cold in toe vessels and sympathetic neuropathy to vasodilation and increased toe temperatures.     

Catecholamines and Diabetic Autonomic Neuropathy

In diabetic patients with autonomic neuropathy plasma noradrenaline concentration, used as an index of sympathetic nervous activity, is low. This decrease is, however, only found in patients with a long duration of diabetes with clinically severe autonomic neuropathy. This apparent insensitivity of plasma catecholamine measurements is not due to changes in the clearance of catecholamines in diabetic autonomic neuropathy. The physiological responses to infused adrenaline and to noradrenaline are enhanced, for noradrenaline mainly cardiovascular responses. Adrenoceptors (alpha and beta adrenoceptors) are not altered in circulating blood cells in diabetic autonomic neuropathy. Thus, a generalized up-regulation of adrenoceptors does not occur in diabetic autonomic neuropathy.     

Prevalence of diabetic autonomic neuropathy measured by simple bedside tests

Summary To investigate the prevalence of diabetic autonomic neuropathy, five simple bedside tests, beat-to-beat variation during quiet respiration, beatto-beat variation during forced respiration, heart rate and blood pressure response to standing, heart rate response to exercise, and heart rate response to Valsalva's manoeuvre were applied to 75 male insulindependent diabetics, mean age 40 years, (range 30–49 years). The subjects were subdivided into three groups according to duration of diabetes, which was between 0 and 40 years. Twenty-eight healthy age-matched male controls were also studied. The prevalence of diabetic autonomic neuropathy in the whole diabetic population indicated by abnormal response in beat-to-beat variation during forced respiration was 27%. Diabetic autonomic neuropathy increased in frequency with duration of disease. Patients with nephropathy or proliferative retinopathy had a significantly higher prevalence of diabetic autonomic neuropathy as indicated by abnormal beat-to-beat variation during forced respirations (p<0.01) than patients without these complications.     

QT Interval Length and Diabetic Autonomic Neuropathy

QT interval length was measured in ECG recordings from three groups of age-matched male subjects: 36 normal subjects, 41 diabetic patients without (DAN-ve), and 34 with (DAN+ve) autonomic neuropathy. ECG samples were selected from previously recorded 24-h ECGs on the basis of a clearly defined T wave and a steady RR interval over 2 min of around 750 ms (80 beats min^?1). There were no significant differences in RR interval between the groups. The two diabetic groups had slightly longer QT measurements (normal 365 ± 14 (±SD) ms, DAN-ve 373 ± 18 ms, DAN+ve 375 ± 23 ms, p = 0.05), and corrected QT (QTc) values (normal 423 ± 15 ms, DAN-ve 430 ± 20 ms, DAN+ve 435 ± 24 ms, p = 0.05). Ten diabetic patients fell above our defined upper limit of normal for QTc (>mean + 2SD). There was a significant correlation in the DAN-ve group between the QT indices and 24-h RR counts (QT r = ?0.38, p < 0.01; QTc r = ?0.40, p < 0.01). We conclude that there are some small alterations in QT interval length in the steady state in diabetic autonomic neuropathy. The changes appear to be due to autonomic impairment, rather than diabetes per se.     

Failure of Improved Glycaemic Control to Reverse Diabetic Autonomic Neuropathy

A prospective trial was conducted in 20 insulin-treated diabetic patients with established autonomic dysfunction to test the effect of a 2-year improvement in glycaemic control. On entry, the patients aged 34.6 ± 10.8 years (mean ± SD), duration 20.2 ± 10.4 years, had evidence of poor control (HbA₁ > 9.5% on at least two consecutive tests, and at least one abnormality in the 11 different neuropathic function tests used. These included four of pupillary function, six of cardiovascular function and one of vibration sensitivity. The method used to improve control was conventional insulin treatment combined with home monitoring of blood glucose and regular adjustment of insulin dosage under the supervision of a diabetic specialist nursing sister. The HbA₁ level on entry was 13.0 ± 0.7% (mean ± SEM) which fell to 10.4 ± 0.4% at 3 months and to 9.3 ± 0.4% at 24 months. The neuropathy tests were performed at 0, 3, 6, 12, 18, and 24 months and significant changes were recorded in five. These changes (in two pupillary and three cardiovascular tests) all indicated worsening function which exceeded that explicable by aging. One cardiovascular test showed slower rates of deterioration in patients achieving the greatest improvements in control. It was concluded that a prolonged period of improved control failed to reverse established autonomic dysfunction of diabetes.     

Cardiovascular Autonomic Neuropathy Is Associated With Macrovascular Risk Factors in Type 2 Diabetes: New Technology Used for Routine Large-Scale Screening Adds New Insight

Background:The objective was to identify the presence of cardiovascular autonomic neuropathy (CAN) in a cohort of individuals with diabetes in outpatient clinics from 4 different parts of Denmark and to explore the difference between type 1 and type 2 diabetes in relation to CAN.Methods:The DAN-Study is a Danish multicenter study focusing on diabetic autonomic neuropathy. Over a period of 12 months, 382 type 1 and 271 type 2 individuals with diabetes were tested for CAN. Patients were randomly recruited and tested during normal visits to outpatient clinics at 4 Danish hospitals. The presence of CAN was quantified by performing 3 cardiovascular reflex tests (response to standing, deep breathing, and valsalva). To describe possible associations, multivariate analysis with CAN as the dependent variable was performed.Results:The prevalence of CAN was higher among patients with type 2 diabetes (35%) compared to patients with type 1 diabetes (25%). Multivariate analysis revealed significant associations between CAN and different risk markers in the 2 populations. In type 1 diabetes patients CAN was associated with microalbuminuria (P < .001), macroalbuminuria (P = .011), simplex retinopathy (P < .001), proliferative retinopathy (P < .001), and peripheral neuropathy (P = .041). Among type 2 diabetes patients CAN was independently associated with high pulse pressure (P < .01), BMI (P = .006), and smoking (P = .025).Conclusion:In this cross-sectional observational study CAN was independently associated with microvascular complication in type 1, whereas in type 2 CAN was associated with macrovascular risk factors.     

Signal-averaged Electrocardiogram in Patients with Insulin-dependent (Type 1) Diabetes Mellitus With and Without Diabetic Neuropathy

The purpose of this study was to investigate the presence of ventricular late potentials derived from signal-averaged ECG in patients with IDDM with and without diabetic neuropathy. Eighty patients with IDDM but without evidence of cardiac disease and 80 age-matched healthy control subjects were investigated. The corrected QT interval was measured from the standard surface electrocardiogram. Ventricular late potentials were derived from signal-averaged electrocardiogram. Out of the 80 diabetic patients, 20 had an autonomic neuropathy, 20 had an isolated peripheral neuropathy, and 40 had no symptoms of neuropathy. The corrected QT interval was significantly prolonged in patients with an autonomic neuropathy as compared with the control group (436 ± 23 ms^.5 vs 384 ± 23 ms^.5, p < 0.001). In the other patient groups there was no significant prolongation of the corrected QT interval. Ventricular late potentials were present in 3 diabetic patients with an isolated peripheral neuropathy and in 1 control subject (NS). No diabetic patient with an autonomic neuropathy had ventricular late potentials. Our data did not indicate an increased incidence of ventricular late potentials derived from signal-averaged electrocardiogram in diabetic patients independent of a coexisting diabetic neuropathy or a prolonged corrected QT interval. © 1997 by John Wiley & Sons, Ltd.     

Reproducibility of Parameters for Assessment of Diabetic Neuropathy

This study evaluated the reproducibility of nerve function assessment in a group of 132 diabetic patients with moderate peripheral polyneuropathy. Patients were investigated at the beginning and the end of the run-in period (a 1-month placebo period) of a multicentre trial of an aldose-reductase inhibitor (Ponalrestat). Reproducibility was evaluated by performing four types of tests: quantitative visual scales of symptoms, quantitative sensory assessment (vibration perception thresholds in medial malleolus and great toe, foot thermal perception threshold to hot and cold), electrophysiological investigations on the dominant side (conduction velocities and potential amplitudes of sensory and median motor nerve, sural and peroneal nerves, amplitudes of F waves of median motor and peroneal nerves) and cardiac autonomic tests (Valsalva, deep-breathing, lying-to-standing). Reproducibility was poor for symptoms, thermal sensitivity, and potential amplitudes. It was satisfactory (total coefficient of variation < 50%) for all the other parameters and even very good (total variation coefficient < 26%, intra-subject variation factors corresponding to < 56% of total variance) for velocities of sensory and median motor and peroneal nerves, the amplitudes of F waves and the three autonomic tests. For most of the parameters total variance was mainly related to inter-subject variability. However, inter-subject variability for the three cardiac autonomic tests was very low and at least one cardiac autonomic test was altered in all the patients. Inter-centre variability was low for all the parameters, except for action potential amplitudes and for F wave velocity of the median motor nerve. This study suggests those parameters that are appropriate for the assessment of diabetic neuropathy and for therapeutic trials. It also shows evidence of cardiac autonomic neuropathy in all these patients with moderate peripheral neuropathy.