Heartbeat and arrhythmia perception in diabetic autonomic neuropathy.

A comparative study of diabetics with autonomic neuropathy (N = 13) as against non-neuropathic diabetics (N = 16) and healthy control persons (N = 20) was carried out with respect to heart rate both at rest and under stress, frequency of cardiac arrhythmias in a 24-h ECG and accuracy of heartbeat and arrhythmia perception. In the subjects with diabetic autonomic neuropathy, the spontaneous variability and stress-induced reactivity of the heart rate as well as the number of tachycardic episodes were reduced, whereas the frequency of ventricular extrasystoles was somewhat increased. Impaired heartbeat perception and a complete loss of perception of arrhythmias as a consequence of neuropathic deafferentation could be demonstrated. Cardiac perception disorders also play a vital role in other clinical problems, e.g. silent myocardial infarction and lack of awareness of hypoglycaemia in diabetes mellitus.     

The effect of diabetic autonomic neuropathy on P-wave duration,dispersion and atrial fibrillation

Introduction

Atrial fibrillation (AF) is the most common sustained arrhythmia. Diabetic autonomic neuropathy (DAN) is a frequent complication of diabetes mellitus and has a negative impact on the cardiovascular system. There are no data about the occurrence of paroxysmal atrial fibrillation (PAF) in the population with DAN.

Material and methods

We analysed the data of 100 patients with PAF. The study population was divided into three groups: group I: 28 patients with diabetes mellitus (DM) and DAN, group II: 34 patients with DM without DAN, and group III: 38 patients without DM. P-wave duration (FPD) and dispersion (PWD) were measured during sinus rhythm and AF episodes were counted during 12 months of follow-up.

Results

Recurrence of PAF was higher in group I (47 episodes/year) compared to groups II and III (26 and 22 episodes/year) – p<0.01. The FPD was longer in group I (137.4 ±12.0 ms vs. 126 ±23.0 ms in II group and 129 ±18.3 ms in group III; p<0.001). The PWD was longer in patients with DAN (53 ±19 ms vs. 36 ±18 ms and 34 ± 20 ms, p<0.001).

Conclusions

The results showed that the presence of DAN caused a significant increase in P-wave duration and dispersion, which might be responsible for the recurrence of AF.     

Metabolic and cardiovascular responses to epinephrine in diabetic autonomic neuropathy

Norepinephrine-induced vasoconstriction, which is mediated by alpha-adrenergic receptors, is accentuated in patients with autonomic neuropathy. In contrast, responses mediated by beta-adrenergic receptors, including vasodilatation and metabolic changes, have not been evaluated in these patients. To study these responses, we administered epinephrine in a graded intravenous infusion (0.5 to 5 micrograms per minute) to seven diabetic patients without neuropathy, seven diabetic patients with autonomic neuropathy, and seven normal subjects. Mean arterial pressure decreased significantly in the patients with autonomic neuropathy (P less than 0.01) but was unchanged in the other groups. Since cardiac output increased to a similar extent in the three groups, the decrease in blood pressure was due to a significantly larger decrease (P less than 0.01) in total peripheral vascular resistance in the patients with autonomic neuropathy. The heart rate increased significantly more during the infusions in the patients with neuropathy than in those without neuropathy. Epinephrine produced a greater increase in blood glucose, the glucose-appearance rate, lactate, glycerol, and free fatty acids in the patients with autonomic neuropathy than in the other groups (P less than 0.05). These findings indicate that several beta-receptor-mediated responses to epinephrine are enhanced in patients with diabetic autonomic neuropathy. The underlying mechanism remains to be elucidated.     

Experimental diabetic autonomic neuropathy characterization in streptozotocin-diabetic Sprague-Dawley rats

Rats with chronic streptozotocin-induced diabetes develop enlargement of the alimentary tract, loss of fecal consistency, and autonomic neuropathy involving the extrinsic innervation of the ileum. In this study we have continued the characterization of the unmyelinated axonopathy involving the ileal mesenteric nerves of outbred Sprague-Dawley rats diabetic for 1.5 to 10 months using ultrastructural methods. Axonopathy in the alimentary tract of chronically diabetic rats is characterized by modest to marked dilation of axons by distinctive subcellular organelles identical with those described in experimental and clinical axonal dystrophies. Lesions are infrequent 1.5 and 3 months after induction of diabetes, increasing rapidly in numbers thereafter. Axonal lesions are reproducibly encountered in the ileum, cecum, and rectum but not in the proximal jejunum of chronically diabetic rats. Sectioning of mesenteric nerves along their longitudinal axes demonstrates the focal and in some instances apparent terminal nature of the axonal dilation. Disappearance of dystrophic axons distal (peripheral) to mesenteric crush injury confirms the origin of the axons extrinsic to the gut wall. Only rare examples of dystrophic diabetic axonopathy were detected within the wall of the ileum, presumably representing involvement of terminal axonal segments within the intrinsic ganglia. Examination of the mesenteric nerves of 18- and 30-month-old control rats failed to demonstrate dystrophic axonopathy, providing evidence that diabetic axonopathy does not represent premature development of an aging change in mesenteric nerves. Examination of the autonomic innervation of various other tissues including spleen, bladder, vas deferens, and iris, as well as the phrenic, sciatic, vagus, and tail nerves of 4- to 12-month diabetic animals, failed to demonstrate reproducible axonopathy comparable to that involving the alimentary tract of the same animals. The paravascular fascicles of ileal mesenteric nerves of 6- to 7-month diabetic and age-matched control rats were examined by morphometric methods and failed to demonstrate significant loss of axons or an appreciable shift in mean fiber diameter.     

Predicting cardiac autonomic neuropathy category for diabetic data with missing values

Cardiovascular autonomic neuropathy (CAN) is a serious and well known complication of diabetes. Previous articles circumvented the problem of missing values in CAN data by deleting all records and fields with missing values and applying classifiers trained on different sets of features that were complete. Most of them also added alternative features to compensate for the deleted ones. Here we introduce and investigate a new method for classifying CAN data with missing values. In contrast to all previous papers, our new method does not delete attributes with missing values, does not use classifiers, and does not add features. Instead it is based on regression and meta-regression combined with the Ewing formula for identifying the classes of CAN. This is the first article using the Ewing formula and regression to classify CAN. We carried out extensive experiments to determine the best combination of regression and meta-regression techniques for classifying CAN data with missing values. The best outcomes have been obtained by the additive regression meta-learner based on M5Rules and combined with the Ewing formula. It has achieved the best accuracy of 99.78% for two classes of CAN, and 98.98% for three classes of CAN. These outcomes are substantially better than previous results obtained in the literature by deleting all missing attributes and applying traditional classifiers to different sets of features without regression. Another advantage of our method is that it does not require practitioners to perform more tests collecting additional alternative features.     

Vasopressin release induced by hypothension is blunted in patients with diabetic autonomic neuropathy

The response of arginin-vasopressin (AVP) to baroreceptor activation (tilt testing) was investigated in patients with diabetic autonomic neuropathy (DAN). The present data show that hypothension induced by upright position showed a slight increase of AVP in patients with DAN in comparison with normal subjects and diabetic patients without DAN. These findings suggest that the blunted AVP response to hypothension may be due to lesions of afferent autonomic pathways present in DAN and plays a role in the pathogenesis of postural hypothension.     

Ultrastructural and immunohistochemical characterization of autonomic neuropathy in genetically diabetic Chinese hamsters

Selected portions of the prevertebral and paravertebral sympathetic and vagal parasympathetic nervous systems have been examined in the genetically diabetic Chinese hamster, an experimental animal model of diabetic gastrointestinal disease. The prevertebral sympathetic superior mesenteric/celiac ganglia, which provide much of the sympathetic innervation of the alimentary tract, developed large numbers of markedly dilated axons, many of which had the ultrastructural features of neuroaxonal dystrophy. Dystrophic axons, many involving presynaptic axonal elements, were increased in frequency in the prevertebral superior mesenteric/celiac ganglia, but not in the paravertebral superior cervical sympathetic ganglia, of chronically diabetic hamsters in comparison with age-matched controls. Dystrophic axons contained substance P- and gastrin-releasing peptide (gastrin-releasing peptide/bombesin)-like staining but were not labeled by antisera directed against vasoactive intestinal peptide, dynorphin-B, somatostatin, leu- and met-enkephalin and neuropeptide tyrosine. Substance P and gastrin-releasing peptide/bombesin containing subpopulations of presynaptic elements in prevertebral sympathetic ganglia are thought to participate in local reflex control of bowel motility and lesions preferentially involving these elements may contribute to bowel dysfunction. Immunohistologic techniques failed to demonstrate dystrophic axons in the superior cervical ganglia. Although morphometric studies failed to show significant axon loss in the abdominal vagus of chronically diabetic Chinese hamsters, evidence of markedly diminished numbers of axons comprising each Schwann cell unit and regenerative collections of Schwann cell processes devoid of axons are consistent with the participation of parasympathetic elements in the pathogenesis of alimentary dysfunction in this model system. These results suggest that selective subpopulations of neuropeptide containing axons are vulnerable to the diabetic condition and that these abnormalities may lead to physiologic dysfunction.     

Gastrointestinal mean transit times in young and middle-aged healthy subjects.

To investigate the effects of age and gender on gastric, small intestinal and colonic mean transit times, a study was conducted in 32 healthy volunteers: eight young women (22-30 years), eight young men (20-28 years), eight middle-aged women (43-51 years) and eight middle-aged men (38-53 years). After ingestion of a meal containing 111Indium-labelled water and 99mTechnetium-labelled omelette imaging of the abdomen was performed at intervals of 30 min until all radioactivity was located in the colon and henceforth at intervals of 24 h until all radioactivity had cleared from the colon. Gastric, small intestinal and colonic mean transit times were calculated. The gastric, small intestinal and colonic mean transit times were significantly longer in women. Ageing was shown to accelerate the gastric and small intestinal transit significantly. In the group of men the colonic mean transit time was unaffected by age, but middle-aged women had a significantly slower colonic transit than young women. We therefore conclude that both age and gender have to be considered when reference values for gastric, small intestinal and colonic mean transit times have to be established.     

Effect of AS-4370 on gastric motility in patients with diabetic autonomic neuropathy]

Delayed gastric emptying in diabetic patients occurs with progress of automatic neuropathy as one late complication. Delayed emptying is deeply correlated with poor glycemic control, due to imbalance between nutrients absorption and effect of exogenous insulin. AS-4370 is a newly developed prokinetic agent which has been reported to selectively activate motility of the upper gastrointestinal tract through enhancing acetylcholine release from nerve terminals within the enteric mural plexus. In this study, we evaluated the effect of AS-4370 on gastric motility in diabetic patients with autonomic neuropathy. Eight diabetic patients with autonomic neuropathy (3 males and 5 females) with mean age of 56 years old (range 29-66) participated to this study after giving written informed consent. Gastric motility was evaluated by gastric emptying and electrogastrography. Gastric emptying study was done using 99mTc-Tin colloid labeled omelet meal served with 2 slices of toast and 200 ml of milk. Electrogastrography was recorded from epigastric skin surface, for 30 minutes before and after meal each. AS-4370, 7.5 mg tid, was given for four weeks after basal recording of gastric motility studies. Following the 4-week treatment with AS-4370, gastric motility studies were repeated. For the motility studies after medication, drug was given 30 minutes before test meal. Gastric retention rate at 150 minutes in all patients were over 45% of upper limit of normal range in basal study with mean value of 69 +/- 5%, which decreased significantly to 52 +/- 5%, with AS-4370 treatment (p < 0.01). Gastric emptying speed, another parameter for gastric emptying also improved with medication.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dynamic cerebral autoregulation assessment using chaotic analysis in diabetic autonomic neuropathy

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.     

皮肤交感反应对糖尿病自主神经病的诊断价值

目的：探讨皮肤交感反应（SSR）检查对诊断糖尿病自主神经病的价值。方法：将122例2型糖尿病患者分为有自主神经症状组（71例）和无自主神经症状组（51例）,每位患者进行神经传导检查及SSR检查。分析比较两组患者SSR与神经传导检查结果的差异。结果：两组间SSR、神经传导的检查结果比较差异无统计学意义（P〉0．05）。43例SSR正常的患者中有29例（65．9％）有自主神经症状,22例（51。2％）病程短于5年;79例SSR异常的患者中有43例（54．4％）有自主神经症状,37例（46．8％）糖化血红蛋白（HbA1C）高于8．5％。结论：SSR与自主神经症状无明显相关性;糖尿病控制情况及病程对SSR结果均有影响。     

Epidermal transient receptor potential vanilloid 1 in idiopathic small nerve fibre disease, diabetic neuropathy and healthy human subjects

AIMS: The transient receptor potential vanilloid 1 (TRPV1) plays an important role in mediating pain and heat. In painful neuropathies, intraepidermal TRPV1 nerve fibre expression is low or absent, suggesting that pain generated is not directly related to sensory nerve fibres. Recent evidence suggests that keratinocytes may act as thermal receptors via TRPV1. The aim was to investigate epidermal TRPV1 expression in patients with neuropathic conditions associated with pain. METHODS AND RESULTS: In a prospective study of distal small nerve fibre neuropathy (DISN; n = 13) and diabetic neuropathy (DN; n = 12) intraepidermal nerve fibre density was assessed using the pan axonal marker PGP 9.5 and epidermal TPVR1 immunoreactivity compared with controls (n = 9). Intraepidermal nerve fibres failed to show TRPV1 immunoreactivity across all groups. There was moderate and strong TRPV1 reactivity of epidermal keratinocytes in 41.8% and 6% for DISN, 32.9% and 2.9% for DN and 25.4% and 5.1% for controls, respectively. Moderate keratinocyte TRPV1 expression was significantly increased in DISN compared with controls (P = 0.01). CONCLUSION: Our study suggests that in human painful neuropathies, epidermal TRPV1 expression is mainly in keratinocytes.     

Oesophageal transit in patients with autonomic dysfunction. The effect of treatment with fludrocortisone.

Oesophageal function was examined by radionuclide transit measurements in 15 patients with severe autonomic deficiency and orthostatic hypothension and 23 healthy volunteers. Seven of the patients were re-examined after treatment for 3 weeks with fludrocortisone acetate (Florinef). Six patients and five control subjects were evaluated before and after i.v. administration of atropine. The mean transit time (MTT) was prolonged (P less than 0.007) and the residual activity increased (P = 0.038) in the patients compared with the control group. Prolonged MTT was associated with oesophageal symptoms. Treatment of orthostatic hypotension with fludrocortisone acetate significantly reduced MTT. Atropine increased MTT and residual activity. The increase in heart rate after atropine was correlated in the patients with MTT before treatment. The results demonstrate the frequent presence of impaired oesophageal function in patients with severe autonomic dysfunction, irrespective of aetiology. The impairment seems to be closely related to parasympathetic insufficiency. The improvement after fludrocortisone may suggest an influence of ion balance on oesophageal function in these patients.     

A form of necrobiosis and atrophy of smooth muscle in diabetic gastric autonomic neuropathy

Pathological changes identified in the muscular wall of the stomach from two young insulin-dependent diabetic patients suffering from severe gastric autonomic neuropathy are presented. Scattered smooth muscle cells appearing as homogeneous round eosinophilic bodies ("M" bodies) among areas of sub-total smooth muscle cell atrophy together with intercellular collagen proliferation were identified in the muscularis propria of the stomach. Ultrastructurally, the "M" bodies are transformed smooth muscle cells undergoing a form of necrobiosis with peculiar intracellular features. These changes appear characteristic of end-stage diabetic gastric autonomic neuropathy when compared with other pathological conditions involving the gastric wall. The degree and extent of involvement of the various components of the gastric wall are discussed.     

Serum ferritin in healthy subjects and type 2 diabetic patients

In order to study the relationship between the serum ferritin level and the components of the insulin resistance syndrome in type 2 diabetic patients, we evaluated fifty type 2 diabetic patients who were selected according to NDDG/WHO criteria from those patients attending Korea University Hospital from 1997 to 1998. Twenty-five healthy non-diabetic subjects of comparable age and sex distribution acted as a control group. The results showed that the value of log ferritin was higher in the type 2 diabetes patients than the control subjects, but not at a statistically significant level (p = 0.09). Log ferritin was correlated with fasting blood sugar level (r = 0.235, p = 0.048) and body mass index (BMI) (r = 0.285, p = 0.05). In the type 2 diabetic patients, log ferritin was correlated with fasting C-peptide (r = 0.478, p = 0.009). In the control subjects, log ferritin was correlated only with BMI (r = 0.477, p = 0.012). In a stepwise multiple regression analysis, the diabetic group showed a significant correlation between fasting C-peptide and log ferritin (p = 0.001). In the control group, the fasting sugar level was significantly correlated with log ferritin (p = 0.034). These results suggest that serum ferritin can be employed as a marker of not only glucose homeostasis but also insulin resistance both in type 2 diabetic and control subjects.     

The effect of ACTH on the plasma level of non-esterified fatty acids in healthy subjects and in diabetic patients

Summary Following an intramuscular injection of ACTH to a group of healthy subjects a decrease was observed in the level of non-esterified fatty acids of the plasma, replaced by an increase in their concentration, whereas in a group of diabetes patients only a stage of decrease was observed under identical conditions. The most marked decrease in the concentration of non-esterified fatty acids in the plasma was noted in cases with a higher initial level. No quantitative relationship could be established between the decrease in the concentration of non-esterified fatty acids in the plasma was noted in cases with a higher initial level. No quantitative relationship could be established between the decrease in the concentration of non-esterified fatty acids and the increase in the amount of free 11-hydroxycorticosteroids of the plasma following an ACTH injection. The results of observations evidence the dependence of the ACTH administration effect on the initial condition of the organism, and agree with the hypothesis of a direct, extraadrenal mechanism of ACTH action on the level of non-esterified fatty acids of the plasma.(Presented by Academician V. V. Parin) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 59, No. 5, pp. 48–51, May, 1965     

Uricosuric effect of irtemazole in healthy subjects

Summary Following a single dose of 50 mg irtemazole per os, plasma uric acid levels decreased after 1 h and fell to 53.5% of the original value within 6–12 h. Renal uric acid excretion increased up to 66 mg/h 30 min after drug application and reached its maximum of 151 mg/h 30 min later. Uric acid clearance also increased after 30 min and reached its maximum of 56 ml/min after 60 min.The response of the kidney to irtemazole is faster than to benzbromarone or probenecid. Lowering of plasma uric acid has a shorter-lasting effect than benzbromarone or probenecid. At 24 h after the application of 50 mg irtemazole the decrease of the plasma uric acid was between 15.4% and 30.0%, or 24.7% on average. Three days after the application the basic plasma uric acid levels were reached again.     

Plasma dihydroxyphenylglycol (DHPG) as an index of diabetic autonomic neuropathy

Forearm venous plasma noradrenalin and dihydroxyphenylglycol (DHPG) concentrations were measured in eight diabetic patients with and eight diabetic patients without neuropathy. Plasma noradrenalin was on average the same in patients with and without neuropathy and correlated to serum creatinine. Plasma DHPG concentrations were significantly reduced in patients with autonomic neuropathy as compared to patients without neuropathy (P less than 0.05). A low plasma DHPG/noradrenalin ratio in forearm venous blood identified all patients with autonomic neuropathy except one (P less than 0.02). Measuring the plasma DHPG/noradrenalin ratio may circumvent the problem of unrepresentative noradrenalin release from the forearm.